Copper

evidence_span

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experimental_model

Copper-deficient mouse models and subcutaneous copper administration

exposure

Systemic copper depletion and restoration

limitations

Opposite tissue responses are reported regulatory context, not a contradiction in the source.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Mouse

plain_language

The intestine responded in the opposite direction, consistent with delivering copper to the rest of the body.

primary_references

[copper-p28931909] Organ-specific regulation of ATP7A abundance is coordinated with systemic copper homeostasis. (2017). https://pubmed.ncbi.nlm.nih.gov/28931909/ DOI: 10.1038/s41598-017-11961-z

tissue_or_cell_type

Intestine, heart, spleen and liver

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 507–518

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Copper-deficient mouse models and subcutaneous copper administration · source_derived_draft · unverified_draft

### copper-atp7a-intestinal-response Low systemic copper increased intestinal ATP7A, while subcutaneous copper lowered it in the same mouse study. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: The intestine responded in the opposite direction, consistent with delivering copper to the rest of the body. organism: Mouse tissue_or_cell_type: Intestine, heart, spleen and liver experimental_model: Copper-deficient mouse models and subcutaneous copper administration limitations: Opposite tissue responses are reported regulatory context, not a contradiction in the source. exposure: Systemic copper depletion and restoration evidence_span: {"source_cache": "artifacts/copper-research/28931909.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "040f84f61342770e57eec0c3e82a0165c000bc5592a54344f92378b48e626c9f", "start_char": 0, "end_char": 1284, "text_sha256": "040f84f61342770e57eec0c3e82a0165c000bc5592a54344f92378b48e626c9f"} [copper-p28931909] Organ-specific regulation of ATP7A abundance is coordinated with systemic copper homeostasis. (2017). https://pubmed.ncbi.nlm.nih.gov/28931909/ DOI: 10.1038/s41598-017-11961-z

evidence_span

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experimental_model

Copper-deficient mouse models and subcutaneous copper administration

exposure

Systemic copper depletion and restoration

limitations

Opposite tissue responses are reported regulatory context, not a contradiction in the source.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Mouse

plain_language

Tissues adjusted their copper-export machinery as supply changed.

primary_references

[copper-p28931909] Organ-specific regulation of ATP7A abundance is coordinated with systemic copper homeostasis. (2017). https://pubmed.ncbi.nlm.nih.gov/28931909/ DOI: 10.1038/s41598-017-11961-z

tissue_or_cell_type

Intestine, heart, spleen and liver

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 494–505

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Copper-deficient mouse models and subcutaneous copper administration · source_derived_draft · unverified_draft

### copper-atp7a-peripheral-response Copper deficiency lowered ATP7A abundance in mouse peripheral tissues; subcutaneous copper restored it. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Tissues adjusted their copper-export machinery as supply changed. organism: Mouse tissue_or_cell_type: Intestine, heart, spleen and liver experimental_model: Copper-deficient mouse models and subcutaneous copper administration limitations: Opposite tissue responses are reported regulatory context, not a contradiction in the source. exposure: Systemic copper depletion and restoration evidence_span: {"source_cache": "artifacts/copper-research/28931909.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "040f84f61342770e57eec0c3e82a0165c000bc5592a54344f92378b48e626c9f", "start_char": 0, "end_char": 1284, "text_sha256": "040f84f61342770e57eec0c3e82a0165c000bc5592a54344f92378b48e626c9f"} [copper-p28931909] Organ-specific regulation of ATP7A abundance is coordinated with systemic copper homeostasis. (2017). https://pubmed.ncbi.nlm.nih.gov/28931909/ DOI: 10.1038/s41598-017-11961-z

evidence_span

{"source_cache": "artifacts/copper-research/12844388.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5b6c40ba96ca6bba0b6d377caf643f3aebba366919c889e2e8f10be4b23a0def", "start_char": 0, "end_char": 1336, "text_sha256": "5b6c40ba96ca6bba0b6d377caf643f3aebba366919c889e2e8f10be4b23a0def"}

experimental_model

Controlled copper intake and stable-isotope balance study

exposure

Twelve men; 0.7, 1.6 or 6 mg/day intake periods with an oral 3 mg isotope challenge

limitations

The isotope challenge was the same at each dietary background. Similar fractional absorption under this test does not mean copper absorption is invariant at every dose.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human men

plain_language

In this experiment, excretion changed more clearly than the measured absorption fraction.

primary_references

[copper-p12844388] Adaptive responses in men fed low- and high-copper diets. (2003). https://pubmed.ncbi.nlm.nih.gov/12844388/ DOI: 10.1079/bjn2003887

tissue_or_cell_type

Whole-body copper handling

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1378–1389

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled copper intake and stable-isotope balance study · source_derived_draft · unverified_draft

### copper-copper-absorption-adaptation True fractional copper absorption after the standardized tracer dose was about 48% at both low and high background intakes, without a significant difference. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this experiment, excretion changed more clearly than the measured absorption fraction. organism: Human men tissue_or_cell_type: Whole-body copper handling experimental_model: Controlled copper intake and stable-isotope balance study limitations: The isotope challenge was the same at each dietary background. Similar fractional absorption under this test does not mean copper absorption is invariant at every dose. exposure: Twelve men; 0.7, 1.6 or 6 mg/day intake periods with an oral 3 mg isotope challenge evidence_span: {"source_cache": "artifacts/copper-research/12844388.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5b6c40ba96ca6bba0b6d377caf643f3aebba366919c889e2e8f10be4b23a0def", "start_char": 0, "end_char": 1336, "text_sha256": "5b6c40ba96ca6bba0b6d377caf643f3aebba366919c889e2e8f10be4b23a0def"} [copper-p12844388] Adaptive responses in men fed low- and high-copper diets. (2003). https://pubmed.ncbi.nlm.nih.gov/12844388/ DOI: 10.1079/bjn2003887

evidence_span

{"source_cache": "artifacts/copper-research/12844388.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5b6c40ba96ca6bba0b6d377caf643f3aebba366919c889e2e8f10be4b23a0def", "start_char": 0, "end_char": 1336, "text_sha256": "5b6c40ba96ca6bba0b6d377caf643f3aebba366919c889e2e8f10be4b23a0def"}

experimental_model

Controlled copper intake and stable-isotope balance study

exposure

Twelve men; 0.7, 1.6 or 6 mg/day intake periods with an oral 3 mg isotope challenge

limitations

The isotope challenge was the same at each dietary background. Similar fractional absorption under this test does not mean copper absorption is invariant at every dose.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human men

plain_language

The body adjusted how much copper it removed.

primary_references

[copper-p12844388] Adaptive responses in men fed low- and high-copper diets. (2003). https://pubmed.ncbi.nlm.nih.gov/12844388/ DOI: 10.1079/bjn2003887

tissue_or_cell_type

Whole-body copper handling

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1365–1376

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled copper intake and stable-isotope balance study · source_derived_draft · unverified_draft

### copper-copper-excretion-adaptation Endogenous copper losses increased from about 0.45 to 0.81 to 2.46 mg/day across the low, medium and high copper-intake conditions. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: The body adjusted how much copper it removed. organism: Human men tissue_or_cell_type: Whole-body copper handling experimental_model: Controlled copper intake and stable-isotope balance study limitations: The isotope challenge was the same at each dietary background. Similar fractional absorption under this test does not mean copper absorption is invariant at every dose. exposure: Twelve men; 0.7, 1.6 or 6 mg/day intake periods with an oral 3 mg isotope challenge evidence_span: {"source_cache": "artifacts/copper-research/12844388.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5b6c40ba96ca6bba0b6d377caf643f3aebba366919c889e2e8f10be4b23a0def", "start_char": 0, "end_char": 1336, "text_sha256": "5b6c40ba96ca6bba0b6d377caf643f3aebba366919c889e2e8f10be4b23a0def"} [copper-p12844388] Adaptive responses in men fed low- and high-copper diets. (2003). https://pubmed.ncbi.nlm.nih.gov/12844388/ DOI: 10.1079/bjn2003887

evidence_span

{"source_cache": "artifacts/copper-research/15325682.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4b6a41a9645d006de2098c2ca83f5aaeab2f1d4d76608b1131dc47d0e2e4148a", "start_char": 0, "end_char": 1606, "text_sha256": "4b6a41a9645d006de2098c2ca83f5aaeab2f1d4d76608b1131dc47d0e2e4148a"}

experimental_model

Long-duration high-copper feeding study

exposure

Nine men; prolonged high copper intake including 7 mg/day supplementation phase

limitations

Small intervention with biomarker outcomes; it does not establish copper as a human methionine-synthase cofactor, B-vitamin depletion, or benefit from high copper intake.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human young men

plain_language

Several vitamin-related blood markers shifted, but that does not identify a new copper-dependent methylation enzyme.

primary_references

[copper-p15325682] Effect of long-term, high-copper intake on the concentrations of plasma homocysteine and B vitamins in young men. (2004). https://pubmed.ncbi.nlm.nih.gov/15325682/ DOI: 10.1016/j.nut.2004.05.011

tissue_or_cell_type

Plasma homocysteine, folate, B12 and PLP

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1183–1194

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Long-duration high-copper feeding study · source_derived_draft · unverified_draft

### copper-copper-homocysteine-folate High copper intake in nine men produced small decreases in plasma homocysteine and folate, without changes in B12 or PLP measures. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Several vitamin-related blood markers shifted, but that does not identify a new copper-dependent methylation enzyme. organism: Human young men tissue_or_cell_type: Plasma homocysteine, folate, B12 and PLP experimental_model: Long-duration high-copper feeding study limitations: Small intervention with biomarker outcomes; it does not establish copper as a human methionine-synthase cofactor, B-vitamin depletion, or benefit from high copper intake. exposure: Nine men; prolonged high copper intake including 7 mg/day supplementation phase evidence_span: {"source_cache": "artifacts/copper-research/15325682.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4b6a41a9645d006de2098c2ca83f5aaeab2f1d4d76608b1131dc47d0e2e4148a", "start_char": 0, "end_char": 1606, "text_sha256": "4b6a41a9645d006de2098c2ca83f5aaeab2f1d4d76608b1131dc47d0e2e4148a"} [copper-p15325682] Effect of long-term, high-copper intake on the concentrations of plasma homocysteine and B vitamins in young men. (2004). https://pubmed.ncbi.nlm.nih.gov/15325682/ DOI: 10.1016/j.nut.2004.05.011

evidence_span

{"source_cache": "artifacts/copper-research/27272565.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f8b7e13cc6ef608ddb589779fa85430ca530508013e710f380f4020c3f2632c7", "start_char": 0, "end_char": 1018, "text_sha256": "f8b7e13cc6ef608ddb589779fa85430ca530508013e710f380f4020c3f2632c7"}

experimental_model

Copper manipulation, purified Pde3b assays and adipocyte signaling

exposure

Copper perturbation and Pde3b cysteine mutations

limitations

This cellular signaling result is not a human weight-loss trial. Copper toxicity and systemic distribution are not captured by increasing one cell-culture signal.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Mouse proteins and 3T3-L1 adipocytes; Atp7b mutant mouse context

plain_language

Copper slowed an enzyme that normally clears the cAMP signal.

primary_references

[copper-p27272565] Copper regulates cyclic-AMP-dependent lipolysis. (2016). https://pubmed.ncbi.nlm.nih.gov/27272565/ DOI: 10.1038/nchembio.2098

tissue_or_cell_type

Adipocytes and purified enzyme

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1196–1207

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Copper manipulation, purified Pde3b assays and adipocyte signaling · source_derived_draft · unverified_draft

### copper-copper-pde3b Copper inhibited mouse PDE3B activity in the biochemical and adipocyte study. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Copper slowed an enzyme that normally clears the cAMP signal. organism: Mouse proteins and 3T3-L1 adipocytes; Atp7b mutant mouse context tissue_or_cell_type: Adipocytes and purified enzyme experimental_model: Copper manipulation, purified Pde3b assays and adipocyte signaling limitations: This cellular signaling result is not a human weight-loss trial. Copper toxicity and systemic distribution are not captured by increasing one cell-culture signal. exposure: Copper perturbation and Pde3b cysteine mutations evidence_span: {"source_cache": "artifacts/copper-research/27272565.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f8b7e13cc6ef608ddb589779fa85430ca530508013e710f380f4020c3f2632c7", "start_char": 0, "end_char": 1018, "text_sha256": "f8b7e13cc6ef608ddb589779fa85430ca530508013e710f380f4020c3f2632c7"} [copper-p27272565] Copper regulates cyclic-AMP-dependent lipolysis. (2016). https://pubmed.ncbi.nlm.nih.gov/27272565/ DOI: 10.1038/nchembio.2098

evidence_span

{"source_cache": "artifacts/copper-research/20699218.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c638594d4e707bb39a8f2e8c1fed15a42982e1dc4d525fda112d28281a853012", "start_char": 0, "end_char": 1749, "text_sha256": "c638594d4e707bb39a8f2e8c1fed15a42982e1dc4d525fda112d28281a853012"}

experimental_model

Intestinal immunolocalization and dietary copper limitation

exposure

Copper limitation in mice

limitations

Apical Ctr1 was observed in the examined mammalian preparations; membrane localization is model dependent and cannot be assigned universally to every human intestinal condition.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Mouse, rat and pig; human HEK293T cells for separate processing experiments

plain_language

The intestine increased an entry route when copper supply fell.

primary_references

[copper-p20699218] Ctr1 is an apical copper transporter in mammalian intestinal epithelial cells in vivo that is controlled at the level of protein stability. (2010). https://pubmed.ncbi.nlm.nih.gov/20699218/ DOI: 10.1074/jbc.m110.143826

tissue_or_cell_type

Intestinal epithelium

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 351–362

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Intestinal immunolocalization and dietary copper limitation · source_derived_draft · unverified_draft

### copper-ctr1-intestinal-adaptation Dietary copper limitation increased total and apically localized Ctr1 protein in mouse intestine. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: The intestine increased an entry route when copper supply fell. organism: Mouse, rat and pig; human HEK293T cells for separate processing experiments tissue_or_cell_type: Intestinal epithelium experimental_model: Intestinal immunolocalization and dietary copper limitation limitations: Apical Ctr1 was observed in the examined mammalian preparations; membrane localization is model dependent and cannot be assigned universally to every human intestinal condition. exposure: Copper limitation in mice evidence_span: {"source_cache": "artifacts/copper-research/20699218.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c638594d4e707bb39a8f2e8c1fed15a42982e1dc4d525fda112d28281a853012", "start_char": 0, "end_char": 1749, "text_sha256": "c638594d4e707bb39a8f2e8c1fed15a42982e1dc4d525fda112d28281a853012"} [copper-p20699218] Ctr1 is an apical copper transporter in mammalian intestinal epithelial cells in vivo that is controlled at the level of protein stability. (2010). https://pubmed.ncbi.nlm.nih.gov/20699218/ DOI: 10.1074/jbc.m110.143826

evidence_span

{"source_cache": "artifacts/copper-research/32203415.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f248044309434e00cd35941d0e525a9c73a07e8d78eead20f7d7b6bdcb5f2915", "start_char": 0, "end_char": 1077, "text_sha256": "f248044309434e00cd35941d0e525a9c73a07e8d78eead20f7d7b6bdcb5f2915"}

experimental_model

Recombinant kinase assays, genetic perturbations and lung tumor models

exposure

Copper exposure, copper-binding mutations and Ctr1 deletion

limitations

Preclinical molecular evidence; not proof that copper supplementation improves autophagy in healthy people or that chelation improves cancer survival.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human recombinant ULK1/ULK2 with complementary mouse systems

plain_language

Copper helps regulate one enzyme that starts cellular recycling.

primary_references

[copper-p32203415] Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma. (2020). https://pubmed.ncbi.nlm.nih.gov/32203415/ DOI: 10.1038/s41556-020-0481-4

tissue_or_cell_type

Autophagy signaling

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1235–1246

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant kinase assays, genetic perturbations and lung tumor models · source_derived_draft · unverified_draft

### copper-cu-ulk1 Direct copper interaction supported ULK1 kinase activity in the experimental system. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Copper helps regulate one enzyme that starts cellular recycling. organism: Human recombinant ULK1/ULK2 with complementary mouse systems tissue_or_cell_type: Autophagy signaling experimental_model: Recombinant kinase assays, genetic perturbations and lung tumor models limitations: Preclinical molecular evidence; not proof that copper supplementation improves autophagy in healthy people or that chelation improves cancer survival. exposure: Copper exposure, copper-binding mutations and Ctr1 deletion evidence_span: {"source_cache": "artifacts/copper-research/32203415.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f248044309434e00cd35941d0e525a9c73a07e8d78eead20f7d7b6bdcb5f2915", "start_char": 0, "end_char": 1077, "text_sha256": "f248044309434e00cd35941d0e525a9c73a07e8d78eead20f7d7b6bdcb5f2915"} [copper-p32203415] Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma. (2020). https://pubmed.ncbi.nlm.nih.gov/32203415/ DOI: 10.1038/s41556-020-0481-4

evidence_span

{"source_cache": "artifacts/copper-research/32203415.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f248044309434e00cd35941d0e525a9c73a07e8d78eead20f7d7b6bdcb5f2915", "start_char": 0, "end_char": 1077, "text_sha256": "f248044309434e00cd35941d0e525a9c73a07e8d78eead20f7d7b6bdcb5f2915"}

experimental_model

Recombinant kinase assays, genetic perturbations and lung tumor models

exposure

Copper exposure, copper-binding mutations and Ctr1 deletion

limitations

Preclinical molecular evidence; not proof that copper supplementation improves autophagy in healthy people or that chelation improves cancer survival.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human recombinant ULK1/ULK2 with complementary mouse systems

plain_language

The related recycling enzyme has a separately recorded copper interaction.

primary_references

[copper-p32203415] Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma. (2020). https://pubmed.ncbi.nlm.nih.gov/32203415/ DOI: 10.1038/s41556-020-0481-4

tissue_or_cell_type

Autophagy signaling

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1248–1259

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant kinase assays, genetic perturbations and lung tumor models · source_derived_draft · unverified_draft

