Homocysteine

cross_nutrient

B6-dependent transsulfuration connects methionine/homocysteine to the cysteine supply for glutathione.

experimental_model

Cultured human hepatoma cell line; metabolic sulfur tracing

limitations

Fraction is culture-specific and traces sulfur, not all glutathione atoms; this experiment did not measure dietary B6 depletion.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

In this cell system, sulfur routed through B6-dependent enzymes helped supply glutathione.

primary_references

[b6-glutathione-2000] The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes (2000). https://pubmed.ncbi.nlm.nih.gov/11041866/ DOI: 10.1021/bi001088w

tissue_or_cell_type

Cultured human hepatoma cell line

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 590–600

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured human hepatoma cell line; metabolic sulfur tracing · source_derived_draft · unverified_draft

### b6-met-transsulfuration-glutathione Tracing in a cultured human hepatoma cell line estimated that transsulfuration supplied homocysteine-derived sulfur to approximately half of the intracellular glutathione pool. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this cell system, sulfur routed through B6-dependent enzymes helped supply glutathione. organism: Homo sapiens tissue_or_cell_type: Cultured human hepatoma cell line experimental_model: Cultured human hepatoma cell line; metabolic sulfur tracing limitations: Fraction is culture-specific and traces sulfur, not all glutathione atoms; this experiment did not measure dietary B6 depletion. cross_nutrient: B6-dependent transsulfuration connects methionine/homocysteine to the cysteine supply for glutathione. [b6-glutathione-2000] The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes (2000). https://pubmed.ncbi.nlm.nih.gov/11041866/ DOI: 10.1021/bi001088w

evidence_access

Primary full text

experimental_model

Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation.

limitations

Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification.

nutrient_topic

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

plain_language

Homocysteine activated an inflammatory signaling branch.

primary_references

Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 20–26

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. · source_derived_draft · unverified_draft

## fulvic-acid-hcy-erk Homocysteine activated an inflammatory signaling branch. Added homocysteine increased ERK phosphorylation in U937 cells. Model: Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. Limitations: Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification. Evidence access: Primary full text Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

evidence_access

Primary full text

experimental_model

Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation.

limitations

Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification.

nutrient_topic

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

plain_language

A second kinase branch responded to homocysteine.

primary_references

Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 28–34

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. · source_derived_draft · unverified_draft

## fulvic-acid-hcy-jnk A second kinase branch responded to homocysteine. Added homocysteine increased JNK phosphorylation in U937 cells. Model: Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. Limitations: Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification. Evidence access: Primary full text Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

evidence_span

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experimental_model

Randomized-order four-period crossover in 20 adults

exposure

2 g/day CGA for 7 days versus placebo; black tea and rutin comparator periods

limitations

High supplemental exposure. Homocysteine is a biomarker; this study did not establish cardiovascular harm, depletion of folate/B12/B6, or failure of the methylation cycle.

nutrient_topic

Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. · Chlorogenic acid / 5-O-caffeoylquinic acid

organism

Human

plain_language

Timing changed the size and precision of the measured effect.

primary_references

[chlorogenic_acid-p11237928] Consumption of high doses of chlorogenic acid, present in coffee, or of black tea increases plasma total homocysteine concentrations in humans. (2001). https://pubmed.ncbi.nlm.nih.gov/11237928/ DOI: 10.1093/ajcn/73.3.532

tissue_or_cell_type

Plasma total homocysteine

Chlorogenic acid: metabolism, signaling and nutrient connections (2026-09-17) · lines 880–891

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized-order four-period crossover in 20 adults · source_derived_draft · unverified_draft

### chlorogenic_acid-fasting-hcy At 20 hours, fasting total homocysteine was 4% higher, a 0.4 micromol/L difference (95% CI 0.0-0.8). Condition category: normal nutrient_topic: Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Timing changed the size and precision of the measured effect. organism: Human tissue_or_cell_type: Plasma total homocysteine experimental_model: Randomized-order four-period crossover in 20 adults limitations: High supplemental exposure. Homocysteine is a biomarker; this study did not establish cardiovascular harm, depletion of folate/B12/B6, or failure of the methylation cycle. exposure: 2 g/day CGA for 7 days versus placebo; black tea and rutin comparator periods evidence_span: {"source_cache": "artifacts/chlorogenic_acid-research/11237928.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b141ca7b40578ff2c375240255347999acc1d82cf721d117c96ff1a057d667e2", "start_char": 0, "end_char": 1765, "text_sha256": "b141ca7b40578ff2c375240255347999acc1d82cf721d117c96ff1a057d667e2"} [chlorogenic_acid-p11237928] Consumption of high doses of chlorogenic acid, present in coffee, or of black tea increases plasma total homocysteine concentrations in humans. (2001). https://pubmed.ncbi.nlm.nih.gov/11237928/ DOI: 10.1093/ajcn/73.3.532

evidence_span

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experimental_model

Randomized-order four-period crossover in 20 adults

exposure

2 g/day CGA for 7 days versus placebo; black tea and rutin comparator periods

limitations

High supplemental exposure. Homocysteine is a biomarker; this study did not establish cardiovascular harm, depletion of folate/B12/B6, or failure of the methylation cycle.

nutrient_topic

Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. · Chlorogenic acid / 5-O-caffeoylquinic acid

organism

Human

plain_language

The methylation connection has a human biomarker result at a high dose.

primary_references

[chlorogenic_acid-p11237928] Consumption of high doses of chlorogenic acid, present in coffee, or of black tea increases plasma total homocysteine concentrations in humans. (2001). https://pubmed.ncbi.nlm.nih.gov/11237928/ DOI: 10.1093/ajcn/73.3.532

tissue_or_cell_type

Plasma total homocysteine

Chlorogenic acid: metabolism, signaling and nutrient connections (2026-09-17) · lines 867–878

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized-order four-period crossover in 20 adults · source_derived_draft · unverified_draft

### chlorogenic_acid-human-hcy At 4-5 hours after dosing, plasma total homocysteine was 12% higher than placebo, a 1.2 micromol/L difference (95% CI 0.6-1.7). Condition category: normal nutrient_topic: Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The methylation connection has a human biomarker result at a high dose. organism: Human tissue_or_cell_type: Plasma total homocysteine experimental_model: Randomized-order four-period crossover in 20 adults limitations: High supplemental exposure. Homocysteine is a biomarker; this study did not establish cardiovascular harm, depletion of folate/B12/B6, or failure of the methylation cycle. exposure: 2 g/day CGA for 7 days versus placebo; black tea and rutin comparator periods evidence_span: {"source_cache": "artifacts/chlorogenic_acid-research/11237928.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b141ca7b40578ff2c375240255347999acc1d82cf721d117c96ff1a057d667e2", "start_char": 0, "end_char": 1765, "text_sha256": "b141ca7b40578ff2c375240255347999acc1d82cf721d117c96ff1a057d667e2"} [chlorogenic_acid-p11237928] Consumption of high doses of chlorogenic acid, present in coffee, or of black tea increases plasma total homocysteine concentrations in humans. (2001). https://pubmed.ncbi.nlm.nih.gov/11237928/ DOI: 10.1093/ajcn/73.3.532