### copper-cu-ulk2 Direct copper interaction also supported ULK2 kinase activity. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: The related recycling enzyme has a separately recorded copper interaction. organism: Human recombinant ULK1/ULK2 with complementary mouse systems tissue_or_cell_type: Autophagy signaling experimental_model: Recombinant kinase assays, genetic perturbations and lung tumor models limitations: Preclinical molecular evidence; not proof that copper supplementation improves autophagy in healthy people or that chelation improves cancer survival. exposure: Copper exposure, copper-binding mutations and Ctr1 deletion evidence_span: {"source_cache": "artifacts/copper-research/32203415.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f248044309434e00cd35941d0e525a9c73a07e8d78eead20f7d7b6bdcb5f2915", "start_char": 0, "end_char": 1077, "text_sha256": "f248044309434e00cd35941d0e525a9c73a07e8d78eead20f7d7b6bdcb5f2915"} [copper-p32203415] Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma. (2020). https://pubmed.ncbi.nlm.nih.gov/32203415/ DOI: 10.1038/s41556-020-0481-4

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/copper-research/22294464.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "008de3f1f584a29a0ce082e6423042ed21585064b2dc900802103fc00b3fee8e", "start_char": 0, "end_char": 1578, "text_sha256": "008de3f1f584a29a0ce082e6423042ed21585064b2dc900802103fc00b3fee8e"}

experimental_model

Dietary copper-deficient rat and mouse tissue comparisons

exposure

Dietary copper depletion

limitations

Tissue ferroportin responses were complex and did not explain copper-deficiency anemia. Do not generalize genetic GPI-ceruloplasmin absence into universal ferroportin destruction during nutritional copper deficiency.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Rat and mouse

plain_language

There is no single demonstrated switch that destroys every iron exporter when copper falls.

primary_references

[copper-p22294464] Copper deficiency has minimal impact on ferroportin expression or function. (2012). https://pubmed.ncbi.nlm.nih.gov/22294464/ DOI: 10.1007/s10534-012-9521-2

tissue_or_cell_type

Liver, spleen and intestinal iron-related tissues

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 884–895

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary copper-deficient rat and mouse tissue comparisons · source_derived_draft · unverified_draft

### copper-cud-ferroportin-boundary Dietary copper deficiency caused little ferroportin mRNA change; protein responses varied and did not account for the anemia across the rodent models. Condition category: nutrient_deficiency nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: There is no single demonstrated switch that destroys every iron exporter when copper falls. organism: Rat and mouse tissue_or_cell_type: Liver, spleen and intestinal iron-related tissues experimental_model: Dietary copper-deficient rat and mouse tissue comparisons limitations: Tissue ferroportin responses were complex and did not explain copper-deficiency anemia. Do not generalize genetic GPI-ceruloplasmin absence into universal ferroportin destruction during nutritional copper deficiency. exposure: Dietary copper depletion evidence_span: {"source_cache": "artifacts/copper-research/22294464.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "008de3f1f584a29a0ce082e6423042ed21585064b2dc900802103fc00b3fee8e", "start_char": 0, "end_char": 1578, "text_sha256": "008de3f1f584a29a0ce082e6423042ed21585064b2dc900802103fc00b3fee8e"} [copper-p22294464] Copper deficiency has minimal impact on ferroportin expression or function. (2012). https://pubmed.ncbi.nlm.nih.gov/22294464/ DOI: 10.1007/s10534-012-9521-2

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/copper-research/15623839.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5e3723e4fdd961caf66979e26614d98cbfbd65f38ba48232428e5302c054c3ac", "start_char": 0, "end_char": 1613, "text_sha256": "5e3723e4fdd961caf66979e26614d98cbfbd65f38ba48232428e5302c054c3ac"}

experimental_model

Controlled copper-deficient versus adequate diets with radiolabeled iron

exposure

Less than 0.3 versus 5 mg copper/kg diet; male and female weanlings

limitations

Animal depletion regimens are not human thresholds. Iron redistribution differed by sex.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Rat

plain_language

Copper shortage reduced part of the intestine’s iron-processing machinery.

primary_references

[copper-p15623839] Dietary copper deficiency reduces iron absorption and duodenal enterocyte hephaestin protein in male and female rats. (2005). https://pubmed.ncbi.nlm.nih.gov/15623839/ DOI: 10.1093/jn/135.1.92

tissue_or_cell_type

Duodenal enterocytes and whole-body iron

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 858–869

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled copper-deficient versus adequate diets with radiolabeled iron · source_derived_draft · unverified_draft

### copper-cud-hephaestin Copper-deficient rats had enterocyte hephaestin protein at about 35% of copper-adequate controls. Condition category: nutrient_deficiency nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Copper shortage reduced part of the intestine’s iron-processing machinery. organism: Rat tissue_or_cell_type: Duodenal enterocytes and whole-body iron experimental_model: Controlled copper-deficient versus adequate diets with radiolabeled iron limitations: Animal depletion regimens are not human thresholds. Iron redistribution differed by sex. exposure: Less than 0.3 versus 5 mg copper/kg diet; male and female weanlings evidence_span: {"source_cache": "artifacts/copper-research/15623839.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5e3723e4fdd961caf66979e26614d98cbfbd65f38ba48232428e5302c054c3ac", "start_char": 0, "end_char": 1613, "text_sha256": "5e3723e4fdd961caf66979e26614d98cbfbd65f38ba48232428e5302c054c3ac"} [copper-p15623839] Dietary copper deficiency reduces iron absorption and duodenal enterocyte hephaestin protein in male and female rats. (2005). https://pubmed.ncbi.nlm.nih.gov/15623839/ DOI: 10.1093/jn/135.1.92

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/copper-research/15623839.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5e3723e4fdd961caf66979e26614d98cbfbd65f38ba48232428e5302c054c3ac", "start_char": 0, "end_char": 1613, "text_sha256": "5e3723e4fdd961caf66979e26614d98cbfbd65f38ba48232428e5302c054c3ac"}

experimental_model

Controlled copper-deficient versus adequate diets with radiolabeled iron

exposure

Less than 0.3 versus 5 mg copper/kg diet; male and female weanlings

limitations

Animal depletion regimens are not human thresholds. Iron redistribution differed by sex.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Rat

plain_language

Adding iron alone does not describe the copper-dependent processing step.

primary_references

[copper-p15623839] Dietary copper deficiency reduces iron absorption and duodenal enterocyte hephaestin protein in male and female rats. (2005). https://pubmed.ncbi.nlm.nih.gov/15623839/ DOI: 10.1093/jn/135.1.92

tissue_or_cell_type

Duodenal enterocytes and whole-body iron

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 871–882

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled copper-deficient versus adequate diets with radiolabeled iron · source_derived_draft · unverified_draft

### copper-cud-iron-absorption Copper-deficient male and female rats absorbed about 60% and 70%, respectively, of the iron absorbed by copper-adequate controls. Condition category: nutrient_deficiency nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding iron alone does not describe the copper-dependent processing step. organism: Rat tissue_or_cell_type: Duodenal enterocytes and whole-body iron experimental_model: Controlled copper-deficient versus adequate diets with radiolabeled iron limitations: Animal depletion regimens are not human thresholds. Iron redistribution differed by sex. exposure: Less than 0.3 versus 5 mg copper/kg diet; male and female weanlings evidence_span: {"source_cache": "artifacts/copper-research/15623839.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5e3723e4fdd961caf66979e26614d98cbfbd65f38ba48232428e5302c054c3ac", "start_char": 0, "end_char": 1613, "text_sha256": "5e3723e4fdd961caf66979e26614d98cbfbd65f38ba48232428e5302c054c3ac"} [copper-p15623839] Dietary copper deficiency reduces iron absorption and duodenal enterocyte hephaestin protein in male and female rats. (2005). https://pubmed.ncbi.nlm.nih.gov/15623839/ DOI: 10.1093/jn/135.1.92

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/copper-research/8988916.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0be30b28f91bce964b969517de4b15eb3ba5905a6f5f1f0a9dc4afa29e9d101b", "start_char": 0, "end_char": 1349, "text_sha256": "0be30b28f91bce964b969517de4b15eb3ba5905a6f5f1f0a9dc4afa29e9d101b"}

experimental_model

Metabolic-ward depletion and repletion study

exposure

Eleven men: 0.66 mg copper/day for 24 days, 0.38 for 42 days, then 2.49 for 24 days

limitations

Small controlled feeding study; regimen-specific changes are not universal diagnostic thresholds or modern intake recommendations.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human young men

plain_language

Both enzyme activity and its amount responded to copper supply.

primary_references

[copper-p8988916] Copper status of young men consuming a low-copper diet. (1997). https://pubmed.ncbi.nlm.nih.gov/8988916/ DOI: 10.1093/ajcn/65.1.72

tissue_or_cell_type

Plasma, urine and erythrocytes

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1339–1350

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolic-ward depletion and repletion study · source_derived_draft · unverified_draft

### copper-human-lowcu-cp Low copper intake reduced ceruloplasmin activity and protein concentration; repletion raised plasma copper and ceruloplasmin protein. Condition category: nutrient_deficiency nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Both enzyme activity and its amount responded to copper supply. organism: Human young men tissue_or_cell_type: Plasma, urine and erythrocytes experimental_model: Metabolic-ward depletion and repletion study limitations: Small controlled feeding study; regimen-specific changes are not universal diagnostic thresholds or modern intake recommendations. exposure: Eleven men: 0.66 mg copper/day for 24 days, 0.38 for 42 days, then 2.49 for 24 days evidence_span: {"source_cache": "artifacts/copper-research/8988916.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0be30b28f91bce964b969517de4b15eb3ba5905a6f5f1f0a9dc4afa29e9d101b", "start_char": 0, "end_char": 1349, "text_sha256": "0be30b28f91bce964b969517de4b15eb3ba5905a6f5f1f0a9dc4afa29e9d101b"} [copper-p8988916] Copper status of young men consuming a low-copper diet. (1997). https://pubmed.ncbi.nlm.nih.gov/8988916/ DOI: 10.1093/ajcn/65.1.72

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/copper-research/8988916.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0be30b28f91bce964b969517de4b15eb3ba5905a6f5f1f0a9dc4afa29e9d101b", "start_char": 0, "end_char": 1349, "text_sha256": "0be30b28f91bce964b969517de4b15eb3ba5905a6f5f1f0a9dc4afa29e9d101b"}

experimental_model

Metabolic-ward depletion and repletion study

exposure

Eleven men: 0.66 mg copper/day for 24 days, 0.38 for 42 days, then 2.49 for 24 days

limitations

Small controlled feeding study; regimen-specific changes are not universal diagnostic thresholds or modern intake recommendations.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human young men

plain_language

Sustained low intake changed the circulating copper measurement.

primary_references

[copper-p8988916] Copper status of young men consuming a low-copper diet. (1997). https://pubmed.ncbi.nlm.nih.gov/8988916/ DOI: 10.1093/ajcn/65.1.72

tissue_or_cell_type

Plasma, urine and erythrocytes

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1326–1337

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolic-ward depletion and repletion study · source_derived_draft · unverified_draft

### copper-human-lowcu-plasma The low-copper period reduced plasma copper in the eleven-man metabolic-ward study. Condition category: nutrient_deficiency nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Sustained low intake changed the circulating copper measurement. organism: Human young men tissue_or_cell_type: Plasma, urine and erythrocytes experimental_model: Metabolic-ward depletion and repletion study limitations: Small controlled feeding study; regimen-specific changes are not universal diagnostic thresholds or modern intake recommendations. exposure: Eleven men: 0.66 mg copper/day for 24 days, 0.38 for 42 days, then 2.49 for 24 days evidence_span: {"source_cache": "artifacts/copper-research/8988916.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0be30b28f91bce964b969517de4b15eb3ba5905a6f5f1f0a9dc4afa29e9d101b", "start_char": 0, "end_char": 1349, "text_sha256": "0be30b28f91bce964b969517de4b15eb3ba5905a6f5f1f0a9dc4afa29e9d101b"} [copper-p8988916] Copper status of young men consuming a low-copper diet. (1997). https://pubmed.ncbi.nlm.nih.gov/8988916/ DOI: 10.1093/ajcn/65.1.72

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/copper-research/8988916.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0be30b28f91bce964b969517de4b15eb3ba5905a6f5f1f0a9dc4afa29e9d101b", "start_char": 0, "end_char": 1349, "text_sha256": "0be30b28f91bce964b969517de4b15eb3ba5905a6f5f1f0a9dc4afa29e9d101b"}

experimental_model

Metabolic-ward depletion and repletion study

exposure

Eleven men: 0.66 mg copper/day for 24 days, 0.38 for 42 days, then 2.49 for 24 days

limitations

Small controlled feeding study; regimen-specific changes are not universal diagnostic thresholds or modern intake recommendations.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human young men

plain_language

Not every copper-related marker responded with the same sensitivity.

primary_references

[copper-p8988916] Copper status of young men consuming a low-copper diet. (1997). https://pubmed.ncbi.nlm.nih.gov/8988916/ DOI: 10.1093/ajcn/65.1.72

tissue_or_cell_type

Plasma, urine and erythrocytes

trigger_kind

biomarker_context Imported condition classification; unverified.

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1352–1363

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolic-ward depletion and repletion study · source_derived_draft · unverified_draft

### copper-human-lowcu-sod-boundary Erythrocyte SOD activity was lower on average during low intake, but did not show a significant time trend across depletion. Condition category: biomarker_context nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Not every copper-related marker responded with the same sensitivity. organism: Human young men tissue_or_cell_type: Plasma, urine and erythrocytes experimental_model: Metabolic-ward depletion and repletion study limitations: Small controlled feeding study; regimen-specific changes are not universal diagnostic thresholds or modern intake recommendations. exposure: Eleven men: 0.66 mg copper/day for 24 days, 0.38 for 42 days, then 2.49 for 24 days evidence_span: {"source_cache": "artifacts/copper-research/8988916.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0be30b28f91bce964b969517de4b15eb3ba5905a6f5f1f0a9dc4afa29e9d101b", "start_char": 0, "end_char": 1349, "text_sha256": "0be30b28f91bce964b969517de4b15eb3ba5905a6f5f1f0a9dc4afa29e9d101b"} [copper-p8988916] Copper status of young men consuming a low-copper diet. (1997). https://pubmed.ncbi.nlm.nih.gov/8988916/ DOI: 10.1093/ajcn/65.1.72

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/copper-research/16950140.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "08532f69fd9530033f8d9afcece9249fc50dd425f57313e120f55ea81cee8f98", "start_char": 0, "end_char": 1026, "text_sha256": "08532f69fd9530033f8d9afcece9249fc50dd425f57313e120f55ea81cee8f98"}

experimental_model

Intestinal epithelial Ctr1 knockout mice

exposure

Intestinal Ctr1 deletion; postnatal copper rescue

limitations

Genetic intestinal transport failure differs from low dietary intake. The indexed abstract does not establish the administration route of the rescue dose.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Mouse

plain_language

Some consequences of the transport defect could be bypassed in this animal experiment.

primary_references

[copper-p16950140] Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. (2006). https://pubmed.ncbi.nlm.nih.gov/16950140/ DOI: 10.1016/j.cmet.2006.08.009

tissue_or_cell_type

Intestine and peripheral organs

trigger_kind

machinery_impairment Imported condition classification; unverified.

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 338–349

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Intestinal epithelial Ctr1 knockout mice · source_derived_draft · unverified_draft

### copper-intestinal-ctr1-copper-rescue A single postnatal copper administration partially rescued growth and viability in intestinal Ctr1 knockout mice. Condition category: machinery_impairment nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Some consequences of the transport defect could be bypassed in this animal experiment. organism: Mouse tissue_or_cell_type: Intestine and peripheral organs experimental_model: Intestinal epithelial Ctr1 knockout mice limitations: Genetic intestinal transport failure differs from low dietary intake. The indexed abstract does not establish the administration route of the rescue dose. exposure: Intestinal Ctr1 deletion; postnatal copper rescue evidence_span: {"source_cache": "artifacts/copper-research/16950140.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "08532f69fd9530033f8d9afcece9249fc50dd425f57313e120f55ea81cee8f98", "start_char": 0, "end_char": 1026, "text_sha256": "08532f69fd9530033f8d9afcece9249fc50dd425f57313e120f55ea81cee8f98"} [copper-p16950140] Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. (2006). https://pubmed.ncbi.nlm.nih.gov/16950140/ DOI: 10.1016/j.cmet.2006.08.009

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/copper-research/18256395.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e855a0286cb633432b654005d756aa1e887ddace4f2a4dc5fee6cca518d895ce", "start_char": 0, "end_char": 2319, "text_sha256": "e855a0286cb633432b654005d756aa1e887ddace4f2a4dc5fee6cca518d895ce"}

experimental_model

Early-treatment Menkes cohort with historical comparison and functional genotyping

exposure

Copper injections begun by 22 days in twelve infants; comparison with fifteen later-treated historical patients

limitations

Not randomized; survival follow-up differed between cohorts. Genotype and residual function influenced outcome, so results cannot be generalized to every ATP7A variant.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human infants

plain_language

Early treatment was associated with much better survival in this cohort, with important comparison limits.

primary_references

[copper-p18256395] Neonatal diagnosis and treatment of Menkes disease. (2008). https://pubmed.ncbi.nlm.nih.gov/18256395/ DOI: 10.1056/nejmoa070613

tissue_or_cell_type

Survival and neurodevelopment

trigger_kind

machinery_impairment Imported condition classification; unverified.

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1443–1454

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Early-treatment Menkes cohort with historical comparison and functional genotyping · source_derived_draft · unverified_draft

### copper-menkes-early-survival Survival was 92% in the twelve early-treated infants at median 4.6-year follow-up versus 13% in the historical late-treatment group at median 1.8 years. Condition category: machinery_impairment nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Early treatment was associated with much better survival in this cohort, with important comparison limits. organism: Human infants tissue_or_cell_type: Survival and neurodevelopment experimental_model: Early-treatment Menkes cohort with historical comparison and functional genotyping limitations: Not randomized; survival follow-up differed between cohorts. Genotype and residual function influenced outcome, so results cannot be generalized to every ATP7A variant. exposure: Copper injections begun by 22 days in twelve infants; comparison with fifteen later-treated historical patients evidence_span: {"source_cache": "artifacts/copper-research/18256395.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e855a0286cb633432b654005d756aa1e887ddace4f2a4dc5fee6cca518d895ce", "start_char": 0, "end_char": 2319, "text_sha256": "e855a0286cb633432b654005d756aa1e887ddace4f2a4dc5fee6cca518d895ce"} [copper-p18256395] Neonatal diagnosis and treatment of Menkes disease. (2008). https://pubmed.ncbi.nlm.nih.gov/18256395/ DOI: 10.1056/nejmoa070613

evidence_span

{"source_cache": "artifacts/hbot-research/6316150.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dc20323f9774c6c743e01f8bdbeedbc42b0ddac982f1e17d53a9591b87bf5379", "start_char": 0, "end_char": 867, "text_sha256": "dc20323f9774c6c743e01f8bdbeedbc42b0ddac982f1e17d53a9591b87bf5379"}

experimental_model

Refinement of the 2 angstrom crystal structure of copper, zinc superoxide dismutase with molecular surface analysis

exposure

Structural and mechanistic analysis of the active site

limitations

Structural chemistry. It explains why the enzyme needs its metals; it is not a statement about dietary copper or zinc.

nutrient_topic

Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Hyperbaric oxygen therapy

organism

Bovine enzyme structure

plain_language

The copper atom itself is what takes and gives back the electron.

primary_references

[hbot-p6316150] Structure and mechanism of copper, zinc superoxide dismutase. (1983). https://pubmed.ncbi.nlm.nih.gov/6316150/ DOI: 10.1038/306284a0

tissue_or_cell_type

Purified enzyme

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 491–502

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Refinement of the 2 angstrom crystal structure of copper, zinc superoxide dismutase with molecular surface analysis · source_derived_draft · unverified_draft

### hbot-sod1-copper-mechanism Copper, zinc superoxide dismutase catalyses the two-step dismutation of superoxide to molecular oxygen and hydrogen peroxide through alternate reduction and oxidation of the active-site copper, with a single complementary binding position for superoxide at the Cu(II) and the activity-important Arg141. Condition category: normal nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: The copper atom itself is what takes and gives back the electron. organism: Bovine enzyme structure tissue_or_cell_type: Purified enzyme experimental_model: Refinement of the 2 angstrom crystal structure of copper, zinc superoxide dismutase with molecular surface analysis limitations: Structural chemistry. It explains why the enzyme needs its metals; it is not a statement about dietary copper or zinc. exposure: Structural and mechanistic analysis of the active site evidence_span: {"source_cache": "artifacts/hbot-research/6316150.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dc20323f9774c6c743e01f8bdbeedbc42b0ddac982f1e17d53a9591b87bf5379", "start_char": 0, "end_char": 867, "text_sha256": "dc20323f9774c6c743e01f8bdbeedbc42b0ddac982f1e17d53a9591b87bf5379"} [hbot-p6316150] Structure and mechanism of copper, zinc superoxide dismutase. (1983). https://pubmed.ncbi.nlm.nih.gov/6316150/ DOI: 10.1038/306284a0

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Zinc (prior_exposure); Blood leukocyte count (increased_endpoint); Serum ceruloplasmin concentration (responsive_marker)

evidence_location

Indexed primary abstract.

evidence_span

{"source_cache": "artifacts/zinc-clinical-sources/prasad1978.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "7c4b85a9dd24c3e3bfd04414c0add5d0fa2bcc8c15b5e46bded351e2a2f01e3f", "utf8_bytes": 487}

experimental_model

Clinical case and additional observations in adults with sickle cell anemia receiving zinc therapy

exposure

Index patient received zinc as an antisickling intervention for two years; copper was subsequently administered.

limitations

Case evidence in a particular disease setting; dose and formulation are not verified from the abstract. Does not establish incidence or a universal zinc:copper supplement ratio.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

Copper replacement improved the reported blood-cell abnormalities.

primary_references

[zn-clin-prasad1978] Hypocupremia induced by zinc therapy in adults. (1978). https://pubmed.ncbi.nlm.nih.gov/359844/ DOI: 10.1001/jama.1978.03290200044019

tissue_or_cell_type

Blood copper and hematology

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1422–1435

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Clinical case and additional observations in adults with sickle cell anemia receiving zinc therapy · source_derived_draft · unverified_draft

### zn-clin-copper-response Copper administration increased erythrocyte size and leukocyte counts in the reported index patient; the authors also reported correction of hypoceruloplasminemia in additional zinc-treated patients. Condition category: nutrient_deficiency nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Copper replacement improved the reported blood-cell abnormalities. organism: Homo sapiens tissue_or_cell_type: Blood copper and hematology experimental_model: Clinical case and additional observations in adults with sickle cell anemia receiving zinc therapy limitations: Case evidence in a particular disease setting; dose and formulation are not verified from the abstract. Does not establish incidence or a universal zinc:copper supplement ratio. exposure: Index patient received zinc as an antisickling intervention for two years; copper was subsequently administered. cross_nutrient: Zinc (prior_exposure); Blood leukocyte count (increased_endpoint); Serum ceruloplasmin concentration (responsive_marker) evidence_location: Indexed primary abstract. evidence_span: {"source_cache": "artifacts/zinc-clinical-sources/prasad1978.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "7c4b85a9dd24c3e3bfd04414c0add5d0fa2bcc8c15b5e46bded351e2a2f01e3f", "utf8_bytes": 487} [zn-clin-prasad1978] Hypocupremia induced by zinc therapy in adults. (1978). https://pubmed.ncbi.nlm.nih.gov/359844/ DOI: 10.1001/jama.1978.03290200044019

cross_nutrient

Zinc (affected_nutrient); Rat intestinal metallothioneins measured without isoform resolution (unchanged_association)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/479878-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "643b0358984f3caac8a20e3202c14a073d11ff88758c7a9637b6f8523195658b"}

experimental_model

Dietary radiotracer experiments in rats

exposure

High dietary zinc or copper and reciprocal 64Cu/65Zn absorption measurements.

limitations

High animal dietary concentrations are not human intake thresholds. Copper displacement from metallothionein was the authors’ mechanistic interpretation.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Rattus norvegicus

plain_language

Copper also affected zinc absorption, with a different response pattern.

primary_references

[zn-sig-479878] Intestinal metallothionein and the mutual antagonism between copper and zinc in the rat. (1979). https://pubmed.ncbi.nlm.nih.gov/479878/ DOI: 10.1016/s0162-0134(00)80054-9

tissue_or_cell_type

Small intestine

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 929–941

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary radiotracer experiments in rats · source_derived_draft · unverified_draft

### zn-sig-copper-zinc-absorption Raising rat dietary copper from 3 to 24 mg/kg reduced 65Zn absorption by about 20%; further increases to 300 mg/kg did not add inhibition or change zinc association with intestinal metallothionein. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Copper also affected zinc absorption, with a different response pattern. organism: Rattus norvegicus tissue_or_cell_type: Small intestine experimental_model: Dietary radiotracer experiments in rats limitations: High animal dietary concentrations are not human intake thresholds. Copper displacement from metallothionein was the authors’ mechanistic interpretation. exposure: High dietary zinc or copper and reciprocal 64Cu/65Zn absorption measurements. cross_nutrient: Zinc (affected_nutrient); Rat intestinal metallothioneins measured without isoform resolution (unchanged_association) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/479878-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "643b0358984f3caac8a20e3202c14a073d11ff88758c7a9637b6f8523195658b"} [zn-sig-479878] Intestinal metallothionein and the mutual antagonism between copper and zinc in the rat. (1979). https://pubmed.ncbi.nlm.nih.gov/479878/ DOI: 10.1016/s0162-0134(00)80054-9

cross_nutrient

Zinc (affected_nutrient)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/3968585-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "ca588cec5326d23dd5f8c9b409ea66fc415043b95af456399e495b8131c8f6ed"}

experimental_model

Isolated vascularly perfused intestine from diet-conditioned rats

exposure

Dietary copper/zinc variation for one week versus direct luminal-metal variation.

limitations

Ex-vivo perfusion and extreme luminal exposure differ from whole-animal feeding; increased metallothionein-bound copper alone did not prove reduced net absorption.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Rattus norvegicus

plain_language

Copper altered zinc movement through, as well as into, intestinal cells.

primary_references

[zn-sig-3968585] Copper and zinc absorption in the rat: mechanism of mutual antagonism. (1985). https://pubmed.ncbi.nlm.nih.gov/3968585/ DOI: 10.1093/jn/115.2.159

tissue_or_cell_type

Small-intestinal mucosa and portal effluent

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 971–983

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated vascularly perfused intestine from diet-conditioned rats · source_derived_draft · unverified_draft

### zn-sig-luminal-copper-zinc High luminal copper increased mucosal zinc accumulation while reducing zinc transfer to portal effluent at the highest luminal zinc concentration. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Copper altered zinc movement through, as well as into, intestinal cells. organism: Rattus norvegicus tissue_or_cell_type: Small-intestinal mucosa and portal effluent experimental_model: Isolated vascularly perfused intestine from diet-conditioned rats limitations: Ex-vivo perfusion and extreme luminal exposure differ from whole-animal feeding; increased metallothionein-bound copper alone did not prove reduced net absorption. exposure: Dietary copper/zinc variation for one week versus direct luminal-metal variation. cross_nutrient: Zinc (affected_nutrient) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/3968585-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "ca588cec5326d23dd5f8c9b409ea66fc415043b95af456399e495b8131c8f6ed"} [zn-sig-3968585] Copper and zinc absorption in the rat: mechanism of mutual antagonism. (1985). https://pubmed.ncbi.nlm.nih.gov/3968585/ DOI: 10.1093/jn/115.2.159

evidence_span

{"source_cache": "artifacts/cold-research/6323422.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dac85ce0ad7c7d5994b97d55b129050a0e7ca8bf96943578d272054db6a07a62", "start_char": 0, "end_char": 1346, "text_sha256": "dac85ce0ad7c7d5994b97d55b129050a0e7ca8bf96943578d272054db6a07a62"}

experimental_model

Copper titration of bovine adrenal dopamine beta-hydroxylase followed by NMR, EPR and inhibitor kinetics

exposure

Titration with copper and measurement of catalytic rate

limitations

Stoichiometry measured three independent ways. It establishes how much copper the enzyme needs, not how much copper a person needs.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Bovine enzyme

plain_language

The enzyme that turns dopamine into noradrenaline needs exactly eight copper atoms to work fully.

primary_references

[cold-p6323422] Kinetic and spectroscopic studies of the interaction of copper with dopamine beta-hydroxylase. (1984). https://pubmed.ncbi.nlm.nih.gov/6323422/ DOI: 10.1016/s0021-9258(17)43105-x

tissue_or_cell_type

Adrenal medulla enzyme

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 559–570

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Copper titration of bovine adrenal dopamine beta-hydroxylase followed by NMR, EPR and inhibitor kinetics · source_derived_draft · unverified_draft

### cold-dbh-copper-stoichiometry Dopamine beta-hydroxylase specifically binds 8 moles of copper per mole of tetramer, confirmed by radiolabel, atomic absorption, NMR and EPR titration, and catalytic rate increased with copper up to that ratio and was constant thereafter, so this stoichiometry is required for maximal activity. Condition category: normal nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: The enzyme that turns dopamine into noradrenaline needs exactly eight copper atoms to work fully. organism: Bovine enzyme tissue_or_cell_type: Adrenal medulla enzyme experimental_model: Copper titration of bovine adrenal dopamine beta-hydroxylase followed by NMR, EPR and inhibitor kinetics limitations: Stoichiometry measured three independent ways. It establishes how much copper the enzyme needs, not how much copper a person needs. exposure: Titration with copper and measurement of catalytic rate evidence_span: {"source_cache": "artifacts/cold-research/6323422.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dac85ce0ad7c7d5994b97d55b129050a0e7ca8bf96943578d272054db6a07a62", "start_char": 0, "end_char": 1346, "text_sha256": "dac85ce0ad7c7d5994b97d55b129050a0e7ca8bf96943578d272054db6a07a62"} [cold-p6323422] Kinetic and spectroscopic studies of the interaction of copper with dopamine beta-hydroxylase. (1984). https://pubmed.ncbi.nlm.nih.gov/6323422/ DOI: 10.1016/s0021-9258(17)43105-x

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/iron-research/27537180.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "59f2a83f1bffcacfed0df109f3690413aa2e6f08be6ad400817c5cbe2165e523", "start_char": 0, "end_char": 1840, "text_sha256": "59f2a83f1bffcacfed0df109f3690413aa2e6f08be6ad400817c5cbe2165e523"}

experimental_model

Five-week factorial iron/copper feeding

exposure

Approximately 8800, 80 or 11 ppm iron crossed with approximately 183, 8 or 0.9 ppm copper

limitations

Very high experimental iron exposure; not an estimate of human supplement risk at ordinary intake. Copper restoration did not normalize every iron measure.

nutrient_topic

Iron research collection; topical membership is not evidence of a direct dietary effect. · Iron

organism

Weanling male Sprague-Dawley rats

plain_language

Correcting the copper-related problem did not mean the excess-iron problem had disappeared.

primary_references

[iron-p27537180] High-Iron Consumption Impairs Growth and Causes Copper-Deficiency Anemia in Weanling Sprague-Dawley Rats. (2016). https://pubmed.ncbi.nlm.nih.gov/27537180/ DOI: 10.1371/journal.pone.0161033

tissue_or_cell_type

Systemic copper and iron status

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Iron: absorption, trafficking, iron-dependent enzymes and nutrient interactions (2026-09-17) · lines 927–938

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Five-week factorial iron/copper feeding · source_derived_draft · unverified_draft

### iron-copper-rescue-tradeoff Additional copper prevented the reported growth, cardiac and anemia disturbances under high-iron feeding, but increased hepatic nonheme iron loading. Condition category: nutrient_deficiency nutrient_topic: Iron research collection; topical membership is not evidence of a direct dietary effect. plain_language: Correcting the copper-related problem did not mean the excess-iron problem had disappeared. organism: Weanling male Sprague-Dawley rats tissue_or_cell_type: Systemic copper and iron status experimental_model: Five-week factorial iron/copper feeding limitations: Very high experimental iron exposure; not an estimate of human supplement risk at ordinary intake. Copper restoration did not normalize every iron measure. exposure: Approximately 8800, 80 or 11 ppm iron crossed with approximately 183, 8 or 0.9 ppm copper evidence_span: {"source_cache": "artifacts/iron-research/27537180.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "59f2a83f1bffcacfed0df109f3690413aa2e6f08be6ad400817c5cbe2165e523", "start_char": 0, "end_char": 1840, "text_sha256": "59f2a83f1bffcacfed0df109f3690413aa2e6f08be6ad400817c5cbe2165e523"} [iron-p27537180] High-Iron Consumption Impairs Growth and Causes Copper-Deficiency Anemia in Weanling Sprague-Dawley Rats. (2016). https://pubmed.ncbi.nlm.nih.gov/27537180/ DOI: 10.1371/journal.pone.0161033

evidence_span

{"source_cache": "artifacts/copper-research/27152332.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "984a9036d5157e29cdef55d42201887d3ff43cf533185148ba4e3f5c143ced09", "start_char": 0, "end_char": 1325, "text_sha256": "984a9036d5157e29cdef55d42201887d3ff43cf533185148ba4e3f5c143ced09"}

experimental_model

Human DBH X-ray crystallography

exposure

Crystal structure at 2.9 angstrom resolution

limitations

Open and closed conformations were observed; the proposed catalytic alternation and fully occupied binuclear states require further evidence. Do not equate a structural model with proof of psychiatric effects from copper intake.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human protein

plain_language

The enzyme changes the spacing of its copper-binding regions; their precise catalytic cycle remains under study.

primary_references

[copper-p27152332] The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution. (2016). https://pubmed.ncbi.nlm.nih.gov/27152332/ DOI: 10.1126/sciadv.1500980

tissue_or_cell_type

Purified dimeric enzyme

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1092–1103

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human DBH X-ray crystallography · source_derived_draft · unverified_draft

### copper-dbh-copper-site-conformations Human DBH displayed open and closed active-site conformations; the closed structure placed its two copper-binding sites about 4–5 angstroms apart. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme changes the spacing of its copper-binding regions; their precise catalytic cycle remains under study. organism: Human protein tissue_or_cell_type: Purified dimeric enzyme experimental_model: Human DBH X-ray crystallography limitations: Open and closed conformations were observed; the proposed catalytic alternation and fully occupied binuclear states require further evidence. Do not equate a structural model with proof of psychiatric effects from copper intake. exposure: Crystal structure at 2.9 angstrom resolution evidence_span: {"source_cache": "artifacts/copper-research/27152332.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "984a9036d5157e29cdef55d42201887d3ff43cf533185148ba4e3f5c143ced09", "start_char": 0, "end_char": 1325, "text_sha256": "984a9036d5157e29cdef55d42201887d3ff43cf533185148ba4e3f5c143ced09"} [copper-p27152332] The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution. (2016). https://pubmed.ncbi.nlm.nih.gov/27152332/ DOI: 10.1126/sciadv.1500980

evidence_span

{"source_cache": "artifacts/copper-research/29237729.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4dd7c6b3cafb3923a0baab088fd82b08e087b7ec8f5fd26ee8b2bad114d54c1", "start_char": 0, "end_char": 1292, "text_sha256": "d4dd7c6b3cafb3923a0baab088fd82b08e087b7ec8f5fd26ee8b2bad114d54c1"}

experimental_model

Carrier perturbation, yeast complementation, bacterial transport and reconstituted liposomes

exposure

SLC25A3 loss or reconstitution; extracellular copper addition

limitations

The study established copper transport and COX dependence; later export findings extend rather than negate this work. Rescue conditions differ between experiments.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human and mouse cells; heterologous yeast and Lactococcus assays

plain_language

The mitochondrial phosphate carrier also moves copper.

primary_references

[copper-p29237729] The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis. (2018). https://pubmed.ncbi.nlm.nih.gov/29237729/ DOI: 10.1074/jbc.ra117.000265

tissue_or_cell_type

Inner mitochondrial membrane

transport_effect

depends Transport supported in heterologous assays and liposomes, with no direction recorded.

transport_pool

the mitochondrial matrix Transport supported in heterologous assays and liposomes, with no direction recorded.