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

availability_state

biomarker_context Imported condition classification; unverified.

cross_nutrient

Methionine handling depends on more than circulating B6.

experimental_model

Double-blind randomized placebo-controlled RA trial: 36 recruited, 33 baseline completers, 28 low-PLP patients eligible for supplementation.

exposure

Pyridoxine hydrochloride 50 mg/day or placebo for 30 days; historical trial exposure, not a regimen recommendation.

limitations

Subgroup findings are exploratory; methotrexate, inflammation and enzyme differences can affect the challenge.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

The homocysteine test did not improve as consistently as the other B6 tests.

primary_references

[b6-chiang2005-trial] Pyridoxine supplementation corrects vitamin B6 deficiency but does not improve inflammation in patients with rheumatoid arthritis (2005). https://pubmed.ncbi.nlm.nih.gov/16277693/ DOI: 10.1186/ar1839

tissue_or_cell_type

Human blood and whole-body measurements

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1497–1508

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized placebo-controlled RA trial: 36 recruited, 33 baseline completers, 28 low-PLP patients eligible for supplementation. · source_derived_draft · unverified_draft

### b6-ra-homocysteine-response-boundary The overall post-methionine homocysteine treatment effect was a nonsignificant trend (P=0.086); an elevated-baseline subgroup showed a stronger signal. Condition category: biomarker_context nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The homocysteine test did not improve as consistently as the other B6 tests. organism: Homo sapiens tissue_or_cell_type: Human blood and whole-body measurements experimental_model: Double-blind randomized placebo-controlled RA trial: 36 recruited, 33 baseline completers, 28 low-PLP patients eligible for supplementation. limitations: Subgroup findings are exploratory; methotrexate, inflammation and enzyme differences can affect the challenge. exposure: Pyridoxine hydrochloride 50 mg/day or placebo for 30 days; historical trial exposure, not a regimen recommendation. cross_nutrient: Methionine handling depends on more than circulating B6. [b6-chiang2005-trial] Pyridoxine supplementation corrects vitamin B6 deficiency but does not improve inflammation in patients with rheumatoid arthritis (2005). https://pubmed.ncbi.nlm.nih.gov/16277693/ DOI: 10.1186/ar1839

evidence_span

{"source_cache": "artifacts/creatine-research/11595668.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0", "start_char": 0, "end_char": 1687, "text_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0"}

experimental_model

Two-week feeding and isolated hepatocyte experiments

exposure

Guanidinoacetate or creatine feeding; guanidinoacetate plus methionine in hepatocytes

limitations

Animal methyl-demand experiment; effect sizes do not predict human homocysteine responses.

nutrient_topic

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

organism

Rats

plain_language

Supplying the finished product reduced a methylation-related blood marker in this animal setting.

primary_references

[creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095

tissue_or_cell_type

Plasma and liver cells

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 698–709

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two-week feeding and isolated hepatocyte experiments · source_derived_draft · unverified_draft

### creatine-creatine-rat-homocysteine Creatine feeding lowered plasma homocysteine by approximately 25% in the rat experiment. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Supplying the finished product reduced a methylation-related blood marker in this animal setting. organism: Rats tissue_or_cell_type: Plasma and liver cells experimental_model: Two-week feeding and isolated hepatocyte experiments limitations: Animal methyl-demand experiment; effect sizes do not predict human homocysteine responses. exposure: Guanidinoacetate or creatine feeding; guanidinoacetate plus methionine in hepatocytes evidence_span: {"source_cache": "artifacts/creatine-research/11595668.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0", "start_char": 0, "end_char": 1687, "text_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0"} [creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095

evidence_span

{"source_cache": "artifacts/creatine-research/26311810.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "055a97365d5a6d864e78eafcfa4a73bc8c425e240487580796a443cf8ef33a04", "start_char": 0, "end_char": 2160, "text_sha256": "055a97365d5a6d864e78eafcfa4a73bc8c425e240487580796a443cf8ef33a04"}

experimental_model

Twelve-week randomized placebo-controlled trial

exposure

Creatine 3 g/day, folic acid 400 micrograms/day, both, or placebo; analyzed groups 101, 153, 103 and 101 respectively

limitations

Group-average effects and exploratory within-person associations are distinct. No general claim of restored methylation or reduced disease risk.

nutrient_topic

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

organism

Bangladeshi adults

plain_language

Adding creatine did not improve the average homocysteine reduction achieved by folic acid in this trial.

primary_references

[creatine-p26311810] Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial. (2015). https://pubmed.ncbi.nlm.nih.gov/26311810/ DOI: 10.3945/jn.115.216739

tissue_or_cell_type

Plasma metabolites

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 750–761

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Twelve-week randomized placebo-controlled trial · source_derived_draft · unverified_draft

### creatine-folate-creatine-hcy Homocysteine fell 23.4% with folic acid alone and 21.0% with creatine plus folic acid; the difference was not significant (P=0.41). Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding creatine did not improve the average homocysteine reduction achieved by folic acid in this trial. organism: Bangladeshi adults tissue_or_cell_type: Plasma metabolites experimental_model: Twelve-week randomized placebo-controlled trial limitations: Group-average effects and exploratory within-person associations are distinct. No general claim of restored methylation or reduced disease risk. exposure: Creatine 3 g/day, folic acid 400 micrograms/day, both, or placebo; analyzed groups 101, 153, 103 and 101 respectively evidence_span: {"source_cache": "artifacts/creatine-research/26311810.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "055a97365d5a6d864e78eafcfa4a73bc8c425e240487580796a443cf8ef33a04", "start_char": 0, "end_char": 2160, "text_sha256": "055a97365d5a6d864e78eafcfa4a73bc8c425e240487580796a443cf8ef33a04"} [creatine-p26311810] Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial. (2015). https://pubmed.ncbi.nlm.nih.gov/26311810/ DOI: 10.3945/jn.115.216739

evidence_span

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experimental_model

Two-week feeding and isolated hepatocyte experiments

exposure

Guanidinoacetate or creatine feeding; guanidinoacetate plus methionine in hepatocytes

limitations

Animal methyl-demand experiment; effect sizes do not predict human homocysteine responses.

nutrient_topic

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

organism

Rats

plain_language

The precursor and finished creatine were metabolically different in liver cells.