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 520–531

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Carrier perturbation, yeast complementation, bacterial transport and reconstituted liposomes · source_derived_draft · unverified_draft

### copper-slc25a3-copper-carrier SLC25A3 supported copper transport in heterologous assays and reconstituted liposomes. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: The mitochondrial phosphate carrier also moves copper. organism: Human and mouse cells; heterologous yeast and Lactococcus assays tissue_or_cell_type: Inner mitochondrial membrane experimental_model: Carrier perturbation, yeast complementation, bacterial transport and reconstituted liposomes limitations: The study established copper transport and COX dependence; later export findings extend rather than negate this work. Rescue conditions differ between experiments. exposure: SLC25A3 loss or reconstitution; extracellular copper addition evidence_span: {"source_cache": "artifacts/copper-research/29237729.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4dd7c6b3cafb3923a0baab088fd82b08e087b7ec8f5fd26ee8b2bad114d54c1", "start_char": 0, "end_char": 1292, "text_sha256": "d4dd7c6b3cafb3923a0baab088fd82b08e087b7ec8f5fd26ee8b2bad114d54c1"} [copper-p29237729] The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis. (2018). https://pubmed.ncbi.nlm.nih.gov/29237729/ DOI: 10.1074/jbc.ra117.000265

evidence_span

{"source_cache": "artifacts/copper-research/19764817.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9a01d0dba5caec8a33a77fdbe7190d7a05bdd6e691a570a890eb6b19d4c692b6", "start_char": 0, "end_char": 1343, "text_sha256": "9a01d0dba5caec8a33a77fdbe7190d7a05bdd6e691a570a890eb6b19d4c692b6"}

experimental_model

Crystallography of recombinant human diamine oxidase and inhibitor complexes

exposure

Native structure and inhibitor binding

limitations

Copper/TPQ dependence is molecular evidence, not a trial of copper for histamine intolerance; DAO activity can have multiple determinants.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human AOC1 expressed in insect cells

plain_language

Histamine-processing machinery includes both a metal and a protein-derived cofactor.

primary_references

[copper-p19764817] Structure and inhibition of human diamine oxidase. (2009). https://pubmed.ncbi.nlm.nih.gov/19764817/ DOI: 10.1021/bi9014192

tissue_or_cell_type

Purified protein

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1014–1025

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystallography of recombinant human diamine oxidase and inhibitor complexes · source_derived_draft · unverified_draft

### copper-aoc1-copper-tpq Human AOC1 has one copper ion and a tyrosine-derived topaquinone in each of its two active sites. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Histamine-processing machinery includes both a metal and a protein-derived cofactor. organism: Human AOC1 expressed in insect cells tissue_or_cell_type: Purified protein experimental_model: Crystallography of recombinant human diamine oxidase and inhibitor complexes limitations: Copper/TPQ dependence is molecular evidence, not a trial of copper for histamine intolerance; DAO activity can have multiple determinants. exposure: Native structure and inhibitor binding evidence_span: {"source_cache": "artifacts/copper-research/19764817.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9a01d0dba5caec8a33a77fdbe7190d7a05bdd6e691a570a890eb6b19d4c692b6", "start_char": 0, "end_char": 1343, "text_sha256": "9a01d0dba5caec8a33a77fdbe7190d7a05bdd6e691a570a890eb6b19d4c692b6"} [copper-p19764817] Structure and inhibition of human diamine oxidase. (2009). https://pubmed.ncbi.nlm.nih.gov/19764817/ DOI: 10.1021/bi9014192

evidence_span

{"source_cache": "artifacts/copper-research/16239734.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "24ea102446aeff31a53b9302d191c0bc572100f8ee82b6ccb1a665432151662b", "start_char": 0, "end_char": 1408, "text_sha256": "24ea102446aeff31a53b9302d191c0bc572100f8ee82b6ccb1a665432151662b"}

experimental_model

X-ray structures of soluble human VAP-1 and inhibitor complex

exposure

Native and inhibitor-bound structure

limitations

Soluble protein structure; proposed gate and adhesion-motif functions are not proven clinical effects of copper intake.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human protein

plain_language

A separate copper amine oxidase has its own catalytic arrangement.

primary_references

[copper-p16239734] Structure of human semicarbazide-sensitive amine oxidase/vascular adhesion protein-1. (2005). https://pubmed.ncbi.nlm.nih.gov/16239734/ DOI: 10.1107/s0907444905028805

tissue_or_cell_type

Purified truncated soluble AOC3

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1040–1051

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray structures of soluble human VAP-1 and inhibitor complex · source_derived_draft · unverified_draft

### copper-aoc3-copper-tpq The human AOC3 structure contained an active-site copper ion and TPQ in its active off-copper conformation. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: A separate copper amine oxidase has its own catalytic arrangement. organism: Human protein tissue_or_cell_type: Purified truncated soluble AOC3 experimental_model: X-ray structures of soluble human VAP-1 and inhibitor complex limitations: Soluble protein structure; proposed gate and adhesion-motif functions are not proven clinical effects of copper intake. exposure: Native and inhibitor-bound structure evidence_span: {"source_cache": "artifacts/copper-research/16239734.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "24ea102446aeff31a53b9302d191c0bc572100f8ee82b6ccb1a665432151662b", "start_char": 0, "end_char": 1408, "text_sha256": "24ea102446aeff31a53b9302d191c0bc572100f8ee82b6ccb1a665432151662b"} [copper-p16239734] Structure of human semicarbazide-sensitive amine oxidase/vascular adhesion protein-1. (2005). https://pubmed.ncbi.nlm.nih.gov/16239734/ DOI: 10.1107/s0907444905028805

evidence_span

{"source_cache": "artifacts/copper-research/24909901.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "abfdc86e4b47b489037af635672033532c905d291127030d9dbcfc02e998c20b", "start_char": 0, "end_char": 1036, "text_sha256": "abfdc86e4b47b489037af635672033532c905d291127030d9dbcfc02e998c20b"}

experimental_model

Copper perturbation, imaging and trafficking assays in hepatocyte systems

exposure

Copper challenge and lysosomal exocytosis perturbation

limitations

The main cellular trafficking observations are mechanistic; experimental copper exposures and mutant rescue do not establish a clinical treatment. Dynactin p62 is DCTN4, not autophagy SQSTM1/p62.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human HepG2 cells with complementary hepatic models

plain_language

A temporary storage compartment helps prepare copper for removal.

primary_references

[copper-p24909901] Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24909901/ DOI: 10.1016/j.devcel.2014.04.033

tissue_or_cell_type

Golgi, lysosomes and canalicular pole

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 429–440

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Copper perturbation, imaging and trafficking assays in hepatocyte systems · source_derived_draft · unverified_draft

### copper-atp7b-lysosomal-loading Lysosomal ATP7B transported copper into the lysosomal lumen. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: A temporary storage compartment helps prepare copper for removal. organism: Human HepG2 cells with complementary hepatic models tissue_or_cell_type: Golgi, lysosomes and canalicular pole experimental_model: Copper perturbation, imaging and trafficking assays in hepatocyte systems limitations: The main cellular trafficking observations are mechanistic; experimental copper exposures and mutant rescue do not establish a clinical treatment. Dynactin p62 is DCTN4, not autophagy SQSTM1/p62. exposure: Copper challenge and lysosomal exocytosis perturbation evidence_span: {"source_cache": "artifacts/copper-research/24909901.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "abfdc86e4b47b489037af635672033532c905d291127030d9dbcfc02e998c20b", "start_char": 0, "end_char": 1036, "text_sha256": "abfdc86e4b47b489037af635672033532c905d291127030d9dbcfc02e998c20b"} [copper-p24909901] Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24909901/ DOI: 10.1016/j.devcel.2014.04.033

evidence_span

{"source_cache": "artifacts/copper-research/12351628.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4492680e4d410b1e32f77dea6aa0c26b2303b26d4fadfef25a350338ac365de3", "start_char": 0, "end_char": 1541, "text_sha256": "4492680e4d410b1e32f77dea6aa0c26b2303b26d4fadfef25a350338ac365de3"}

experimental_model

Human ceruloplasmin expression, radiocopper labeling and in-vitro loading

exposure

Wild-type and copper-site mutants including G631R

limitations

The final conformation required six occupied sites in these assays; no hierarchy was apparent. Do not confuse this structural requirement with circulating protein concentration.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human protein expressed in Chinese hamster ovary cells

plain_language

The protein needs coordinated metal loading to reach its mature form.

primary_references

[copper-p12351628] Mechanisms of copper incorporation into human ceruloplasmin. (2002). https://pubmed.ncbi.nlm.nih.gov/12351628/ DOI: 10.1074/jbc.m206246200

tissue_or_cell_type

Secretory protein biosynthesis

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1053–1064

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human ceruloplasmin expression, radiocopper labeling and in-vitro loading · source_derived_draft · unverified_draft

### copper-cp-six-site-loading Ceruloplasmin copper incorporation was cooperative, and its final conformational state required occupation of all six copper-binding sites in the tested system. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: The protein needs coordinated metal loading to reach its mature form. organism: Human protein expressed in Chinese hamster ovary cells tissue_or_cell_type: Secretory protein biosynthesis experimental_model: Human ceruloplasmin expression, radiocopper labeling and in-vitro loading limitations: The final conformation required six occupied sites in these assays; no hierarchy was apparent. Do not confuse this structural requirement with circulating protein concentration. exposure: Wild-type and copper-site mutants including G631R evidence_span: {"source_cache": "artifacts/copper-research/12351628.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4492680e4d410b1e32f77dea6aa0c26b2303b26d4fadfef25a350338ac365de3", "start_char": 0, "end_char": 1541, "text_sha256": "4492680e4d410b1e32f77dea6aa0c26b2303b26d4fadfef25a350338ac365de3"} [copper-p12351628] Mechanisms of copper incorporation into human ceruloplasmin. (2002). https://pubmed.ncbi.nlm.nih.gov/12351628/ DOI: 10.1074/jbc.m206246200

evidence_span

{"source_cache": "artifacts/copper-research/11734551.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e7b07ef7169b07bef414cdfb8996cffda2636f9a1bcd93b556d22bdce980a03c", "start_char": 0, "end_char": 1144, "text_sha256": "e7b07ef7169b07bef414cdfb8996cffda2636f9a1bcd93b556d22bdce980a03c"}

experimental_model

Human CTR1 expression and radiocopper transport assays

exposure

CTR1 expression; pH and potassium changes in culture

limitations

Transport kinetics in cells; elevated assay potassium is not evidence that potassium supplements improve human copper status.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human protein in human HEK293 cells

plain_language

CTR1 is a controlled entry route for copper into cells.

primary_references

[copper-p11734551] Biochemical characterization of the human copper transporter Ctr1. (2002). https://pubmed.ncbi.nlm.nih.gov/11734551/ DOI: 10.1074/jbc.m104728200

tissue_or_cell_type

Plasma membrane

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 247–258

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human CTR1 expression and radiocopper transport assays · source_derived_draft · unverified_draft

### copper-ctr1-uptake Human CTR1 supported high-affinity, saturable, metal-selective copper uptake at the plasma membrane. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: CTR1 is a controlled entry route for copper into cells. organism: Human protein in human HEK293 cells tissue_or_cell_type: Plasma membrane experimental_model: Human CTR1 expression and radiocopper transport assays limitations: Transport kinetics in cells; elevated assay potassium is not evidence that potassium supplements improve human copper status. exposure: CTR1 expression; pH and potassium changes in culture evidence_span: {"source_cache": "artifacts/copper-research/11734551.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e7b07ef7169b07bef414cdfb8996cffda2636f9a1bcd93b556d22bdce980a03c", "start_char": 0, "end_char": 1144, "text_sha256": "e7b07ef7169b07bef414cdfb8996cffda2636f9a1bcd93b556d22bdce980a03c"} [copper-p11734551] Biochemical characterization of the human copper transporter Ctr1. (2002). https://pubmed.ncbi.nlm.nih.gov/11734551/ DOI: 10.1074/jbc.m104728200

evidence_span

{"source_cache": "artifacts/copper-research/24717435.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4eee319f693bd307d3930073167395e5ef454f07d976ca834539b637ec4406ef", "start_char": 0, "end_char": 1471, "text_sha256": "4eee319f693bd307d3930073167395e5ef454f07d976ca834539b637ec4406ef"}

experimental_model

Copper-binding MEK1 mutants, CTR1 perturbation and tumor models

exposure

CTR1 reduction, MEK1 copper-binding disruption and chelation

limitations

Preclinical mechanism; does not establish dietary copper as a cancer cause or copper restriction as a treatment.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human and mouse experimental systems

plain_language

Copper binding influenced an enzyme in a growth-signaling chain.

primary_references

[copper-p24717435] Copper is required for oncogenic BRAF signalling and tumorigenesis. (2014). https://pubmed.ncbi.nlm.nih.gov/24717435/ DOI: 10.1038/nature13180

tissue_or_cell_type

BRAF V600E-driven signaling and tumor models

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1222–1233

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Copper-binding MEK1 mutants, CTR1 perturbation and tumor models · source_derived_draft · unverified_draft

### copper-cu-mek1-signaling MEK1 mutations disrupting copper binding reduced BRAF V600E-driven signaling in the tested human and mouse systems. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Copper binding influenced an enzyme in a growth-signaling chain. organism: Human and mouse experimental systems tissue_or_cell_type: BRAF V600E-driven signaling and tumor models experimental_model: Copper-binding MEK1 mutants, CTR1 perturbation and tumor models limitations: Preclinical mechanism; does not establish dietary copper as a cancer cause or copper restriction as a treatment. exposure: CTR1 reduction, MEK1 copper-binding disruption and chelation evidence_span: {"source_cache": "artifacts/copper-research/24717435.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4eee319f693bd307d3930073167395e5ef454f07d976ca834539b637ec4406ef", "start_char": 0, "end_char": 1471, "text_sha256": "4eee319f693bd307d3930073167395e5ef454f07d976ca834539b637ec4406ef"} [copper-p24717435] Copper is required for oncogenic BRAF signalling and tumorigenesis. (2014). https://pubmed.ncbi.nlm.nih.gov/24717435/ DOI: 10.1038/nature13180

evidence_span

{"source_cache": "artifacts/copper-research/27152332.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "984a9036d5157e29cdef55d42201887d3ff43cf533185148ba4e3f5c143ced09", "start_char": 0, "end_char": 1325, "text_sha256": "984a9036d5157e29cdef55d42201887d3ff43cf533185148ba4e3f5c143ced09"}

experimental_model

Human DBH X-ray crystallography

exposure

Crystal structure at 2.9 angstrom resolution

limitations

Open and closed conformations were observed; the proposed catalytic alternation and fully occupied binuclear states require further evidence. Do not equate a structural model with proof of psychiatric effects from copper intake.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human protein

plain_language

Copper is part of the enzyme that converts one neurotransmitter into another.

primary_references

[copper-p27152332] The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution. (2016). https://pubmed.ncbi.nlm.nih.gov/27152332/ DOI: 10.1126/sciadv.1500980

tissue_or_cell_type

Purified dimeric enzyme

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1079–1090

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human DBH X-ray crystallography · source_derived_draft · unverified_draft

### copper-dbh-neurotransmitter-step Human DBH is the copper-enzyme step converting dopamine to norepinephrine; the study resolved its catalytic-core architecture. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Copper is part of the enzyme that converts one neurotransmitter into another. organism: Human protein tissue_or_cell_type: Purified dimeric enzyme experimental_model: Human DBH X-ray crystallography limitations: Open and closed conformations were observed; the proposed catalytic alternation and fully occupied binuclear states require further evidence. Do not equate a structural model with proof of psychiatric effects from copper intake. exposure: Crystal structure at 2.9 angstrom resolution evidence_span: {"source_cache": "artifacts/copper-research/27152332.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "984a9036d5157e29cdef55d42201887d3ff43cf533185148ba4e3f5c143ced09", "start_char": 0, "end_char": 1325, "text_sha256": "984a9036d5157e29cdef55d42201887d3ff43cf533185148ba4e3f5c143ced09"} [copper-p27152332] The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution. (2016). https://pubmed.ncbi.nlm.nih.gov/27152332/ DOI: 10.1126/sciadv.1500980

evidence_span

{"source_cache": "artifacts/copper-research/16274220.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7f88de566cf98e9aad1df97f91b7b37a4d8e685b842c164db25a196b09c0b976", "start_char": 0, "end_char": 1880, "text_sha256": "7f88de566cf98e9aad1df97f91b7b37a4d8e685b842c164db25a196b09c0b976"}

experimental_model

Purified recombinant human hephaestin

exposure

Fe(II) substrate and apotransferrin assays

limitations

Soluble recombinant construct; average measured copper loading of 3.13 atoms is not a universal mature-protein stoichiometry.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human protein produced in baby hamster kidney cells

plain_language

A copper enzyme changes iron into the form needed for the next transport step.

primary_references

[copper-p16274220] Recombinant expression and functional characterization of human hephaestin: a multicopper oxidase with ferroxidase activity. (2005). https://pubmed.ncbi.nlm.nih.gov/16274220/ DOI: 10.1021/bi051559k

tissue_or_cell_type

Purified soluble hephaestin construct

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 767–778

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human hephaestin · source_derived_draft · unverified_draft

### copper-heph-ferroxidation Recombinant copper-containing human hephaestin oxidized Fe(II), with an apparent substrate Km of 2.1 micromolar. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: A copper enzyme changes iron into the form needed for the next transport step. organism: Human protein produced in baby hamster kidney cells tissue_or_cell_type: Purified soluble hephaestin construct experimental_model: Purified recombinant human hephaestin limitations: Soluble recombinant construct; average measured copper loading of 3.13 atoms is not a universal mature-protein stoichiometry. exposure: Fe(II) substrate and apotransferrin assays evidence_span: {"source_cache": "artifacts/copper-research/16274220.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7f88de566cf98e9aad1df97f91b7b37a4d8e685b842c164db25a196b09c0b976", "start_char": 0, "end_char": 1880, "text_sha256": "7f88de566cf98e9aad1df97f91b7b37a4d8e685b842c164db25a196b09c0b976"} [copper-p16274220] Recombinant expression and functional characterization of human hephaestin: a multicopper oxidase with ferroxidase activity. (2005). https://pubmed.ncbi.nlm.nih.gov/16274220/ DOI: 10.1021/bi051559k

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/copper-research/3337044.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2302118b1dad186fdee87512abf58f47a36d430e329057c87b24e57e52e331cc", "start_char": 0, "end_char": 882, "text_sha256": "2302118b1dad186fdee87512abf58f47a36d430e329057c87b24e57e52e331cc"}

experimental_model

Factorial dietary copper, iron and ascorbate feeding experiment

exposure

Copper 0.42 versus 5.74 micrograms/g diet; iron 38 versus 191 micrograms/g; ascorbate 0 versus 1%, for 20 days

limitations

Animal feed concentrations cannot be converted into a human supplement rule. Baseline copper status modified effects.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Rat

plain_language

A nutrient combination worsened the deficit in this animal setting.

primary_references

[copper-p3337044] Adverse effects of high dietary iron and ascorbic acid on copper status in copper-deficient and copper-adequate rats. (1988). https://pubmed.ncbi.nlm.nih.gov/3337044/ DOI: 10.1093/ajcn/47.1.96

tissue_or_cell_type

Intestinal uptake, blood and tissues

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1157–1168

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Factorial dietary copper, iron and ascorbate feeding experiment · source_derived_draft · unverified_draft

### copper-iron-vitc-lowcu-anemia High iron together with dietary ascorbate aggravated anemia in copper-deficient rats. Condition category: nutrient_deficiency nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: A nutrient combination worsened the deficit in this animal setting. organism: Rat tissue_or_cell_type: Intestinal uptake, blood and tissues experimental_model: Factorial dietary copper, iron and ascorbate feeding experiment limitations: Animal feed concentrations cannot be converted into a human supplement rule. Baseline copper status modified effects. exposure: Copper 0.42 versus 5.74 micrograms/g diet; iron 38 versus 191 micrograms/g; ascorbate 0 versus 1%, for 20 days evidence_span: {"source_cache": "artifacts/copper-research/3337044.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2302118b1dad186fdee87512abf58f47a36d430e329057c87b24e57e52e331cc", "start_char": 0, "end_char": 882, "text_sha256": "2302118b1dad186fdee87512abf58f47a36d430e329057c87b24e57e52e331cc"} [copper-p3337044] Adverse effects of high dietary iron and ascorbic acid on copper status in copper-deficient and copper-adequate rats. (1988). https://pubmed.ncbi.nlm.nih.gov/3337044/ DOI: 10.1093/ajcn/47.1.96

availability_state

machinery_impairment Imported condition classification; unverified.

curation_topic

copper · Copper

experimental_condition

Control; ATP7A overexpression tested as rescue Akt2 loss · Mouse Akt2-null genotype Condition belongs to the full experimental contrast; do not separate a joint intervention.

experimental_contrast

{"intervention": "Akt2 loss", "comparator": "Control; ATP7A overexpression tested as rescue", "endpoint": "SOD3 activity", "effect_direction": "decrease", "combination": "single", "conditions": [{"entity_slug": "mouse-akt2-null", "state": "Akt2 loss"}]} Explicit extracted experimental comparison; source-derived draft.

experimental_model

Mouse Akt2-null vascular experiments; primary abstract reviewed

limitations

Genetic signaling defect, not dietary copper deficiency. Mechanistic phosphorylation experiments are not substituted for human causal evidence.

primary_references

Sudhahar et al. 2018; DOI:10.1161/ATVBAHA.117.309819; PMID:29301787; https://pubmed.ncbi.nlm.nih.gov/29301787/

trigger_kind

machinery_impairment Imported condition classification; unverified.