primary_references

[creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095

tissue_or_cell_type

Plasma and liver cells

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 711–722

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two-week feeding and isolated hepatocyte experiments · source_derived_draft · unverified_draft

### creatine-gaa-hepatocyte-hcy-export Guanidinoacetate increased homocysteine export from methionine-supplied rat hepatocytes, whereas added creatine did not. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The precursor and finished creatine were metabolically different in liver cells. organism: Rats tissue_or_cell_type: Plasma and liver cells experimental_model: Two-week feeding and isolated hepatocyte experiments limitations: Animal methyl-demand experiment; effect sizes do not predict human homocysteine responses. exposure: Guanidinoacetate or creatine feeding; guanidinoacetate plus methionine in hepatocytes evidence_span: {"source_cache": "artifacts/creatine-research/11595668.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0", "start_char": 0, "end_char": 1687, "text_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0"} [creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095

evidence_span

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experimental_model

Two-week feeding and isolated hepatocyte experiments

exposure

Guanidinoacetate or creatine feeding; guanidinoacetate plus methionine in hepatocytes

limitations

Animal methyl-demand experiment; effect sizes do not predict human homocysteine responses.

nutrient_topic

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

organism

Rats

plain_language

Providing more precursor increased the load on the methylation step in these rats.

primary_references

[creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095

tissue_or_cell_type

Plasma and liver cells

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 685–696

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two-week feeding and isolated hepatocyte experiments · source_derived_draft · unverified_draft

### creatine-gaa-homocysteine Guanidinoacetate feeding raised plasma homocysteine by approximately 50% in the rat experiment. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Providing more precursor increased the load on the methylation step in these rats. organism: Rats tissue_or_cell_type: Plasma and liver cells experimental_model: Two-week feeding and isolated hepatocyte experiments limitations: Animal methyl-demand experiment; effect sizes do not predict human homocysteine responses. exposure: Guanidinoacetate or creatine feeding; guanidinoacetate plus methionine in hepatocytes evidence_span: {"source_cache": "artifacts/creatine-research/11595668.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0", "start_char": 0, "end_char": 1687, "text_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0"} [creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095

evidence_span

{"source_cache": "artifacts/creatine-research/26311810.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "055a97365d5a6d864e78eafcfa4a73bc8c425e240487580796a443cf8ef33a04", "start_char": 0, "end_char": 2160, "text_sha256": "055a97365d5a6d864e78eafcfa4a73bc8c425e240487580796a443cf8ef33a04"}

experimental_model

Twelve-week randomized placebo-controlled trial

exposure

Creatine 3 g/day, folic acid 400 micrograms/day, both, or placebo; analyzed groups 101, 153, 103 and 101 respectively

limitations

Group-average effects and exploratory within-person associations are distinct. No general claim of restored methylation or reduced disease risk.

nutrient_topic

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

organism

Bangladeshi adults

plain_language

Reducing precursor production did not automatically produce a lower homocysteine result in people.

primary_references

[creatine-p26311810] Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial. (2015). https://pubmed.ncbi.nlm.nih.gov/26311810/ DOI: 10.3945/jn.115.216739

tissue_or_cell_type

Plasma metabolites

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 737–748

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Twelve-week randomized placebo-controlled trial · source_derived_draft · unverified_draft

### creatine-human-hcy-null Creatine alone did not significantly lower total plasma homocysteine compared with placebo (P=0.35). Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reducing precursor production did not automatically produce a lower homocysteine result in people. organism: Bangladeshi adults tissue_or_cell_type: Plasma metabolites experimental_model: Twelve-week randomized placebo-controlled trial limitations: Group-average effects and exploratory within-person associations are distinct. No general claim of restored methylation or reduced disease risk. exposure: Creatine 3 g/day, folic acid 400 micrograms/day, both, or placebo; analyzed groups 101, 153, 103 and 101 respectively evidence_span: {"source_cache": "artifacts/creatine-research/26311810.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "055a97365d5a6d864e78eafcfa4a73bc8c425e240487580796a443cf8ef33a04", "start_char": 0, "end_char": 2160, "text_sha256": "055a97365d5a6d864e78eafcfa4a73bc8c425e240487580796a443cf8ef33a04"} [creatine-p26311810] Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial. (2015). https://pubmed.ncbi.nlm.nih.gov/26311810/ DOI: 10.3945/jn.115.216739

cross_nutrient

Folate-cycle biomarker response was genotype dependent.

experimental_model

Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65.

exposure

1.6 mg/day riboflavin versus placebo for 12 weeks; experimental regimen.

genotype

MTHFR 677CC or 677CT

limitations

Null findings in modest samples do not prove an effect is impossible; context differs from the TT arm.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Homo sapiens

plain_language

A better B2 test result did not automatically lower homocysteine in everyone.

primary_references

[b2-mcnulty2006] Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism (2006). https://pubmed.ncbi.nlm.nih.gov/16380544/ DOI: 10.1161/circulationaha.105.580332

tissue_or_cell_type

Human clinical setting

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1500–1512

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65. · source_derived_draft · unverified_draft

### b2-cc-ct-homocysteine-nonresponse No homocysteine response was observed in the CC or CT groups despite improved riboflavin-status measures in all genotype groups. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A better B2 test result did not automatically lower homocysteine in everyone. organism: Homo sapiens tissue_or_cell_type: Human clinical setting experimental_model: Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65. limitations: Null findings in modest samples do not prove an effect is impossible; context differs from the TT arm. exposure: 1.6 mg/day riboflavin versus placebo for 12 weeks; experimental regimen. cross_nutrient: Folate-cycle biomarker response was genotype dependent. genotype: MTHFR 677CC or 677CT [b2-mcnulty2006] Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism (2006). https://pubmed.ncbi.nlm.nih.gov/16380544/ DOI: 10.1161/circulationaha.105.580332

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

B2 cofactor supply interacts with folate-cycle enzyme genotype.

experimental_model

Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65.

exposure

1.6 mg/day riboflavin versus placebo for 12 weeks; experimental regimen.

genotype

MTHFR 677TT; common variant rather than complete loss of enzyme

limitations

Small genotype strata; subgroup magnitude is not an expected response for every TT carrier. The trial did not test cardiovascular events.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Homo sapiens

plain_language

In this trial, improving B2 supply lowered a folate-pathway blood marker in people with two copies of the studied MTHFR variant.

primary_references

[b2-mcnulty2006] Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism (2006). https://pubmed.ncbi.nlm.nih.gov/16380544/ DOI: 10.1161/circulationaha.105.580332

tissue_or_cell_type

Human clinical setting

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1486–1498

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65. · source_derived_draft · unverified_draft

### b2-tt-homocysteine-response Riboflavin lowered plasma homocysteine in the MTHFR 677TT group by 22% overall; the lower-baseline-B2 subgroup showed a 40% decrease. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this trial, improving B2 supply lowered a folate-pathway blood marker in people with two copies of the studied MTHFR variant. organism: Homo sapiens tissue_or_cell_type: Human clinical setting experimental_model: Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65. limitations: Small genotype strata; subgroup magnitude is not an expected response for every TT carrier. The trial did not test cardiovascular events. exposure: 1.6 mg/day riboflavin versus placebo for 12 weeks; experimental regimen. cross_nutrient: B2 cofactor supply interacts with folate-cycle enzyme genotype. genotype: MTHFR 677TT; common variant rather than complete loss of enzyme [b2-mcnulty2006] Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism (2006). https://pubmed.ncbi.nlm.nih.gov/16380544/ DOI: 10.1161/circulationaha.105.580332

availability_state

biomarker_context Imported condition classification; unverified.

cross_nutrient

Folate and B12 both participate in homocysteine remethylation.

experimental_model

Selected clear-cut deficiency series: 434 B12 episodes in 406 patients and 123 folate episodes in 119 patients.

exposure

Serum MMA and total homocysteine assays; elevation defined above three standard deviations of the reference mean.

limitations

Circulating concentration is not a direct MTR activity measurement.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

This marker is shared by connected nutrient pathways, so it cannot identify B12 deficiency by itself.

primary_references

[b12-savage1994] Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies (1994). https://pubmed.ncbi.nlm.nih.gov/8154512/ DOI: 10.1016/0002-9343(94)90149-x

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1474–1485

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Selected clear-cut deficiency series: 434 B12 episodes in 406 patients and 123 folate episodes in 119 patients. · source_derived_draft · unverified_draft

### b12-deficiency-homocysteine-frequency Total homocysteine was elevated in 95.9% of the B12-deficiency episodes; it was also elevated in 91% of the folate-deficiency episodes. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This marker is shared by connected nutrient pathways, so it cannot identify B12 deficiency by itself. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Selected clear-cut deficiency series: 434 B12 episodes in 406 patients and 123 folate episodes in 119 patients. limitations: Circulating concentration is not a direct MTR activity measurement. exposure: Serum MMA and total homocysteine assays; elevation defined above three standard deviations of the reference mean. cross_nutrient: Folate and B12 both participate in homocysteine remethylation. [b12-savage1994] Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies (1994). https://pubmed.ncbi.nlm.nih.gov/8154512/ DOI: 10.1016/0002-9343(94)90149-x

availability_state

biomarker_context Imported condition classification; unverified.

cross_nutrient

Direct combined B12/folic-acid exposure.

experimental_model

Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency.

exposure

Cyanocobalamin 1000 micrograms/day, cyanocobalamin 1000 micrograms plus folic acid 400 micrograms/day, or placebo for 24 weeks.

limitations

The combined group cannot isolate the contribution of folic acid versus B12.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The two connected vitamins changed the shared marker.

primary_references

[b12-eussen2006] Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial (2006). https://pubmed.ncbi.nlm.nih.gov/16895884/ DOI: 10.1093/ajcn/84.2.361

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1536–1547

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency. · source_derived_draft · unverified_draft

### b12-eussen-folate-homocysteine B12 plus folic acid increased red-cell folate and decreased total homocysteine by 36%; B12 treatment corrected mild biochemical deficiency. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two connected vitamins changed the shared marker. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency. limitations: The combined group cannot isolate the contribution of folic acid versus B12. exposure: Cyanocobalamin 1000 micrograms/day, cyanocobalamin 1000 micrograms plus folic acid 400 micrograms/day, or placebo for 24 weeks. cross_nutrient: Direct combined B12/folic-acid exposure. [b12-eussen2006] Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial (2006). https://pubmed.ncbi.nlm.nih.gov/16895884/ DOI: 10.1093/ajcn/84.2.361

cross_nutrient

Preserves the B12/folate/homocysteine measurements without a universal depletion cascade.

experimental_model

Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes.

exposure

Metformin 850 mg three times daily versus placebo for 4.3 years; historical experimental exposure.

limitations

End-study B12 strata are not randomized mediators. The folate decrease lost significance after adjustment for BMI and smoking.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

A B12 effect did not make the overall homocysteine trial result statistically significant.

primary_references

[b12-dejager2010] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

tissue_or_cell_type

Human blood or whole-person endpoints

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1636–1647

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes. · source_derived_draft · unverified_draft

### b12-metformin-homocysteine-boundary The overall metformin-versus-placebo homocysteine change was +5% (95% CI -1% to 11%; P=0.091), although participants with low end-study B12 had higher homocysteine. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A B12 effect did not make the overall homocysteine trial result statistically significant. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes. limitations: End-study B12 strata are not randomized mediators. The folate decrease lost significance after adjustment for BMI and smoking. exposure: Metformin 850 mg three times daily versus placebo for 4.3 years; historical experimental exposure. cross_nutrient: Preserves the B12/folate/homocysteine measurements without a universal depletion cascade. [b12-dejager2010] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

availability_state

biomarker_context Imported condition classification; unverified.

cross_nutrient

The measured interaction concerns B12 status and total folate, not all folate formulations equally.

experimental_model

Cross-sectional adult NHANES III 1991–1994 (4940) and NHANES 1999–2002 (5473) analyses, exclusions for several confounders.

exposure

Measured serum folate, B12, total homocysteine and MMA; stratification at serum B12 148 pmol/L; no randomized folate exposure.

limitations

No direct enzyme-flux measurement or causal proof of folate toxicity. Survey subsets and B12 definitions differ from the older-adult cognition analysis.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

More circulating folate did not guarantee a better B12-related marker.

primary_references

[fol-selhub2007] In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations (2007). https://pubmed.ncbi.nlm.nih.gov/18056804/ DOI: 10.1073/pnas.0709487104

tissue_or_cell_type

Human blood or whole-person clinical endpoints

trigger_kind

biomarker_context Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1567–1578

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cross-sectional adult NHANES III 1991–1994 (4940) and NHANES 1999–2002 (5473) analyses, exclusions for several confounders. · source_derived_draft · unverified_draft

### fol-b12-interaction-homocysteine In low-serum-B12 strata, circulating total homocysteine increased as folate increased above approximately 20 nmol/L; the relationship ran oppositely in B12-replete strata. Condition category: biomarker_context nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: More circulating folate did not guarantee a better B12-related marker. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Cross-sectional adult NHANES III 1991–1994 (4940) and NHANES 1999–2002 (5473) analyses, exclusions for several confounders. limitations: No direct enzyme-flux measurement or causal proof of folate toxicity. Survey subsets and B12 definitions differ from the older-adult cognition analysis. exposure: Measured serum folate, B12, total homocysteine and MMA; stratification at serum B12 148 pmol/L; no randomized folate exposure. cross_nutrient: The measured interaction concerns B12 status and total folate, not all folate formulations equally. [fol-selhub2007] In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations (2007). https://pubmed.ncbi.nlm.nih.gov/18056804/ DOI: 10.1073/pnas.0709487104