Diabetes cascade: targeted primary-source supplement · lines 42–42

See claim-local references; curated paraphrases reviewed 2026-09-20. · supports · Mouse Akt2-null vascular experiments; primary abstract reviewed · source_derived_draft · unverified_draft

Akt2-null vessels or vascular smooth-muscle cells had lower SOD3 activity, rescued by ATP7A overexpression. Model: Mouse Akt2-null vascular experiments; primary abstract reviewed. Limits: Genetic signaling defect, not dietary copper deficiency. Mechanistic phosphorylation experiments are not substituted for human causal evidence. Primary reference: Sudhahar et al. 2018; DOI:10.1161/ATVBAHA.117.309819; PMID:29301787; https://pubmed.ncbi.nlm.nih.gov/29301787/

availability_state

biomarker_context Imported condition classification; unverified.

curation_topic

copper · Copper

experimental_condition

Control vascular specimens Type 2 diabetes vascular specimens · Human vascular specimens from patients with type 2 diabetes Condition belongs to the full experimental contrast; do not separate a joint intervention.

experimental_contrast

{"intervention": "Type 2 diabetes vascular specimens", "comparator": "Control vascular specimens", "endpoint": "ATP7A protein abundance", "effect_direction": "decrease", "combination": "single", "conditions": [{"entity_slug": "human-t2d-vessel-state", "state": "Type 2 diabetes vascular specimens"}]} Explicit extracted experimental comparison; source-derived draft.

experimental_model

Human vascular specimens; primary abstract reviewed

limitations

Observational human finding; detailed sampling and covariate analysis require full-methods review.

primary_references

Sudhahar et al. 2018; DOI:10.1161/ATVBAHA.117.309819; PMID:29301787; https://pubmed.ncbi.nlm.nih.gov/29301787/

trigger_kind

biomarker_context Imported condition classification; unverified.

Diabetes cascade: targeted primary-source supplement · lines 39–39

See claim-local references; curated paraphrases reviewed 2026-09-20. · supports · Human vascular specimens; primary abstract reviewed · source_derived_draft · unverified_draft

Vascular specimens from patients with type 2 diabetes showed lower ATP7A protein. Model: Human vascular specimens; primary abstract reviewed. Limits: Observational human finding; detailed sampling and covariate analysis require full-methods review. Primary reference: Sudhahar et al. 2018; DOI:10.1161/ATVBAHA.117.309819; PMID:29301787; https://pubmed.ncbi.nlm.nih.gov/29301787/

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/hbot-research/10221913.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8f6658330988f9b33331f49c1599734e070075a33fa8f32a3a6025d9f0fbc0b8", "start_char": 0, "end_char": 1176, "text_sha256": "8f6658330988f9b33331f49c1599734e070075a33fa8f32a3a6025d9f0fbc0b8"}

experimental_model

Yeast genetics with purified copper chaperone and apo-enzyme reconstitution

exposure

CCS deletion, elevated copper, and abrogation of metallothioneins

limitations

A yeast system with purified protein reconstitution. The free-copper conclusion is drawn from this system and its metallothionein manipulations.

nutrient_topic

Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Hyperbaric oxygen therapy

organism

Saccharomyces cerevisiae and purified proteins

plain_language

Copper is handed over by a dedicated carrier, not picked up loose.

primary_references

[hbot-p10221913] Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. (1999). https://pubmed.ncbi.nlm.nih.gov/10221913/ DOI: 10.1126/science.284.5415.805

tissue_or_cell_type

Cytosol

trigger_kind

machinery_impairment Imported condition classification; unverified.

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 504–515

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Yeast genetics with purified copper chaperone and apo-enzyme reconstitution · source_derived_draft · unverified_draft

### hbot-ccs-required The copper chaperone for superoxide dismutase is necessary for expression of an active copper-bound superoxide dismutase in vivo despite the enzyme’s 6 femtomolar dissociation constant for copper, and purified Cu(I)-CCS was sufficient to activate the apo-enzyme but necessary only when free copper was strictly limited. Condition category: machinery_impairment nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Copper is handed over by a dedicated carrier, not picked up loose. organism: Saccharomyces cerevisiae and purified proteins tissue_or_cell_type: Cytosol experimental_model: Yeast genetics with purified copper chaperone and apo-enzyme reconstitution limitations: A yeast system with purified protein reconstitution. The free-copper conclusion is drawn from this system and its metallothionein manipulations. exposure: CCS deletion, elevated copper, and abrogation of metallothioneins evidence_span: {"source_cache": "artifacts/hbot-research/10221913.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8f6658330988f9b33331f49c1599734e070075a33fa8f32a3a6025d9f0fbc0b8", "start_char": 0, "end_char": 1176, "text_sha256": "8f6658330988f9b33331f49c1599734e070075a33fa8f32a3a6025d9f0fbc0b8"} [hbot-p10221913] Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. (1999). https://pubmed.ncbi.nlm.nih.gov/10221913/ DOI: 10.1126/science.284.5415.805

evidence_span

{"source_cache": "artifacts/hbot-research/10221913.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8f6658330988f9b33331f49c1599734e070075a33fa8f32a3a6025d9f0fbc0b8", "start_char": 0, "end_char": 1176, "text_sha256": "8f6658330988f9b33331f49c1599734e070075a33fa8f32a3a6025d9f0fbc0b8"}

experimental_model

Yeast genetics with purified copper chaperone and apo-enzyme reconstitution

exposure

CCS deletion, elevated copper, and abrogation of metallothioneins

limitations

A yeast system with purified protein reconstitution. The free-copper conclusion is drawn from this system and its metallothionein manipulations.

nutrient_topic

Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Hyperbaric oxygen therapy

organism

Saccharomyces cerevisiae and purified proteins

plain_language

There is effectively no loose copper in a cell; every atom is held by something.

primary_references

[hbot-p10221913] Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. (1999). https://pubmed.ncbi.nlm.nih.gov/10221913/ DOI: 10.1126/science.284.5415.805

tissue_or_cell_type

Cytosol

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 517–528

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Yeast genetics with purified copper chaperone and apo-enzyme reconstitution · source_derived_draft · unverified_draft

### hbot-free-copper-limit The chaperone requirement was bypassed by elevated copper and by removing intracellular copper scavengers such as the metallothioneins, indicating that intracellular free copper is limited to less than one free copper ion per cell and that a pool of free copper is not used to activate metalloenzymes. Condition category: normal nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: There is effectively no loose copper in a cell; every atom is held by something. organism: Saccharomyces cerevisiae and purified proteins tissue_or_cell_type: Cytosol experimental_model: Yeast genetics with purified copper chaperone and apo-enzyme reconstitution limitations: A yeast system with purified protein reconstitution. The free-copper conclusion is drawn from this system and its metallothionein manipulations. exposure: CCS deletion, elevated copper, and abrogation of metallothioneins evidence_span: {"source_cache": "artifacts/hbot-research/10221913.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8f6658330988f9b33331f49c1599734e070075a33fa8f32a3a6025d9f0fbc0b8", "start_char": 0, "end_char": 1176, "text_sha256": "8f6658330988f9b33331f49c1599734e070075a33fa8f32a3a6025d9f0fbc0b8"} [hbot-p10221913] Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. (1999). https://pubmed.ncbi.nlm.nih.gov/10221913/ DOI: 10.1126/science.284.5415.805

evidence_span

{"source_cache": "artifacts/curcumin-research/24634837.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3c64f5d7dd7206fa30f155d11ee68a90c72432b6ff1837922ee17ef1e811fec7", "start_char": 0, "end_char": 1451, "text_sha256": "3c64f5d7dd7206fa30f155d11ee68a90c72432b6ff1837922ee17ef1e811fec7"}

experimental_model

Six-month feeding comparison in C57BL/6J mice

exposure

Diet containing 0.2% curcumin versus unsupplemented diet

limitations

Long-term mouse findings cannot be equated with acute human supplementation. Expression changes may be adaptive responses, not direct target binding.

nutrient_topic

Curcumin research collection; topical membership is not evidence of a direct dietary effect. · Curcumin

organism

Mus musculus

plain_language

Copper did not mirror the iron result.

primary_references

[curcumin-p24634837] Curcumin may impair iron status when fed to mice for six months. (2014). https://pubmed.ncbi.nlm.nih.gov/24634837/ DOI: 10.1016/j.redox.2014.01.018

tissue_or_cell_type

Liver and spleen

Curcumin: metabolism, signaling and nutrient connections (2026-09-17) · lines 723–734

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Six-month feeding comparison in C57BL/6J mice · source_derived_draft · unverified_draft

### curcumin-mouse-copper-null The study did not find reduced liver copper stores. Condition category: normal nutrient_topic: Curcumin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Copper did not mirror the iron result. organism: Mus musculus tissue_or_cell_type: Liver and spleen experimental_model: Six-month feeding comparison in C57BL/6J mice limitations: Long-term mouse findings cannot be equated with acute human supplementation. Expression changes may be adaptive responses, not direct target binding. exposure: Diet containing 0.2% curcumin versus unsupplemented diet evidence_span: {"source_cache": "artifacts/curcumin-research/24634837.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3c64f5d7dd7206fa30f155d11ee68a90c72432b6ff1837922ee17ef1e811fec7", "start_char": 0, "end_char": 1451, "text_sha256": "3c64f5d7dd7206fa30f155d11ee68a90c72432b6ff1837922ee17ef1e811fec7"} [curcumin-p24634837] Curcumin may impair iron status when fed to mice for six months. (2014). https://pubmed.ncbi.nlm.nih.gov/24634837/ DOI: 10.1016/j.redox.2014.01.018

evidence_access

Primary full text; Results and catalytic assays

experimental_model

Human intramelanosomal domain expressed in insect cells; activity assays.

limitations

Same metabolite identity as L-DOPA in catecholamine synthesis, but different enzyme and compartment.

nutrient_topic

L-Tyrosine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Tyrosine

plain_language

A different enzyme uses the same amino acid for pigment chemistry.

primary_references

Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24392141/ · DOI 10.1371/journal.pone.0084494

L-Tyrosine: catecholamines, thyroid chemistry, pigment, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 148–154

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human intramelanosomal domain expressed in insect cells; activity assays. · source_derived_draft · unverified_draft

## l-tyrosine-tyr-dopa A different enzyme uses the same amino acid for pigment chemistry. Purified recombinant human tyrosinase showed monophenolase activity with L-tyrosine, the initial hydroxylation step toward pigment. Model: Human intramelanosomal domain expressed in insect cells; activity assays. Limitations: Same metabolite identity as L-DOPA in catecholamine synthesis, but different enzyme and compartment. Evidence access: Primary full text; Results and catalytic assays Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24392141/ · DOI 10.1371/journal.pone.0084494

evidence_access

Primary full text; Results and catalytic assays

experimental_model

Purified human enzyme; L-DOPA colorimetric assays.

limitations

A colorimetric enzyme rate does not establish whole-body melanin output.

nutrient_topic

L-Tyrosine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Tyrosine

plain_language

The pigment route includes a separate oxidation step.

primary_references

Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24392141/ · DOI 10.1371/journal.pone.0084494

L-Tyrosine: catecholamines, thyroid chemistry, pigment, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 156–162

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human enzyme; L-DOPA colorimetric assays. · source_derived_draft · unverified_draft

## l-tyrosine-tyr-quinone The pigment route includes a separate oxidation step. Recombinant human tyrosinase also showed diphenol oxidase activity with L-DOPA, supporting the next oxidation toward dopaquinone. Model: Purified human enzyme; L-DOPA colorimetric assays. Limitations: A colorimetric enzyme rate does not establish whole-body melanin output. Evidence access: Primary full text; Results and catalytic assays Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24392141/ · DOI 10.1371/journal.pone.0084494

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_span

{"source_cache": "artifacts/zinc-transport-sources/22737083-abstract.txt", "locator": "Primary indexed abstract; tissue elemental analysis", "file_sha256": "4643d3986c556a001c45365febbb07095bcdc8bc604e30488d3fb98a23511a4b"}

experimental_model

Tamoxifen-inducible enterocyte-specific knockout and tissue elemental analysis

exposure

Conditional gene deletion compared with intact controls.

limitations

A genetic transport defect is not interchangeable with low intake. Total tissue zinc does not resolve labile versus protein-bound zinc. Tissue accumulation is not proof of systemic nutritional adequacy of the other metals.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Mus musculus

plain_language

Loss of zinc uptake disrupted the distribution of several other metals.

primary_references

[zinc-trans-22737083] A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity. (2012). https://pubmed.ncbi.nlm.nih.gov/22737083/ DOI: 10.1371/journal.pgen.1002766

tissue_or_cell_type

Small intestine, liver, pancreas

trigger_kind

machinery_impairment Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 585–597

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Tamoxifen-inducible enterocyte-specific knockout and tissue elemental analysis · source_derived_draft · unverified_draft

### zinc-trans-zip4-other-metals After enterocyte Zip4 deletion in mice, liver iron, manganese and copper gradually accumulated as the zinc-depletion disease progressed. Condition category: machinery_impairment nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Loss of zinc uptake disrupted the distribution of several other metals. organism: Mus musculus tissue_or_cell_type: Small intestine, liver, pancreas experimental_model: Tamoxifen-inducible enterocyte-specific knockout and tissue elemental analysis limitations: A genetic transport defect is not interchangeable with low intake. Total tissue zinc does not resolve labile versus protein-bound zinc. Tissue accumulation is not proof of systemic nutritional adequacy of the other metals. exposure: Conditional gene deletion compared with intact controls. cross_nutrient: false evidence_span: {"source_cache": "artifacts/zinc-transport-sources/22737083-abstract.txt", "locator": "Primary indexed abstract; tissue elemental analysis", "file_sha256": "4643d3986c556a001c45365febbb07095bcdc8bc604e30488d3fb98a23511a4b"} [zinc-trans-22737083] A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity. (2012). https://pubmed.ncbi.nlm.nih.gov/22737083/ DOI: 10.1371/journal.pgen.1002766

cross_nutrient

Copper (affected_nutrient); Serum zinc concentration (increased_marker); Erythrocyte copper/zinc superoxide dismutase activity (decreased_marker)

evidence_location

Indexed primary abstract.

evidence_span

{"source_cache": "artifacts/zinc-clinical-sources/yadrick1989.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "e2d70d43dded75edb026cac237f238d9e59399db6094098796e169f20e819443", "utf8_bytes": 969}

experimental_model

Ten-week zinc or zinc-plus-iron intervention in adult women

exposure

50 mg elemental zinc/day as gluconate, with or without 50 mg iron/day as ferrous sulfate monohydrate.

limitations

Reported comparisons are within-group pretreatment versus 10 weeks, not placebo-adjusted effects. ESOD is a functional biomarker, not a diagnosis of symptomatic copper deficiency.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

A rising zinc blood level and unchanged ceruloplasmin did not capture every functional change.

primary_references

[zn-clin-yadrick1989] Iron, copper, and zinc status: response to supplementation with zinc or zinc and iron in adult females. (1989). https://pubmed.ncbi.nlm.nih.gov/2912000/ DOI: 10.1093/ajcn/49.1.145

tissue_or_cell_type

Blood and erythrocytes

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1211–1224

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ten-week zinc or zinc-plus-iron intervention in adult women · source_derived_draft · unverified_draft

### zn-clin-ceruloplasmin-null Serum ceruloplasmin was unchanged in both intervention groups despite lower erythrocyte Cu/Zn-superoxide dismutase activity; serum zinc rose in both groups. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: A rising zinc blood level and unchanged ceruloplasmin did not capture every functional change. organism: Homo sapiens tissue_or_cell_type: Blood and erythrocytes experimental_model: Ten-week zinc or zinc-plus-iron intervention in adult women limitations: Reported comparisons are within-group pretreatment versus 10 weeks, not placebo-adjusted effects. ESOD is a functional biomarker, not a diagnosis of symptomatic copper deficiency. exposure: 50 mg elemental zinc/day as gluconate, with or without 50 mg iron/day as ferrous sulfate monohydrate. cross_nutrient: Copper (affected_nutrient); Serum zinc concentration (increased_marker); Erythrocyte copper/zinc superoxide dismutase activity (decreased_marker) evidence_location: Indexed primary abstract. evidence_span: {"source_cache": "artifacts/zinc-clinical-sources/yadrick1989.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "e2d70d43dded75edb026cac237f238d9e59399db6094098796e169f20e819443", "utf8_bytes": 969} [zn-clin-yadrick1989] Iron, copper, and zinc status: response to supplementation with zinc or zinc and iron in adult females. (1989). https://pubmed.ncbi.nlm.nih.gov/2912000/ DOI: 10.1093/ajcn/49.1.145

cross_nutrient

Copper (affected_nutrient); Iron (coadministered_nutrient); Zinc(II) ion (administered_element)

evidence_location

Indexed primary abstract.

evidence_span

{"source_cache": "artifacts/zinc-clinical-sources/yadrick1989.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "e2d70d43dded75edb026cac237f238d9e59399db6094098796e169f20e819443", "utf8_bytes": 969}

experimental_model

Ten-week zinc or zinc-plus-iron intervention in adult women

exposure

50 mg elemental zinc/day as gluconate, with or without 50 mg iron/day as ferrous sulfate monohydrate.

limitations

Reported comparisons are within-group pretreatment versus 10 weeks, not placebo-adjusted effects. ESOD is a functional biomarker, not a diagnosis of symptomatic copper deficiency.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

Adding iron did not prevent the fall in this copper/zinc enzyme marker.

primary_references

[zn-clin-yadrick1989] Iron, copper, and zinc status: response to supplementation with zinc or zinc and iron in adult females. (1989). https://pubmed.ncbi.nlm.nih.gov/2912000/ DOI: 10.1093/ajcn/49.1.145

tissue_or_cell_type

Blood and erythrocytes

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1181–1194

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ten-week zinc or zinc-plus-iron intervention in adult women · source_derived_draft · unverified_draft

### zn-clin-esod-zinc After ten weeks, erythrocyte Cu/Zn-superoxide dismutase activity was lower than pretreatment in both the zinc-only and zinc-plus-iron groups (P<0.05). Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding iron did not prevent the fall in this copper/zinc enzyme marker. organism: Homo sapiens tissue_or_cell_type: Blood and erythrocytes experimental_model: Ten-week zinc or zinc-plus-iron intervention in adult women limitations: Reported comparisons are within-group pretreatment versus 10 weeks, not placebo-adjusted effects. ESOD is a functional biomarker, not a diagnosis of symptomatic copper deficiency. exposure: 50 mg elemental zinc/day as gluconate, with or without 50 mg iron/day as ferrous sulfate monohydrate. cross_nutrient: Copper (affected_nutrient); Iron (coadministered_nutrient); Zinc(II) ion (administered_element) evidence_location: Indexed primary abstract. evidence_span: {"source_cache": "artifacts/zinc-clinical-sources/yadrick1989.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "e2d70d43dded75edb026cac237f238d9e59399db6094098796e169f20e819443", "utf8_bytes": 969} [zn-clin-yadrick1989] Iron, copper, and zinc status: response to supplementation with zinc or zinc and iron in adult females. (1989). https://pubmed.ncbi.nlm.nih.gov/2912000/ DOI: 10.1093/ajcn/49.1.145

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Copper (deficient_nutrient); Erythrocyte mean cell volume (reduced_endpoint); Blood neutrophil count (reduced_endpoint); Serum ceruloplasmin concentration (associated_marker)

evidence_location

Indexed primary abstract.

evidence_span

{"source_cache": "artifacts/zinc-clinical-sources/prasad1978.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "7c4b85a9dd24c3e3bfd04414c0add5d0fa2bcc8c15b5e46bded351e2a2f01e3f", "utf8_bytes": 487}

experimental_model

Clinical case and additional observations in adults with sickle cell anemia receiving zinc therapy

exposure

Index patient received zinc as an antisickling intervention for two years; copper was subsequently administered.

limitations

Case evidence in a particular disease setting; dose and formulation are not verified from the abstract. Does not establish incidence or a universal zinc:copper supplement ratio.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

Long zinc treatment was associated with copper shortage and blood-cell changes.

primary_references

[zn-clin-prasad1978] Hypocupremia induced by zinc therapy in adults. (1978). https://pubmed.ncbi.nlm.nih.gov/359844/ DOI: 10.1001/jama.1978.03290200044019

tissue_or_cell_type

Blood copper and hematology

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1407–1420

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Clinical case and additional observations in adults with sickle cell anemia receiving zinc therapy · source_derived_draft · unverified_draft

### zn-clin-hypocupremia An adult with sickle cell anemia developed hypocupremia after two years of zinc therapy, accompanied by microcytosis and relative neutropenia. Additional zinc-treated patients had varying hypoceruloplasminemia. Condition category: nutrient_deficiency nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Long zinc treatment was associated with copper shortage and blood-cell changes. organism: Homo sapiens tissue_or_cell_type: Blood copper and hematology experimental_model: Clinical case and additional observations in adults with sickle cell anemia receiving zinc therapy limitations: Case evidence in a particular disease setting; dose and formulation are not verified from the abstract. Does not establish incidence or a universal zinc:copper supplement ratio. exposure: Index patient received zinc as an antisickling intervention for two years; copper was subsequently administered. cross_nutrient: Copper (deficient_nutrient); Erythrocyte mean cell volume (reduced_endpoint); Blood neutrophil count (reduced_endpoint); Serum ceruloplasmin concentration (associated_marker) evidence_location: Indexed primary abstract. evidence_span: {"source_cache": "artifacts/zinc-clinical-sources/prasad1978.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "7c4b85a9dd24c3e3bfd04414c0add5d0fa2bcc8c15b5e46bded351e2a2f01e3f", "utf8_bytes": 487} [zn-clin-prasad1978] Hypocupremia induced by zinc therapy in adults. (1978). https://pubmed.ncbi.nlm.nih.gov/359844/ DOI: 10.1001/jama.1978.03290200044019

cross_nutrient

Copper (retained_nutrient); Copper bound to rat intestinal metallothioneins (retained_complex)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/479878-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "643b0358984f3caac8a20e3202c14a073d11ff88758c7a9637b6f8523195658b"}

experimental_model

Dietary radiotracer experiments in rats

exposure

High dietary zinc or copper and reciprocal 64Cu/65Zn absorption measurements.

limitations

High animal dietary concentrations are not human intake thresholds. Copper displacement from metallothionein was the authors’ mechanistic interpretation.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Rattus norvegicus

plain_language

Induced binding proteins provide a mechanism for retaining copper in the gut.

primary_references

[zn-sig-479878] Intestinal metallothionein and the mutual antagonism between copper and zinc in the rat. (1979). https://pubmed.ncbi.nlm.nih.gov/479878/ DOI: 10.1016/s0162-0134(00)80054-9

tissue_or_cell_type

Small intestine

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 915–927

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary radiotracer experiments in rats · source_derived_draft · unverified_draft

### zn-sig-copper-mt-retention The increased intestinal 64Cu was predominantly metallothionein-associated; the authors inferred copper displacement of zinc after zinc-induced metallothionein synthesis. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Induced binding proteins provide a mechanism for retaining copper in the gut. organism: Rattus norvegicus tissue_or_cell_type: Small intestine experimental_model: Dietary radiotracer experiments in rats limitations: High animal dietary concentrations are not human intake thresholds. Copper displacement from metallothionein was the authors’ mechanistic interpretation. exposure: High dietary zinc or copper and reciprocal 64Cu/65Zn absorption measurements. cross_nutrient: Copper (retained_nutrient); Copper bound to rat intestinal metallothioneins (retained_complex) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/479878-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "643b0358984f3caac8a20e3202c14a073d11ff88758c7a9637b6f8523195658b"} [zn-sig-479878] Intestinal metallothionein and the mutual antagonism between copper and zinc in the rat. (1979). https://pubmed.ncbi.nlm.nih.gov/479878/ DOI: 10.1016/s0162-0134(00)80054-9

cross_nutrient

Copper (affected_nutrient)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/3968585-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "ca588cec5326d23dd5f8c9b409ea66fc415043b95af456399e495b8131c8f6ed"}

experimental_model

Isolated vascularly perfused intestine from diet-conditioned rats

exposure

Dietary copper/zinc variation for one week versus direct luminal-metal variation.

limitations

Ex-vivo perfusion and extreme luminal exposure differ from whole-animal feeding; increased metallothionein-bound copper alone did not prove reduced net absorption.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Rattus norvegicus

plain_language

At high luminal exposure, copper entry or transfer was inhibited.

primary_references

[zn-sig-3968585] Copper and zinc absorption in the rat: mechanism of mutual antagonism. (1985). https://pubmed.ncbi.nlm.nih.gov/3968585/ DOI: 10.1093/jn/115.2.159

tissue_or_cell_type

Small-intestinal mucosa and portal effluent

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 957–969

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated vascularly perfused intestine from diet-conditioned rats · source_derived_draft · unverified_draft

### zn-sig-luminal-zinc-copper High luminal zinc reduced both mucosal cytosolic copper and copper transfer into portal effluent in the perfused-rat-intestine experiments. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: At high luminal exposure, copper entry or transfer was inhibited. organism: Rattus norvegicus tissue_or_cell_type: Small-intestinal mucosa and portal effluent experimental_model: Isolated vascularly perfused intestine from diet-conditioned rats limitations: Ex-vivo perfusion and extreme luminal exposure differ from whole-animal feeding; increased metallothionein-bound copper alone did not prove reduced net absorption. exposure: Dietary copper/zinc variation for one week versus direct luminal-metal variation. cross_nutrient: Copper (affected_nutrient) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/3968585-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "ca588cec5326d23dd5f8c9b409ea66fc415043b95af456399e495b8131c8f6ed"} [zn-sig-3968585] Copper and zinc absorption in the rat: mechanism of mutual antagonism. (1985). https://pubmed.ncbi.nlm.nih.gov/3968585/ DOI: 10.1093/jn/115.2.159

cross_nutrient

Copper (affected_nutrient); Intestinal copper absorption (unchanged_endpoint); Rat intestinal metallothioneins measured without isoform resolution (binding_proteins)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/3968585-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "ca588cec5326d23dd5f8c9b409ea66fc415043b95af456399e495b8131c8f6ed"}

experimental_model

Isolated vascularly perfused intestine from diet-conditioned rats

exposure

Dietary copper/zinc variation for one week versus direct luminal-metal variation.

limitations

Ex-vivo perfusion and extreme luminal exposure differ from whole-animal feeding; increased metallothionein-bound copper alone did not prove reduced net absorption.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Rattus norvegicus

plain_language

More copper on a binding protein did not always mean less copper absorption.

primary_references

[zn-sig-3968585] Copper and zinc absorption in the rat: mechanism of mutual antagonism. (1985). https://pubmed.ncbi.nlm.nih.gov/3968585/ DOI: 10.1093/jn/115.2.159

tissue_or_cell_type

Small-intestinal mucosa and portal effluent

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 943–955

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated vascularly perfused intestine from diet-conditioned rats · source_derived_draft · unverified_draft

### zn-sig-mt-binding-not-absorption After the tested dietary conditioning, high zinc increased metallothionein-bound copper without changing intracellular copper concentration or significantly altering measured copper absorption in the perfused intestine. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: More copper on a binding protein did not always mean less copper absorption. organism: Rattus norvegicus tissue_or_cell_type: Small-intestinal mucosa and portal effluent experimental_model: Isolated vascularly perfused intestine from diet-conditioned rats limitations: Ex-vivo perfusion and extreme luminal exposure differ from whole-animal feeding; increased metallothionein-bound copper alone did not prove reduced net absorption. exposure: Dietary copper/zinc variation for one week versus direct luminal-metal variation. cross_nutrient: Copper (affected_nutrient); Intestinal copper absorption (unchanged_endpoint); Rat intestinal metallothioneins measured without isoform resolution (binding_proteins) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/3968585-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "ca588cec5326d23dd5f8c9b409ea66fc415043b95af456399e495b8131c8f6ed"} [zn-sig-3968585] Copper and zinc absorption in the rat: mechanism of mutual antagonism. (1985). https://pubmed.ncbi.nlm.nih.gov/3968585/ DOI: 10.1093/jn/115.2.159

cross_nutrient

Copper (affected_nutrient); Intestinal mucosal copper retention (increased_endpoint)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/479878-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "643b0358984f3caac8a20e3202c14a073d11ff88758c7a9637b6f8523195658b"}

experimental_model

Dietary radiotracer experiments in rats

exposure

High dietary zinc or copper and reciprocal 64Cu/65Zn absorption measurements.

limitations

High animal dietary concentrations are not human intake thresholds. Copper displacement from metallothionein was the authors’ mechanistic interpretation.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Rattus norvegicus

plain_language

Very high zinc trapped more copper in the intestine while less was absorbed.

primary_references

[zn-sig-479878] Intestinal metallothionein and the mutual antagonism between copper and zinc in the rat. (1979). https://pubmed.ncbi.nlm.nih.gov/479878/ DOI: 10.1016/s0162-0134(00)80054-9

tissue_or_cell_type

Small intestine

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 901–913

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary radiotracer experiments in rats · source_derived_draft · unverified_draft

### zn-sig-zinc-copper-absorption Rat diets with zinc up to 450 mg/kg did not change 64Cu absorption; 900 mg/kg reduced it by about 40% and increased mucosal 64Cu uptake. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Very high zinc trapped more copper in the intestine while less was absorbed. organism: Rattus norvegicus tissue_or_cell_type: Small intestine experimental_model: Dietary radiotracer experiments in rats limitations: High animal dietary concentrations are not human intake thresholds. Copper displacement from metallothionein was the authors’ mechanistic interpretation. exposure: High dietary zinc or copper and reciprocal 64Cu/65Zn absorption measurements. cross_nutrient: Copper (affected_nutrient); Intestinal mucosal copper retention (increased_endpoint) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/479878-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "643b0358984f3caac8a20e3202c14a073d11ff88758c7a9637b6f8523195658b"} [zn-sig-479878] Intestinal metallothionein and the mutual antagonism between copper and zinc in the rat. (1979). https://pubmed.ncbi.nlm.nih.gov/479878/ DOI: 10.1016/s0162-0134(00)80054-9

evidence_access

Primary abstract

experimental_model

Single oral radiocopper dose to 10-12-day-old rats; 0.93 mg Cu/L with 10 mg fulvic/L; chemical fractionation.

limitations

Binding is not evidence of improved systemic delivery.

nutrient_topic

Fulvic acid collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Fulvic acid (heterogeneous humic fraction)

plain_language

Copper can bind components of the mixture.

primary_references

Intestinal absorption of copper from drinking water containing fulvic acids and an infant formula mixture studied in a suckling rat model. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10406087/ · DOI 10.1023/a:1009233802104

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 76–82

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Single oral radiocopper dose to 10-12-day-old rats; 0.93 mg Cu/L with 10 mg fulvic/L; chemical fractionation. · source_derived_draft · unverified_draft

## fulvic-acid-copper-binding Copper can bind components of the mixture. Dialysis and centrifugation showed copper association with the tested fulvic mixture. Model: Single oral radiocopper dose to 10-12-day-old rats; 0.93 mg Cu/L with 10 mg fulvic/L; chemical fractionation. Limitations: Binding is not evidence of improved systemic delivery. Evidence access: Primary abstract Intestinal absorption of copper from drinking water containing fulvic acids and an infant formula mixture studied in a suckling rat model. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10406087/ · DOI 10.1023/a:1009233802104

evidence_access

Primary abstract

experimental_model

Suckling-rat tracer study; water and formula matrices.

limitations

The abstract switches to Cd when describing circulatory absorption. That sentence is not silently treated as a verified copper result; no infant recommendation follows.

nutrient_topic

Fulvic acid collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Fulvic acid (heterogeneous humic fraction)

plain_language

Copper stayed in the intestinal lining longer.

primary_references

Intestinal absorption of copper from drinking water containing fulvic acids and an infant formula mixture studied in a suckling rat model. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10406087/ · DOI 10.1023/a:1009233802104

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 84–90

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Suckling-rat tracer study; water and formula matrices. · source_derived_draft · unverified_draft

## fulvic-acid-copper-retention Copper stayed in the intestinal lining longer. Fulvic exposure increased intestinal mucosal copper retention at six hours without markedly changing lumen-to-mucosa uptake. Model: Suckling-rat tracer study; water and formula matrices. Limitations: The abstract switches to Cd when describing circulatory absorption. That sentence is not silently treated as a verified copper result; no infant recommendation follows. Evidence access: Primary abstract Intestinal absorption of copper from drinking water containing fulvic acids and an infant formula mixture studied in a suckling rat model. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10406087/ · DOI 10.1023/a:1009233802104

evidence_access

Primary full text

experimental_model

Zebrafish larvae; FulvoFeed for 96 hours, wash, then copper 50 micromolar for 2 hours; ROS fluorescence assay.

limitations

mg C/L expresses organic carbon, not supplement mass. Washing reduced direct external copper-complexation confounding. ROS is an indirect inflammatory endpoint; proposed radical/aromatic explanations were not isolated genetic or binding tests. This is a concentration-dependent result, not an unexplained contradiction with the lower-dose result.

nutrient_topic

Fulvic acid collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Fulvic acid (heterogeneous humic fraction)

plain_language

Higher tested exposures amplified the same stress readout.

primary_references

Modification of the chemically induced inflammation assay reveals the Janus face of a phenol rich fulvic acid. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35393468/ · DOI 10.1038/s41598-022-09782-w

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 204–210

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Zebrafish larvae; FulvoFeed for 96 hours, wash, then copper 50 micromolar for 2 hours; ROS fluorescence assay. · source_derived_draft · unverified_draft

## fulvic-acid-zebrafish-high Higher tested exposures amplified the same stress readout. FulvoFeed at 300 or 500 mg C/L increased the subsequent copper-associated ROS response. Model: Zebrafish larvae; FulvoFeed for 96 hours, wash, then copper 50 micromolar for 2 hours; ROS fluorescence assay. Limitations: mg C/L expresses organic carbon, not supplement mass. Washing reduced direct external copper-complexation confounding. ROS is an indirect inflammatory endpoint; proposed radical/aromatic explanations were not isolated genetic or binding tests. This is a concentration-dependent result, not an unexplained contradiction with the lower-dose result. Evidence access: Primary full text Modification of the chemically induced inflammation assay reveals the Janus face of a phenol rich fulvic acid. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35393468/ · DOI 10.1038/s41598-022-09782-w

evidence_access

Primary full text

experimental_model

Zebrafish larvae; FulvoFeed for 96 hours, wash, then copper 50 micromolar for 2 hours; ROS fluorescence assay.

limitations

mg C/L expresses organic carbon, not supplement mass. Washing reduced direct external copper-complexation confounding. ROS is an indirect inflammatory endpoint; proposed radical/aromatic explanations were not isolated genetic or binding tests.

nutrient_topic

Fulvic acid collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Fulvic acid (heterogeneous humic fraction)

plain_language

Lower tested exposures dampened the stress readout.