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Folate and B12 meet at methionine synthase; this experiment manipulated folate intake.

experimental_model

Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion.

exposure

Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet.

limitations

A concentration is not direct enzyme flux; B12 status, kidney function and other inputs also affect this marker.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

A shortage made a connected methionine-recycling marker rise.

primary_references

[fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204

tissue_or_cell_type

Human blood or whole-person clinical endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1408–1419

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. · source_derived_draft · unverified_draft

### fol-depletion-homocysteine Controlled depletion lowered plasma folate and significantly raised plasma homocysteine in eight postmenopausal women. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A shortage made a connected methionine-recycling marker rise. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. limitations: A concentration is not direct enzyme flux; B12 status, kidney function and other inputs also affect this marker. exposure: Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet. cross_nutrient: Folate and B12 meet at methionine synthase; this experiment manipulated folate intake. [fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204

cross_nutrient

Directly records the combined B6/B12/folic-acid exposure.

experimental_model

Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years.

exposure

Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate.

limitations

Folate, B6 and B12 were administered together; their individual contributions cannot be separated.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The biochemical target changed in the trial.

primary_references

[fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900

tissue_or_cell_type

Human blood or whole-person clinical endpoints

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1617–1628

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. · source_derived_draft · unverified_draft

### fol-hope2-homocysteine Mean homocysteine fell 2.4 micromol/L with the combined B vitamins and rose 0.8 micromol/L with placebo. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The biochemical target changed in the trial. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. limitations: Folate, B6 and B12 were administered together; their individual contributions cannot be separated. exposure: Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate. cross_nutrient: Directly records the combined B6/B12/folic-acid exposure. [fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion.

exposure

Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet.

limitations

Historical experimental intakes in eight participants do not establish a universal requirement or treatment regimen.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Different folate-related measurements did not recover identically.

primary_references

[fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204

tissue_or_cell_type

Human blood or whole-person clinical endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1433–1443

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. · source_derived_draft · unverified_draft

### fol-repletion-endpoint-difference During repletion, elevated homocysteine decreased with total folate intake 516 but not 286 micrograms/day, while the DNA methylation readout improved across 286–516 micrograms/day. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Different folate-related measurements did not recover identically. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. limitations: Historical experimental intakes in eight participants do not establish a universal requirement or treatment regimen. exposure: Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet. [fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Loss of betaine recycling burdens shared homocysteine handling.

experimental_model

Bhmt-null mice and wild-type controls.

limitations

Complete knockout, not common human polymorphisms.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Mus musculus

plain_language

Other pathways did not fully compensate.

primary_references

[teng-2011] Deletion of betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas (2011). https://pubmed.ncbi.nlm.nih.gov/21878621/ DOI: 10.1074/jbc.m111.265348

tissue_or_cell_type

Liver and plasma

trigger_kind

machinery_impairment Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 634–644

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bhmt-null mice and wild-type controls. · source_derived_draft · unverified_draft

### folate-methyl-bhmt-ko-hcy Bhmt deletion raised hepatic total homocysteine sixfold and plasma total homocysteine eightfold in mice. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Other pathways did not fully compensate. organism: Mus musculus tissue_or_cell_type: Liver and plasma experimental_model: Bhmt-null mice and wild-type controls. limitations: Complete knockout, not common human polymorphisms. cross_nutrient: Loss of betaine recycling burdens shared homocysteine handling. [teng-2011] Deletion of betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas (2011). https://pubmed.ncbi.nlm.nih.gov/21878621/ DOI: 10.1074/jbc.m111.265348

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Folate/betaine compensation has limits.

experimental_model

Bhmt-null and wild-type mice; four-week folate feeding.

exposure

0, 2 or 20 mg folate/kg diet

limitations

Mouse four-week experiment, not a human treatment rule.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Mus musculus

plain_language

Extra folate did not restore this missing route.

primary_references

[teng-2012] Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake (2012). https://pubmed.ncbi.nlm.nih.gov/23014492/ DOI: 10.3945/jn.112.166835

tissue_or_cell_type

Plasma

trigger_kind

machinery_impairment Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 668–679

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bhmt-null and wild-type mice; four-week folate feeding. · source_derived_draft · unverified_draft

### folate-methyl-folate-no-hcy-rescue-bhmt Feeding 20 mg folate/kg diet did not ameliorate elevated plasma homocysteine in Bhmt-null mice. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Extra folate did not restore this missing route. organism: Mus musculus tissue_or_cell_type: Plasma experimental_model: Bhmt-null and wild-type mice; four-week folate feeding. limitations: Mouse four-week experiment, not a human treatment rule. exposure: 0, 2 or 20 mg folate/kg diet cross_nutrient: Folate/betaine compensation has limits. [teng-2012] Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake (2012). https://pubmed.ncbi.nlm.nih.gov/23014492/ DOI: 10.3945/jn.112.166835

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Mtrr gene-trap hypomorphic mice and controls.

limitations

Not all human MTRR variants.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Mus musculus

plain_language

Partial reactivation failure impaired homocysteine handling.

primary_references

[elmore-2007] Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase (2007). https://pubmed.ncbi.nlm.nih.gov/17369066/ DOI: 10.1016/j.ymgme.2007.02.001

tissue_or_cell_type

Plasma

trigger_kind

machinery_impairment Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 566–575

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mtrr gene-trap hypomorphic mice and controls. · source_derived_draft · unverified_draft

### folate-methyl-mtrr-mouse-hcy Hypomorphic Mtrr gt/gt mice had higher plasma homocysteine than controls. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Partial reactivation failure impaired homocysteine handling. organism: Mus musculus tissue_or_cell_type: Plasma experimental_model: Mtrr gene-trap hypomorphic mice and controls. limitations: Not all human MTRR variants. [elmore-2007] Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase (2007). https://pubmed.ncbi.nlm.nih.gov/17369066/ DOI: 10.1016/j.ymgme.2007.02.001

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

B6-dependent sulfur metabolism connects to glutathione, with blood and cellular pools distinguished.

experimental_model

Nine healthy adults (five women, four men; ages 20–30), controlled restriction with fasting stable-isotope measurements.

exposure

Four weeks below 0.5 mg/day dietary B6; overnight-fasted tracer protocol.

limitations

Plasma total glutathione is not intracellular reduced GSH, tissue antioxidant capacity or synthesis rate.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

This experiment did not find a universal glutathione collapse.

primary_references

[b6-davis2006] Plasma glutathione and cystathionine concentrations are elevated but cysteine flux is unchanged by dietary vitamin B-6 restriction in young men and women (2006). https://pubmed.ncbi.nlm.nih.gov/16424114/ DOI: 10.1093/jn/136.2.373

tissue_or_cell_type

Human blood and whole-body measurements

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1321–1332

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine healthy adults (five women, four men; ages 20–30), controlled restriction with fasting stable-isotope measurements. · source_derived_draft · unverified_draft

### b6-fasting-total-glutathione Plasma total glutathione rose 38% during restriction; plasma cysteine, homocysteine and CRP did not significantly change. Condition category: nutrient_deficiency nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This experiment did not find a universal glutathione collapse. organism: Homo sapiens tissue_or_cell_type: Human blood and whole-body measurements experimental_model: Nine healthy adults (five women, four men; ages 20–30), controlled restriction with fasting stable-isotope measurements. limitations: Plasma total glutathione is not intracellular reduced GSH, tissue antioxidant capacity or synthesis rate. exposure: Four weeks below 0.5 mg/day dietary B6; overnight-fasted tracer protocol. cross_nutrient: B6-dependent sulfur metabolism connects to glutathione, with blood and cellular pools distinguished. [b6-davis2006] Plasma glutathione and cystathionine concentrations are elevated but cysteine flux is unchanged by dietary vitamin B-6 restriction in young men and women (2006). https://pubmed.ncbi.nlm.nih.gov/16424114/ DOI: 10.1093/jn/136.2.373

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

B6 intersects methionine/folate metabolism; this experiment does not establish B12 or folate depletion.

experimental_model

Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics.

exposure

28 days dietary B6 restriction; plasma PLP49±4 to 19±2 nmol/L.

limitations

Null group means do not establish identical responses or preserved DNA methylation in every tissue.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

Lower B6 did not make this measured process uniformly fail.

primary_references

[b6-lamers2011] Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women (2011). https://pubmed.ncbi.nlm.nih.gov/21430249/ DOI: 10.3945/jn.110.134197

tissue_or_cell_type

Human blood and whole-body measurements

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1346–1357

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics. · source_derived_draft · unverified_draft

### b6-fed-remethylation-preserved Mean postprandial homocysteine remethylation did not significantly change after restriction, with substantial individual variation. Condition category: nutrient_deficiency nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Lower B6 did not make this measured process uniformly fail. organism: Homo sapiens tissue_or_cell_type: Human blood and whole-body measurements experimental_model: Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics. limitations: Null group means do not establish identical responses or preserved DNA methylation in every tissue. exposure: 28 days dietary B6 restriction; plasma PLP49±4 to 19±2 nmol/L. cross_nutrient: B6 intersects methionine/folate metabolism; this experiment does not establish B12 or folate depletion. [b6-lamers2011] Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women (2011). https://pubmed.ncbi.nlm.nih.gov/21430249/ DOI: 10.3945/jn.110.134197

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

B6 intersects methionine/folate metabolism; this experiment does not establish B12 or folate depletion.

experimental_model

Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics.

exposure

28 days dietary B6 restriction; plasma PLP49±4 to 19±2 nmol/L.

limitations

Null group means do not establish identical responses or preserved DNA methylation in every tissue.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

Lower B6 did not make this measured process uniformly fail.

primary_references

[b6-lamers2011] Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women (2011). https://pubmed.ncbi.nlm.nih.gov/21430249/ DOI: 10.3945/jn.110.134197

tissue_or_cell_type

Human blood and whole-body measurements

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1359–1370

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics. · source_derived_draft · unverified_draft

### b6-fed-transmethylation-preserved Mean postprandial transmethylation did not significantly change after restriction, with substantial individual variation. Condition category: nutrient_deficiency nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Lower B6 did not make this measured process uniformly fail. organism: Homo sapiens tissue_or_cell_type: Human blood and whole-body measurements experimental_model: Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics. limitations: Null group means do not establish identical responses or preserved DNA methylation in every tissue. exposure: 28 days dietary B6 restriction; plasma PLP49±4 to 19±2 nmol/L. cross_nutrient: B6 intersects methionine/folate metabolism; this experiment does not establish B12 or folate depletion. [b6-lamers2011] Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women (2011). https://pubmed.ncbi.nlm.nih.gov/21430249/ DOI: 10.3945/jn.110.134197

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

B6 intersects methionine/folate metabolism; this experiment does not establish B12 or folate depletion.

experimental_model

Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics.

exposure

28 days dietary B6 restriction; plasma PLP49±4 to 19±2 nmol/L.

limitations

Null group means do not establish identical responses or preserved DNA methylation in every tissue.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

Lower B6 did not make this measured process uniformly fail.

primary_references

[b6-lamers2011] Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women (2011). https://pubmed.ncbi.nlm.nih.gov/21430249/ DOI: 10.3945/jn.110.134197

tissue_or_cell_type

Human blood and whole-body measurements

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1372–1383

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics. · source_derived_draft · unverified_draft

### b6-fed-transsulfuration-preserved Mean postprandial total transsulfuration did not significantly change after restriction, with substantial individual variation. Condition category: nutrient_deficiency nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Lower B6 did not make this measured process uniformly fail. organism: Homo sapiens tissue_or_cell_type: Human blood and whole-body measurements experimental_model: Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics. limitations: Null group means do not establish identical responses or preserved DNA methylation in every tissue. exposure: 28 days dietary B6 restriction; plasma PLP49±4 to 19±2 nmol/L. cross_nutrient: B6 intersects methionine/folate metabolism; this experiment does not establish B12 or folate depletion. [b6-lamers2011] Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women (2011). https://pubmed.ncbi.nlm.nih.gov/21430249/ DOI: 10.3945/jn.110.134197

cross_nutrient

Methionine-derived sulfur enters cysteine synthesis.

experimental_model

Recombinant truncated human CBS crystallography

limitations

Enzyme chemistry alone does not predict whole-body homocysteine during mild deficiency.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

This B6-dependent step channels homocysteine into transsulfuration.

primary_references

[b6-cbs-2001] Structure of human cystathionine beta-synthase: a unique pyridoxal 5'-phosphate-dependent heme protein. (2001). https://pmc.ncbi.nlm.nih.gov/articles/PMC149156/ DOI: 10.1093/emboj/20.15.3910

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 517–527

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant truncated human CBS crystallography · source_derived_draft · unverified_draft