primary_references

Modification of the chemically induced inflammation assay reveals the Janus face of a phenol rich fulvic acid. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35393468/ · DOI 10.1038/s41598-022-09782-w

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 196–202

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Zebrafish larvae; FulvoFeed for 96 hours, wash, then copper 50 micromolar for 2 hours; ROS fluorescence assay. · source_derived_draft · unverified_draft

## fulvic-acid-zebrafish-low Lower tested exposures dampened the stress readout. FulvoFeed at 5 or 50 mg C/L reduced the subsequent copper-associated ROS response. Model: Zebrafish larvae; FulvoFeed for 96 hours, wash, then copper 50 micromolar for 2 hours; ROS fluorescence assay. Limitations: mg C/L expresses organic carbon, not supplement mass. Washing reduced direct external copper-complexation confounding. ROS is an indirect inflammatory endpoint; proposed radical/aromatic explanations were not isolated genetic or binding tests. Evidence access: Primary full text Modification of the chemically induced inflammation assay reveals the Janus face of a phenol rich fulvic acid. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35393468/ · DOI 10.1038/s41598-022-09782-w

evidence_span

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experimental_model

Cell-free oxidation and cultured-cell injury assays

exposure

Dopamine with and without copper; theanine concentration-ratio experiments

limitations

High experimental substrate ratios; no human copper-depletion, Parkinson disease treatment or systemic chelation conclusion. Cellular protection does not establish effective brain exposure.

nutrient_topic

L-Theanine research collection; topical membership is not evidence of a direct dietary effect. · L-Theanine

organism

Human SH-SY5Y cell line and chemical systems

plain_language

Cell survival was measured separately from the chemical oxidation assay.

primary_references

[theanine-p39499422] L-Theanine Effectively Protects Against Copper-Facilitated Dopamine Oxidation: Implication for Relieving Dopamine Overflow-Associated Neurotoxicities. (2025). https://pubmed.ncbi.nlm.nih.gov/39499422/ DOI: 10.1007/s12035-024-04601-x

tissue_or_cell_type

Copper-facilitated dopamine oxidation

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 744–755

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-free oxidation and cultured-cell injury assays · source_derived_draft · unverified_draft

### theanine-copper-cell-protection Theanine protected SH-SY5Y cells against the injury produced by dopamine plus copper. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cell survival was measured separately from the chemical oxidation assay. organism: Human SH-SY5Y cell line and chemical systems tissue_or_cell_type: Copper-facilitated dopamine oxidation experimental_model: Cell-free oxidation and cultured-cell injury assays limitations: High experimental substrate ratios; no human copper-depletion, Parkinson disease treatment or systemic chelation conclusion. Cellular protection does not establish effective brain exposure. exposure: Dopamine with and without copper; theanine concentration-ratio experiments evidence_span: {"source_cache": "artifacts/theanine-research/39499422.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "abb7a869056bc8c43d6792b2a4ff9a1b15738facf454daeb3f92df383932b9c4", "start_char": 0, "end_char": 1871, "text_sha256": "abb7a869056bc8c43d6792b2a4ff9a1b15738facf454daeb3f92df383932b9c4"} [theanine-p39499422] L-Theanine Effectively Protects Against Copper-Facilitated Dopamine Oxidation: Implication for Relieving Dopamine Overflow-Associated Neurotoxicities. (2025). https://pubmed.ncbi.nlm.nih.gov/39499422/ DOI: 10.1007/s12035-024-04601-x

evidence_span

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experimental_model

Cell-free oxidation and cultured-cell injury assays

exposure

Dopamine with and without copper; theanine concentration-ratio experiments

limitations

High experimental substrate ratios; no human copper-depletion, Parkinson disease treatment or systemic chelation conclusion. Cellular protection does not establish effective brain exposure.

nutrient_topic

L-Theanine research collection; topical membership is not evidence of a direct dietary effect. · L-Theanine

organism

Human SH-SY5Y cell line and chemical systems

plain_language

Copper changed the chemistry of dopamine oxidation, and theanine interfered with that chemistry in the assay.

primary_references

[theanine-p39499422] L-Theanine Effectively Protects Against Copper-Facilitated Dopamine Oxidation: Implication for Relieving Dopamine Overflow-Associated Neurotoxicities. (2025). https://pubmed.ncbi.nlm.nih.gov/39499422/ DOI: 10.1007/s12035-024-04601-x

tissue_or_cell_type

Copper-facilitated dopamine oxidation

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 731–742

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-free oxidation and cultured-cell injury assays · source_derived_draft · unverified_draft

### theanine-copper-dopamine-oxidation Theanine suppressed copper-facilitated dopamine oxidation; the authors attributed this to copper chelation. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Copper changed the chemistry of dopamine oxidation, and theanine interfered with that chemistry in the assay. organism: Human SH-SY5Y cell line and chemical systems tissue_or_cell_type: Copper-facilitated dopamine oxidation experimental_model: Cell-free oxidation and cultured-cell injury assays limitations: High experimental substrate ratios; no human copper-depletion, Parkinson disease treatment or systemic chelation conclusion. Cellular protection does not establish effective brain exposure. exposure: Dopamine with and without copper; theanine concentration-ratio experiments evidence_span: {"source_cache": "artifacts/theanine-research/39499422.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "abb7a869056bc8c43d6792b2a4ff9a1b15738facf454daeb3f92df383932b9c4", "start_char": 0, "end_char": 1871, "text_sha256": "abb7a869056bc8c43d6792b2a4ff9a1b15738facf454daeb3f92df383932b9c4"} [theanine-p39499422] L-Theanine Effectively Protects Against Copper-Facilitated Dopamine Oxidation: Implication for Relieving Dopamine Overflow-Associated Neurotoxicities. (2025). https://pubmed.ncbi.nlm.nih.gov/39499422/ DOI: 10.1007/s12035-024-04601-x

evidence_access

Primary full text

experimental_model

Reconstituted human LAT1; radiotracer uptake, copper mass spectrometry and mutagenesis; representative assay 40 micromolar histidine plus 20 micromolar copper sulfate.

limitations

This in-vitro uniport finding does not establish human copper delivery, safety or treatment efficacy.

nutrient_topic

L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine

plain_language

Binding copper changed how the histidine-containing species crossed this transporter.

primary_references

LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanism. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37692288/ · DOI 10.1016/j.isci.2023.107738

transport_effect

raises Transported without the internal counter-substrate ordinary antiport needs, so this record is a uniport measurement.

transport_pool

the proteoliposome interior Transported without the internal counter-substrate ordinary antiport needs, so this record is a uniport measurement.

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 82–88

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Reconstituted human LAT1; radiotracer uptake, copper mass spectrometry and mutagenesis; representative assay 40 micromolar histidine plus 20 micromolar copper sulfate. · source_derived_draft · unverified_draft

## histidine-lat1-copper-complex Binding copper changed how the histidine-containing species crossed this transporter. Purified human LAT1 transported Cu(His)2 without the internal counter-substrate required for ordinary amino-acid antiport. Model: Reconstituted human LAT1; radiotracer uptake, copper mass spectrometry and mutagenesis; representative assay 40 micromolar histidine plus 20 micromolar copper sulfate. Limitations: This in-vitro uniport finding does not establish human copper delivery, safety or treatment efficacy. Evidence access: Primary full text LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanism. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37692288/ · DOI 10.1016/j.isci.2023.107738

evidence_span

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experimental_model

Steady-state kinetics of dopamine beta-monooxygenase with structurally distinct reductants

exposure

Ascorbate, ferrocyanide or dopamine itself as the reducing agent, with deuterium isotope effects

limitations

A kinetic comparison identifying ascorbate as the presumed physiological reductant and locating a separate binding site for it. Truncated abstract; the reductant site is inferred from kinetics and modelling.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Bovine enzyme

plain_language

Vitamin C is what hands the enzyme back its electrons, and without it the reaction crawls.

primary_references

[cold-p3676254] Characterization of alternate reductant binding and electron transfer in the dopamine beta-monooxygenase reaction. (1987). https://pubmed.ncbi.nlm.nih.gov/3676254/ DOI: 10.1021/bi00391a013

tissue_or_cell_type

Purified enzyme

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 585–596

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Steady-state kinetics of dopamine beta-monooxygenase with structurally distinct reductants · source_derived_draft · unverified_draft

### cold-ascorbate-reductant Ascorbate is the presumed in vivo reductant of dopamine beta-monooxygenase; the one-electron reductant ferrocyanide was nearly as kinetically competent, while dopamine as sole reductant reduced enzymic copper in a rate-limiting step 40-fold slower than with ascorbate, and the reductant binds at a site physically distinct from the substrate site. Condition category: normal nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Vitamin C is what hands the enzyme back its electrons, and without it the reaction crawls. organism: Bovine enzyme tissue_or_cell_type: Purified enzyme experimental_model: Steady-state kinetics of dopamine beta-monooxygenase with structurally distinct reductants limitations: A kinetic comparison identifying ascorbate as the presumed physiological reductant and locating a separate binding site for it. Truncated abstract; the reductant site is inferred from kinetics and modelling. exposure: Ascorbate, ferrocyanide or dopamine itself as the reducing agent, with deuterium isotope effects evidence_span: {"source_cache": "artifacts/cold-research/3676254.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e929132eed0f1c94ab0bdbef6e31bca7ecbed222cf9b585e17a1cfae7e93c82a", "start_char": 0, "end_char": 1648, "text_sha256": "e929132eed0f1c94ab0bdbef6e31bca7ecbed222cf9b585e17a1cfae7e93c82a"} [cold-p3676254] Characterization of alternate reductant binding and electron transfer in the dopamine beta-monooxygenase reaction. (1987). https://pubmed.ncbi.nlm.nih.gov/3676254/ DOI: 10.1021/bi00391a013

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

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experimental_model

Copper titration of bovine adrenal dopamine beta-hydroxylase followed by NMR, EPR and inhibitor kinetics

exposure

Titration with copper and measurement of catalytic rate

limitations

Stoichiometry measured three independent ways. It establishes how much copper the enzyme needs, not how much copper a person needs.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Bovine enzyme

plain_language

Short the enzyme of copper and it runs proportionally slower.

primary_references

[cold-p6323422] Kinetic and spectroscopic studies of the interaction of copper with dopamine beta-hydroxylase. (1984). https://pubmed.ncbi.nlm.nih.gov/6323422/ DOI: 10.1016/s0021-9258(17)43105-x

tissue_or_cell_type

Adrenal medulla enzyme

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 572–583

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Copper titration of bovine adrenal dopamine beta-hydroxylase followed by NMR, EPR and inhibitor kinetics · source_derived_draft · unverified_draft

### cold-copper-free-dbh-activity Below a ratio of eight copper atoms per tetramer, the measured rate of enzymatic catalysis rose in proportion to the copper present rather than being maximal. Condition category: nutrient_deficiency nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Short the enzyme of copper and it runs proportionally slower. organism: Bovine enzyme tissue_or_cell_type: Adrenal medulla enzyme experimental_model: Copper titration of bovine adrenal dopamine beta-hydroxylase followed by NMR, EPR and inhibitor kinetics limitations: Stoichiometry measured three independent ways. It establishes how much copper the enzyme needs, not how much copper a person needs. exposure: Titration with copper and measurement of catalytic rate evidence_span: {"source_cache": "artifacts/cold-research/6323422.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dac85ce0ad7c7d5994b97d55b129050a0e7ca8bf96943578d272054db6a07a62", "start_char": 0, "end_char": 1346, "text_sha256": "dac85ce0ad7c7d5994b97d55b129050a0e7ca8bf96943578d272054db6a07a62"} [cold-p6323422] Kinetic and spectroscopic studies of the interaction of copper with dopamine beta-hydroxylase. (1984). https://pubmed.ncbi.nlm.nih.gov/6323422/ DOI: 10.1016/s0021-9258(17)43105-x

evidence_span

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experimental_model

Winter swimmers compared with people who had never taken part, sampled for erythrocyte and plasma antioxidants

exposure

Habitual ice bathing

limitations

A cross-sectional comparison, so self-selection cannot be excluded. The authors frame it as adaptation to repeated oxidative stress.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Human

plain_language

People who swim in ice water carry more antioxidant defence at rest.

primary_references

[cold-p10396606] Improved antioxidative protection in winter swimmers. (1999). https://pubmed.ncbi.nlm.nih.gov/10396606/ DOI: 10.1093/qjmed/92.4.193

tissue_or_cell_type

Erythrocytes and plasma

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 689–700

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Winter swimmers compared with people who had never taken part, sampled for erythrocyte and plasma antioxidants · source_derived_draft · unverified_draft

### cold-winter-swimmer-antioxidants Baseline reduced glutathione concentration and erythrocyte superoxide dismutase and catalase activities were higher in winter swimmers than in controls, which the authors interpret as an adaptive response to repeated oxidative stress and postulate as a mechanism of increased tolerance to environmental stress. Condition category: normal nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: People who swim in ice water carry more antioxidant defence at rest. organism: Human tissue_or_cell_type: Erythrocytes and plasma experimental_model: Winter swimmers compared with people who had never taken part, sampled for erythrocyte and plasma antioxidants limitations: A cross-sectional comparison, so self-selection cannot be excluded. The authors frame it as adaptation to repeated oxidative stress. exposure: Habitual ice bathing evidence_span: {"source_cache": "artifacts/cold-research/10396606.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fdd2deec82fad8f9e148848c443d5b173ec42c0e07d9045c59773f7109883a7b", "start_char": 0, "end_char": 1139, "text_sha256": "fdd2deec82fad8f9e148848c443d5b173ec42c0e07d9045c59773f7109883a7b"} [cold-p10396606] Improved antioxidative protection in winter swimmers. (1999). https://pubmed.ncbi.nlm.nih.gov/10396606/ DOI: 10.1093/qjmed/92.4.193

cross_nutrient

Copper and zinc cofactor identity in SOD1 is distinguished from Mn-dependent SOD2.

experimental_model

NMR of copper-depleted human SOD1 C6A/C111S preparation

exposure

Copper-depleted zinc-containing disulfide-reduced preparation

limitations

The study structurally examined the C6A/C111S copper-depleted, zinc-containing preparation. This identity statement does not assert Mn can replace either SOD1 metal.

nutrient_topic

Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese

organism

Homo sapiens protein

plain_language

SOD1 and SOD2 use different metals.

primary_references

[mn-enz-16291742] Human SOD1 before harboring the catalytic metal: solution structure of copper-depleted, disulfide-reduced form. (2006). https://pubmed.ncbi.nlm.nih.gov/16291742/ DOI: 10.1074/jbc.m506497200

tissue_or_cell_type

Purified SOD1

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 458–469

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · NMR of copper-depleted human SOD1 C6A/C111S preparation · source_derived_draft · unverified_draft

### mn-enz-sod1-distinct-metals Human SOD1 maturation involves copper and zinc insertion and a Cys57–Cys146 disulfide; this is a different metalloprotein system from manganese SOD2. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: SOD1 and SOD2 use different metals. organism: Homo sapiens protein tissue_or_cell_type: Purified SOD1 experimental_model: NMR of copper-depleted human SOD1 C6A/C111S preparation limitations: The study structurally examined the C6A/C111S copper-depleted, zinc-containing preparation. This identity statement does not assert Mn can replace either SOD1 metal. exposure: Copper-depleted zinc-containing disulfide-reduced preparation cross_nutrient: Copper and zinc cofactor identity in SOD1 is distinguished from Mn-dependent SOD2. [mn-enz-16291742] Human SOD1 before harboring the catalytic metal: solution structure of copper-depleted, disulfide-reduced form. (2006). https://pubmed.ncbi.nlm.nih.gov/16291742/ DOI: 10.1074/jbc.m506497200

availability_state

nutrient_deficiency Imported condition classification; unverified.

dose

Dietary copper 6 or 1.6 mg/kg diet; water with or without 30% w/v fructose

duration

4 weeks

evidence_access

Primary full-text methods/results and metadata inspected.

evidence_scope

literature_reviewed; source-specific curation

experimental_model

Male weanling Sprague-Dawley rats

exposure_scope

Isolated fructose with copper restriction

limitations

High-fructose component experiment. Copper concentrations refer to diet, not body weight. Ctr1 expression is not direct copper flux, and human HFCS-induced copper deficiency is not established.

nutrient_topic

HFCS chapter: actual formulation studies, component biochemistry and interventions are explicitly distinguished. · High-Fructose Corn Syrup / HFCS

organism

Male weanling Sprague-Dawley rats

plain_language

The combination of marginal copper deficiency and fructose feeding increased hepatic triglyceride and liver injury in rats.

primary_references

High fructose feeding induces copper deficiency in Sprague-Dawley rats: a novel mechanism for obesity related fatty liver. (2012). https://pubmed.ncbi.nlm.nih.gov/21781943/ DOI: 10.1016/j.jhep.2011.05.030

route

Oral diet and drinking water

tissue

Copper status, duodenum and hepatic triglyceride

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

High-Fructose Corn Syrup: mechanism of action and metabolic impact (2026-09-20) · lines 521–531

Original AI-assisted curation of twenty primary studies and official FDA composition information, with one reused canonical glucose-transport claim. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · Male weanling Sprague-Dawley rats · source_derived_draft · unverified_draft

## hfcs-copper-liver The combination of marginal copper deficiency and fructose feeding increased hepatic triglyceride and liver injury in rats. Model/species: Male weanling Sprague-Dawley rats Tissue: Copper status, duodenum and hepatic triglyceride Exposure: Dietary copper 6 or 1.6 mg/kg diet; water with or without 30% w/v fructose Route: Oral diet and drinking water Duration: 4 weeks Exposure scope: Isolated fructose with copper restriction Limits: High-fructose component experiment. Copper concentrations refer to diet, not body weight. Ctr1 expression is not direct copper flux, and human HFCS-induced copper deficiency is not established. Reference: High fructose feeding induces copper deficiency in Sprague-Dawley rats: a novel mechanism for obesity related fatty liver. (2012). https://pubmed.ncbi.nlm.nih.gov/21781943/ DOI: 10.1016/j.jhep.2011.05.030 Access: Primary full-text methods/results and metadata inspected.

dose

Dietary copper 6 or 1.6 mg/kg diet; water with or without 30% w/v fructose

duration

4 weeks

evidence_access

Primary full-text methods/results and metadata inspected.

evidence_scope

literature_reviewed; source-specific curation

experimental_model

Male weanling Sprague-Dawley rats

exposure_scope

Isolated fructose with copper restriction

limitations

High-fructose component experiment. Copper concentrations refer to diet, not body weight. Ctr1 expression is not direct copper flux, and human HFCS-induced copper deficiency is not established.