### b6-met-cbs-condensation PLP-dependent human CBS condenses serine with homocysteine to produce cystathionine. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This B6-dependent step channels homocysteine into transsulfuration. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant truncated human CBS crystallography limitations: Enzyme chemistry alone does not predict whole-body homocysteine during mild deficiency. cross_nutrient: Methionine-derived sulfur enters cysteine synthesis. [b6-cbs-2001] Structure of human cystathionine beta-synthase: a unique pyridoxal 5'-phosphate-dependent heme protein. (2001). https://pmc.ncbi.nlm.nih.gov/articles/PMC149156/ DOI: 10.1093/emboj/20.15.3910

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human infant, liver/red-cell/fibroblast assays and genetic analysis.

limitations

Single rare-disease case; not evidence of the same block in ordinary dietary variation.

nutrient_topic

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

plain_language

Abundant methyl-donor substrate can coexist with blocked recycling.

primary_references

S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15024124/ · DOI 10.1073/pnas.0400658101

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 180–186

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human infant, liver/red-cell/fibroblast assays and genetic analysis. · source_derived_draft · unverified_draft

## methionine-ahcy-loss Abundant methyl-donor substrate can coexist with blocked recycling. The index AHCY-deficient patient had very low enzyme activity and markedly elevated plasma SAH, SAM and methionine. Model: Human infant, liver/red-cell/fibroblast assays and genetic analysis. Limitations: Single rare-disease case; not evidence of the same block in ordinary dietary variation. Evidence access: Primary abstract S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15024124/ · DOI 10.1073/pnas.0400658101

evidence_access

Primary abstract

experimental_model

Established reaction in the human AHCY-deficiency investigation.

limitations

Reaction equilibrium and cellular product removal matter; plasma concentrations do not uniquely define tissue flux.

nutrient_topic

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

plain_language

After methyl transfer, the spent donor must be processed.

primary_references

S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15024124/ · DOI 10.1073/pnas.0400658101

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 172–178

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established reaction in the human AHCY-deficiency investigation. · source_derived_draft · unverified_draft

## methionine-ahcy-reaction After methyl transfer, the spent donor must be processed. AHCY catalyzes reversible conversion between SAH and adenosine plus homocysteine; product clearance favors net SAH removal. Model: Established reaction in the human AHCY-deficiency investigation. Limitations: Reaction equilibrium and cellular product removal matter; plasma concentrations do not uniquely define tissue flux. Evidence access: Primary abstract S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15024124/ · DOI 10.1073/pnas.0400658101

evidence_access

Primary abstract

experimental_model

Human CBS structural study with SAM-bound activated conformation.

limitations

Allosteric regulation does not establish in-vivo flux under every nutritional condition.

nutrient_topic

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

plain_language

A plentiful methyl donor can turn up the sulfur-transfer branch.

primary_references

Structural insight into the molecular mechanism of allosteric activation of human cystathionine β-synthase by S-adenosylmethionine. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25197074/ · DOI 10.1073/pnas.1414545111

L-Methionine: transport, methylation, sulfur metabolism 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 · Human CBS structural study with SAM-bound activated conformation. · source_derived_draft · unverified_draft

## methionine-cbs-sam-allostery A plentiful methyl donor can turn up the sulfur-transfer branch. SAM binding rearranged the human CBS regulatory domain and relieved autoinhibition, improving access to its catalytic pocket. Model: Human CBS structural study with SAM-bound activated conformation. Limitations: Allosteric regulation does not establish in-vivo flux under every nutritional condition. Evidence access: Primary abstract Structural insight into the molecular mechanism of allosteric activation of human cystathionine β-synthase by S-adenosylmethionine. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25197074/ · DOI 10.1073/pnas.1414545111

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Randomized crossover human loading study.

limitations

Challenge dose is not ordinary food intake; response depends on metabolism and context.

nutrient_topic

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

plain_language

A large acute load challenges recycling and sulfur disposal.

primary_references

Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9799203/ · DOI 10.1161/01.cir.98.18.1848

trigger_kind

biomarker_context Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 412–418

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Randomized crossover human loading study. · source_derived_draft · unverified_draft

## methionine-load-homocysteine A large acute load challenges recycling and sulfur disposal. A 0.1 g/kg oral methionine load increased mean plasma homocysteine from 7.9 to 23.1 micromolar at four hours in 24 healthy volunteers. Model: Randomized crossover human loading study. Limitations: Challenge dose is not ordinary food intake; response depends on metabolism and context. Evidence access: Primary abstract Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9799203/ · DOI 10.1161/01.cir.98.18.1848

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Healthy adults; 0.1 g/kg oral load and brachial-artery measurements.

limitations

Does not isolate homocysteine as the sole mediator or demonstrate long-term cardiovascular events.

nutrient_topic

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

plain_language

The loading experiment also measured a vascular response.

primary_references

Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9799203/ · DOI 10.1161/01.cir.98.18.1848

trigger_kind

biomarker_context Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 420–426

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Healthy adults; 0.1 g/kg oral load and brachial-artery measurements. · source_derived_draft · unverified_draft

## methionine-load-vascular The loading experiment also measured a vascular response. The methionine-loading visit showed reduced flow-mediated dilation alongside higher homocysteine; the time courses were similar in a smaller follow-up group. Model: Healthy adults; 0.1 g/kg oral load and brachial-artery measurements. Limitations: Does not isolate homocysteine as the sole mediator or demonstrate long-term cardiovascular events. Evidence access: Primary abstract Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9799203/ · DOI 10.1161/01.cir.98.18.1848

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Engineered yeast; 13C labeling and metabolic/enzyme assays.

limitations

Not a phenotype demonstrated for common human MTHFR polymorphisms.

nutrient_topic

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

plain_language

Removing a feedback brake can waste energy rather than improve the pathway.

primary_references

Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32934008/ · DOI 10.1074/jbc.RA120.015129

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 220–226

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Engineered yeast; 13C labeling and metabolic/enzyme assays. · source_derived_draft · unverified_draft

## methionine-mthfr-feedback-loss Removing a feedback brake can waste energy rather than improve the pathway. Feedback-insensitive yeast MTHFR mutants underwent excessive methionine/SAM cycling with ATP and nucleotide depletion and poor growth in methionine-containing medium. Model: Engineered yeast; 13C labeling and metabolic/enzyme assays. Limitations: Not a phenotype demonstrated for common human MTHFR polymorphisms. Evidence access: Primary abstract Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32934008/ · DOI 10.1074/jbc.RA120.015129

cross_nutrient

B2 flavins support reactivation of B12-dependent folate/homocysteine metabolism.

evidence_location

Abstract

experimental_model

Recombinant human MTRR purification, flavin analysis, NADPH spectroscopy and methionine-synthase reconstitution.