nutrient_topic

HFCS chapter: actual formulation studies, component biochemistry and interventions are explicitly distinguished. · High-Fructose Corn Syrup / HFCS

organism

Male weanling Sprague-Dawley rats

plain_language

High-fructose feeding worsened copper status in the rat dietary experiment.

primary_references

High fructose feeding induces copper deficiency in Sprague-Dawley rats: a novel mechanism for obesity related fatty liver. (2012). https://pubmed.ncbi.nlm.nih.gov/21781943/ DOI: 10.1016/j.jhep.2011.05.030

route

Oral diet and drinking water

tissue

Copper status, duodenum and hepatic triglyceride

High-Fructose Corn Syrup: mechanism of action and metabolic impact (2026-09-20) · lines 497–507

Original AI-assisted curation of twenty primary studies and official FDA composition information, with one reused canonical glucose-transport claim. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · Male weanling Sprague-Dawley rats · source_derived_draft · unverified_draft

## hfcs-copper-status High-fructose feeding worsened copper status in the rat dietary experiment. Model/species: Male weanling Sprague-Dawley rats Tissue: Copper status, duodenum and hepatic triglyceride Exposure: Dietary copper 6 or 1.6 mg/kg diet; water with or without 30% w/v fructose Route: Oral diet and drinking water Duration: 4 weeks Exposure scope: Isolated fructose with copper restriction Limits: High-fructose component experiment. Copper concentrations refer to diet, not body weight. Ctr1 expression is not direct copper flux, and human HFCS-induced copper deficiency is not established. Reference: High fructose feeding induces copper deficiency in Sprague-Dawley rats: a novel mechanism for obesity related fatty liver. (2012). https://pubmed.ncbi.nlm.nih.gov/21781943/ DOI: 10.1016/j.jhep.2011.05.030 Access: Primary full-text methods/results and metadata inspected.

availability_state

nutrient_deficiency Imported condition classification; unverified.

dose

Dietary copper 6 or 1.6 mg/kg diet; water with or without 30% w/v fructose

duration

4 weeks

evidence_access

Primary full-text methods/results and metadata inspected.

evidence_scope

literature_reviewed; source-specific curation

experimental_model

Male weanling Sprague-Dawley rats

exposure_scope

Isolated fructose with copper restriction

limitations

High-fructose component experiment. Copper concentrations refer to diet, not body weight. Ctr1 expression is not direct copper flux, and human HFCS-induced copper deficiency is not established.

nutrient_topic

HFCS chapter: actual formulation studies, component biochemistry and interventions are explicitly distinguished. · High-Fructose Corn Syrup / HFCS

organism

Male weanling Sprague-Dawley rats

plain_language

Fructose feeding prevented the duodenal Ctr1 increase otherwise observed with marginal copper deficiency in rats.

primary_references

High fructose feeding induces copper deficiency in Sprague-Dawley rats: a novel mechanism for obesity related fatty liver. (2012). https://pubmed.ncbi.nlm.nih.gov/21781943/ DOI: 10.1016/j.jhep.2011.05.030

route

Oral diet and drinking water

tissue

Copper status, duodenum and hepatic triglyceride

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

High-Fructose Corn Syrup: mechanism of action and metabolic impact (2026-09-20) · lines 509–519

Original AI-assisted curation of twenty primary studies and official FDA composition information, with one reused canonical glucose-transport claim. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · Male weanling Sprague-Dawley rats · source_derived_draft · unverified_draft

## hfcs-copper-transporter Fructose feeding prevented the duodenal Ctr1 increase otherwise observed with marginal copper deficiency in rats. Model/species: Male weanling Sprague-Dawley rats Tissue: Copper status, duodenum and hepatic triglyceride Exposure: Dietary copper 6 or 1.6 mg/kg diet; water with or without 30% w/v fructose Route: Oral diet and drinking water Duration: 4 weeks Exposure scope: Isolated fructose with copper restriction Limits: High-fructose component experiment. Copper concentrations refer to diet, not body weight. Ctr1 expression is not direct copper flux, and human HFCS-induced copper deficiency is not established. Reference: High fructose feeding induces copper deficiency in Sprague-Dawley rats: a novel mechanism for obesity related fatty liver. (2012). https://pubmed.ncbi.nlm.nih.gov/21781943/ DOI: 10.1016/j.jhep.2011.05.030 Access: Primary full-text methods/results and metadata inspected.

evidence_span

{"source_cache": "artifacts/lutein-research/24310343.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "617cbda47a00c8fc552395a255003b013afa72aca6640c5c2e49d2b4caf09a72", "start_char": 0, "end_char": 2419, "text_sha256": "617cbda47a00c8fc552395a255003b013afa72aca6640c5c2e49d2b4caf09a72"}

experimental_model

Exploratory secondary analyses of AREDS2

exposure

L+Z 10/2 mg; direct comparison with beta-carotene on AREDS background

limitations

Exploratory contrasts and different confidence thresholds do not contradict the prespecified primary analysis.

nutrient_topic

Lutein research collection; topical membership is not evidence of a direct dietary effect. · Lutein

organism

Same AREDS2 cohort, not an independent replication

plain_language

The same comparison did not show benefit for every subtype.

primary_references

[lutein-p24310343] Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. (2014). https://pubmed.ncbi.nlm.nih.gov/24310343/ DOI: 10.1001/jamaophthalmol.2013.7376

tissue_or_cell_type

Late AMD subtypes

Lutein: metabolism, signaling and nutrient connections (2026-09-17) · lines 775–786

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Exploratory secondary analyses of AREDS2 · source_derived_draft · unverified_draft

### lutein-areds-replacement-atrophy-null Central geographic atrophy HR was 0.94 (95% CI 0.70–1.26), without a significant difference. Condition category: normal nutrient_topic: Lutein research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same comparison did not show benefit for every subtype. organism: Same AREDS2 cohort, not an independent replication tissue_or_cell_type: Late AMD subtypes experimental_model: Exploratory secondary analyses of AREDS2 limitations: Exploratory contrasts and different confidence thresholds do not contradict the prespecified primary analysis. exposure: L+Z 10/2 mg; direct comparison with beta-carotene on AREDS background evidence_span: {"source_cache": "artifacts/lutein-research/24310343.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "617cbda47a00c8fc552395a255003b013afa72aca6640c5c2e49d2b4caf09a72", "start_char": 0, "end_char": 2419, "text_sha256": "617cbda47a00c8fc552395a255003b013afa72aca6640c5c2e49d2b4caf09a72"} [lutein-p24310343] Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. (2014). https://pubmed.ncbi.nlm.nih.gov/24310343/ DOI: 10.1001/jamaophthalmol.2013.7376

evidence_span

{"source_cache": "artifacts/lutein-research/24310343.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "617cbda47a00c8fc552395a255003b013afa72aca6640c5c2e49d2b4caf09a72", "start_char": 0, "end_char": 2419, "text_sha256": "617cbda47a00c8fc552395a255003b013afa72aca6640c5c2e49d2b4caf09a72"}

experimental_model

Exploratory secondary analyses of AREDS2

exposure

L+Z 10/2 mg; direct comparison with beta-carotene on AREDS background

limitations

Exploratory contrasts and different confidence thresholds do not contradict the prespecified primary analysis.

nutrient_topic

Lutein research collection; topical membership is not evidence of a direct dietary effect. · Lutein

organism

Same AREDS2 cohort, not an independent replication

plain_language

Replacement comparison favored the xanthophyll pair.

primary_references

[lutein-p24310343] Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. (2014). https://pubmed.ncbi.nlm.nih.gov/24310343/ DOI: 10.1001/jamaophthalmol.2013.7376

tissue_or_cell_type

Late AMD subtypes

Lutein: metabolism, signaling and nutrient connections (2026-09-17) · lines 749–760

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Exploratory secondary analyses of AREDS2 · source_derived_draft · unverified_draft

### lutein-areds-replacement-late Exploratory L+Z versus beta-carotene comparison gave late-AMD HR 0.82 (95% CI 0.69–0.96). Condition category: normal nutrient_topic: Lutein research collection; topical membership is not evidence of a direct dietary effect. plain_language: Replacement comparison favored the xanthophyll pair. organism: Same AREDS2 cohort, not an independent replication tissue_or_cell_type: Late AMD subtypes experimental_model: Exploratory secondary analyses of AREDS2 limitations: Exploratory contrasts and different confidence thresholds do not contradict the prespecified primary analysis. exposure: L+Z 10/2 mg; direct comparison with beta-carotene on AREDS background evidence_span: {"source_cache": "artifacts/lutein-research/24310343.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "617cbda47a00c8fc552395a255003b013afa72aca6640c5c2e49d2b4caf09a72", "start_char": 0, "end_char": 2419, "text_sha256": "617cbda47a00c8fc552395a255003b013afa72aca6640c5c2e49d2b4caf09a72"} [lutein-p24310343] Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. (2014). https://pubmed.ncbi.nlm.nih.gov/24310343/ DOI: 10.1001/jamaophthalmol.2013.7376

evidence_span

{"source_cache": "artifacts/lutein-research/24310343.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "617cbda47a00c8fc552395a255003b013afa72aca6640c5c2e49d2b4caf09a72", "start_char": 0, "end_char": 2419, "text_sha256": "617cbda47a00c8fc552395a255003b013afa72aca6640c5c2e49d2b4caf09a72"}

experimental_model

Exploratory secondary analyses of AREDS2

exposure

L+Z 10/2 mg; direct comparison with beta-carotene on AREDS background

limitations

Exploratory contrasts and different confidence thresholds do not contradict the prespecified primary analysis.

nutrient_topic

Lutein research collection; topical membership is not evidence of a direct dietary effect. · Lutein

organism

Same AREDS2 cohort, not an independent replication

plain_language

The subtype result favored the pair for neovascular AMD.

primary_references

[lutein-p24310343] Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. (2014). https://pubmed.ncbi.nlm.nih.gov/24310343/ DOI: 10.1001/jamaophthalmol.2013.7376

tissue_or_cell_type

Late AMD subtypes

Lutein: metabolism, signaling and nutrient connections (2026-09-17) · lines 762–773

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Exploratory secondary analyses of AREDS2 · source_derived_draft · unverified_draft

### lutein-areds-replacement-neovascular The corresponding neovascular-AMD HR was 0.78 (95% CI 0.64–0.94). Condition category: normal nutrient_topic: Lutein research collection; topical membership is not evidence of a direct dietary effect. plain_language: The subtype result favored the pair for neovascular AMD. organism: Same AREDS2 cohort, not an independent replication tissue_or_cell_type: Late AMD subtypes experimental_model: Exploratory secondary analyses of AREDS2 limitations: Exploratory contrasts and different confidence thresholds do not contradict the prespecified primary analysis. exposure: L+Z 10/2 mg; direct comparison with beta-carotene on AREDS background evidence_span: {"source_cache": "artifacts/lutein-research/24310343.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "617cbda47a00c8fc552395a255003b013afa72aca6640c5c2e49d2b4caf09a72", "start_char": 0, "end_char": 2419, "text_sha256": "617cbda47a00c8fc552395a255003b013afa72aca6640c5c2e49d2b4caf09a72"} [lutein-p24310343] Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. (2014). https://pubmed.ncbi.nlm.nih.gov/24310343/ DOI: 10.1001/jamaophthalmol.2013.7376

evidence_span

{"source_cache": "artifacts/molybdenum-research/19965379.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "166eb55335870bc9843fdb0c61becaa318603b25c601bbfa8f69a469dab89e57", "start_char": 0, "end_char": 950, "text_sha256": "166eb55335870bc9843fdb0c61becaa318603b25c601bbfa8f69a469dab89e57"}

experimental_model

Yeast Atx1 crystallography, spectroscopy and copper-transfer experiments

exposure

Tetrathiomolybdate exposure

limitations

Drug and yeast-protein chemistry; not evidence that normal human dietary molybdate strips copper from proteins.

nutrient_topic

Molybdenum research collection; topical membership is not evidence of a direct dietary effect. · Molybdenum

organism

Saccharomyces cerevisiae proteins; comparison with animal drug complexes

plain_language

A sulfur-rich molybdenum drug can trap copper in a protein complex.

primary_references

[mo-p19965379] Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation. (2010). https://pubmed.ncbi.nlm.nih.gov/19965379/ DOI: 10.1126/science.1179907

tissue_or_cell_type

Purified copper chaperones

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 1600–1611

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Yeast Atx1 crystallography, spectroscopy and copper-transfer experiments · source_derived_draft · unverified_draft

### mo-ttm-copper-cluster Tetrathiomolybdate formed a stable sulfur-bridged copper-molybdenum cluster with yeast Atx1. Condition category: normal nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: A sulfur-rich molybdenum drug can trap copper in a protein complex. organism: Saccharomyces cerevisiae proteins; comparison with animal drug complexes tissue_or_cell_type: Purified copper chaperones experimental_model: Yeast Atx1 crystallography, spectroscopy and copper-transfer experiments limitations: Drug and yeast-protein chemistry; not evidence that normal human dietary molybdate strips copper from proteins. exposure: Tetrathiomolybdate exposure evidence_span: {"source_cache": "artifacts/molybdenum-research/19965379.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "166eb55335870bc9843fdb0c61becaa318603b25c601bbfa8f69a469dab89e57", "start_char": 0, "end_char": 950, "text_sha256": "166eb55335870bc9843fdb0c61becaa318603b25c601bbfa8f69a469dab89e57"} [mo-p19965379] Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation. (2010). https://pubmed.ncbi.nlm.nih.gov/19965379/ DOI: 10.1126/science.1179907

evidence_span

{"source_cache": "artifacts/molybdenum-research/19965379.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "166eb55335870bc9843fdb0c61becaa318603b25c601bbfa8f69a469dab89e57", "start_char": 0, "end_char": 950, "text_sha256": "166eb55335870bc9843fdb0c61becaa318603b25c601bbfa8f69a469dab89e57"}

experimental_model

Yeast Atx1 crystallography, spectroscopy and copper-transfer experiments

exposure

Tetrathiomolybdate exposure

limitations

Drug and yeast-protein chemistry; not evidence that normal human dietary molybdate strips copper from proteins.

nutrient_topic

Molybdenum research collection; topical membership is not evidence of a direct dietary effect. · Molybdenum

organism

Saccharomyces cerevisiae proteins; comparison with animal drug complexes

plain_language

Trapping the copper interrupted its handoff to another protein.

primary_references

[mo-p19965379] Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation. (2010). https://pubmed.ncbi.nlm.nih.gov/19965379/ DOI: 10.1126/science.1179907

tissue_or_cell_type

Purified copper chaperones

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 1613–1624

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Yeast Atx1 crystallography, spectroscopy and copper-transfer experiments · source_derived_draft · unverified_draft

### mo-ttm-copper-transfer The drug-Atx1 complex inhibited copper transfer between copper-trafficking proteins in the experimental system. Condition category: normal nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: Trapping the copper interrupted its handoff to another protein. organism: Saccharomyces cerevisiae proteins; comparison with animal drug complexes tissue_or_cell_type: Purified copper chaperones experimental_model: Yeast Atx1 crystallography, spectroscopy and copper-transfer experiments limitations: Drug and yeast-protein chemistry; not evidence that normal human dietary molybdate strips copper from proteins. exposure: Tetrathiomolybdate exposure evidence_span: {"source_cache": "artifacts/molybdenum-research/19965379.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "166eb55335870bc9843fdb0c61becaa318603b25c601bbfa8f69a469dab89e57", "start_char": 0, "end_char": 950, "text_sha256": "166eb55335870bc9843fdb0c61becaa318603b25c601bbfa8f69a469dab89e57"} [mo-p19965379] Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation. (2010). https://pubmed.ncbi.nlm.nih.gov/19965379/ DOI: 10.1126/science.1179907

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/iron-research/27537180.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "59f2a83f1bffcacfed0df109f3690413aa2e6f08be6ad400817c5cbe2165e523", "start_char": 0, "end_char": 1840, "text_sha256": "59f2a83f1bffcacfed0df109f3690413aa2e6f08be6ad400817c5cbe2165e523"}

experimental_model

Five-week factorial iron/copper feeding

exposure

Approximately 8800, 80 or 11 ppm iron crossed with approximately 183, 8 or 0.9 ppm copper

limitations

Very high experimental iron exposure; not an estimate of human supplement risk at ordinary intake. Copper restoration did not normalize every iron measure.

nutrient_topic

Iron research collection; topical membership is not evidence of a direct dietary effect. · Iron

organism

Weanling male Sprague-Dawley rats

plain_language

Anemia developed despite abundant iron because another part of iron handling became deficient.

primary_references

[iron-p27537180] High-Iron Consumption Impairs Growth and Causes Copper-Deficiency Anemia in Weanling Sprague-Dawley Rats. (2016). https://pubmed.ncbi.nlm.nih.gov/27537180/ DOI: 10.1371/journal.pone.0161033

tissue_or_cell_type

Systemic copper and iron status

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Iron: absorption, trafficking, iron-dependent enzymes and nutrient interactions (2026-09-17) · lines 914–925

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Five-week factorial iron/copper feeding · source_derived_draft · unverified_draft

### iron-high-iron-copper-deficiency Very-high-iron feeding caused low serum/tissue copper, reduced circulating ceruloplasmin activity, anemia and cardiac hypertrophy in the studied rats. Condition category: nutrient_deficiency nutrient_topic: Iron research collection; topical membership is not evidence of a direct dietary effect. plain_language: Anemia developed despite abundant iron because another part of iron handling became deficient. organism: Weanling male Sprague-Dawley rats tissue_or_cell_type: Systemic copper and iron status experimental_model: Five-week factorial iron/copper feeding limitations: Very high experimental iron exposure; not an estimate of human supplement risk at ordinary intake. Copper restoration did not normalize every iron measure. exposure: Approximately 8800, 80 or 11 ppm iron crossed with approximately 183, 8 or 0.9 ppm copper evidence_span: {"source_cache": "artifacts/iron-research/27537180.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "59f2a83f1bffcacfed0df109f3690413aa2e6f08be6ad400817c5cbe2165e523", "start_char": 0, "end_char": 1840, "text_sha256": "59f2a83f1bffcacfed0df109f3690413aa2e6f08be6ad400817c5cbe2165e523"} [iron-p27537180] High-Iron Consumption Impairs Growth and Causes Copper-Deficiency Anemia in Weanling Sprague-Dawley Rats. (2016). https://pubmed.ncbi.nlm.nih.gov/27537180/ DOI: 10.1371/journal.pone.0161033