exposure

Purified-enzyme assay

limitations

Reconstituted biochemistry; the accessible abstract identifies human MTRR but not the target MTR species. No dietary B2/B12 synergy was tested.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Homo sapiens

plain_language

The flavin reductase helps restore an enzyme that uses B12 and methylfolate.

primary_references

[olteanu2001] Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation. (2001). https://pubmed.ncbi.nlm.nih.gov/11466310/ DOI: 10.1074/jbc.m103707200

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1122–1134

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTRR purification, flavin analysis, NADPH spectroscopy and methionine-synthase reconstitution. · source_derived_draft · unverified_draft

### b2-mtrr-mtr-reactivation Reconstituted assays showed human MTRR sufficient to support NADPH-dependent activity of cobalamin-dependent methionine synthase. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The flavin reductase helps restore an enzyme that uses B12 and methylfolate. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human MTRR purification, flavin analysis, NADPH spectroscopy and methionine-synthase reconstitution. limitations: Reconstituted biochemistry; the accessible abstract identifies human MTRR but not the target MTR species. No dietary B2/B12 synergy was tested. exposure: Purified-enzyme assay cross_nutrient: B2 flavins support reactivation of B12-dependent folate/homocysteine metabolism. evidence_location: Abstract [olteanu2001] Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation. (2001). https://pubmed.ncbi.nlm.nih.gov/11466310/ DOI: 10.1074/jbc.m103707200

evidence_access

Primary full text

experimental_model

Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation.

limitations

Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification.

nutrient_topic

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

plain_language

Less inflammatory-enzyme message was produced.

primary_references

Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 60–66

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. · source_derived_draft · unverified_draft

## fulvic-acid-cox-expression Less inflammatory-enzyme message was produced. Fulvic pretreatment reduced homocysteine-induced COX-2 mRNA in primary monocytes and U937 cells. Model: Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. Limitations: Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification. Evidence access: Primary full text Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

evidence_access

Primary full text

experimental_model

Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation.

limitations

Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification.

nutrient_topic

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

plain_language

The preparation dampened the ERK response.

primary_references

Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 36–42

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. · source_derived_draft · unverified_draft

## fulvic-acid-fa-erk The preparation dampened the ERK response. Fulvic pretreatment reduced homocysteine-stimulated ERK phosphorylation. Model: Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. Limitations: Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification. Evidence access: Primary full text Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

evidence_access

Primary full text

experimental_model

Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation.

limitations

Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification.

nutrient_topic

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

plain_language

The preparation dampened the JNK response.

primary_references

Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 44–50

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. · source_derived_draft · unverified_draft

## fulvic-acid-fa-jnk The preparation dampened the JNK response. Fulvic pretreatment reduced homocysteine-stimulated JNK phosphorylation. Model: Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. Limitations: Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification. Evidence access: Primary full text Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

evidence_access

Primary full text

experimental_model

Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation.

limitations

Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification. ChIP is a cultured-cell result; the paper uses in vivo to mean within cells.

nutrient_topic

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

plain_language

The inflammatory transcription factor occupied the promoter less.

primary_references

Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 52–58

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. · source_derived_draft · unverified_draft

## fulvic-acid-p65-binding The inflammatory transcription factor occupied the promoter less. Fulvic pretreatment reduced p65 binding at the COX-2 promoter in stimulated U937 cells. Model: Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. Limitations: Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification. ChIP is a cultured-cell result; the paper uses in vivo to mean within cells. Evidence access: Primary full text Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

evidence_access

Primary full text

experimental_model

Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation.

limitations

Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification. This is not a demonstrated direct COX-2 catalytic inhibitor.

nutrient_topic

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

plain_language

The downstream prostaglandin output also fell.

primary_references

Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 68–74

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. · source_derived_draft · unverified_draft

## fulvic-acid-pge-output The downstream prostaglandin output also fell. Fulvic pretreatment reduced PGE2 release after homocysteine stimulation. Model: Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. Limitations: Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification. This is not a demonstrated direct COX-2 catalytic inhibitor. Evidence access: Primary full text Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

availability_state

biomarker_context Imported condition classification; unverified.

experimental_model

Double-blind randomized trial: 201 adults aged at least 75 with B12 107–210 pmol/L, without anemia or relevant neurologic/cognitive signs; 191 had outcome assessment.

exposure

Oral cyanocobalamin 1 mg/day versus placebo for 12 months.

limitations

Blood responses do not establish delivery or functional recovery in every tissue.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The tablets changed the biochemical measurements.

primary_references

[b12-dangour2015] Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial (2015). https://pubmed.ncbi.nlm.nih.gov/26135351/ DOI: 10.3945/ajcn.115.110775

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1512–1522

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 201 adults aged at least 75 with B12 107–210 pmol/L, without anemia or relevant neurologic/cognitive signs; 191 had outcome assessment. · source_derived_draft · unverified_draft

### b12-dangour-status-response Cyanocobalamin increased serum B12 and holotranscobalamin and reduced total homocysteine during the 12-month trial. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The tablets changed the biochemical measurements. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 201 adults aged at least 75 with B12 107–210 pmol/L, without anemia or relevant neurologic/cognitive signs; 191 had outcome assessment. limitations: Blood responses do not establish delivery or functional recovery in every tissue. exposure: Oral cyanocobalamin 1 mg/day versus placebo for 12 months. [b12-dangour2015] Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial (2015). https://pubmed.ncbi.nlm.nih.gov/26135351/ DOI: 10.3945/ajcn.115.110775

availability_state

biomarker_context Imported condition classification; unverified.

experimental_model

Double-blind randomized trial: 79 referred infants younger than eight months with plasma total homocysteine at least 6.5 micromol/L, from 105 assessed.

exposure

One 400-microgram intramuscular hydroxocobalamin injection (42 infants) versus sham injection (37); one-month follow-up.

limitations

One-month response does not define a treatment regimen for other infants.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Both connected metabolic markers responded to the intervention.

primary_references

[b12-torsvik2013] Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study (2013). https://pubmed.ncbi.nlm.nih.gov/24025626/ DOI: 10.3945/ajcn.113.061549

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1734–1744

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 79 referred infants younger than eight months with plasma total homocysteine at least 6.5 micromol/L, from 105 assessed. · source_derived_draft · unverified_draft

### b12-infant-biochemical-response After injection, total homocysteine fell 54% and MMA 84%; placebo showed no significant changes. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Both connected metabolic markers responded to the intervention. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 79 referred infants younger than eight months with plasma total homocysteine at least 6.5 micromol/L, from 105 assessed. limitations: One-month response does not define a treatment regimen for other infants. exposure: One 400-microgram intramuscular hydroxocobalamin injection (42 infants) versus sham injection (37); one-month follow-up. [b12-torsvik2013] Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study (2013). https://pubmed.ncbi.nlm.nih.gov/24025626/ DOI: 10.3945/ajcn.113.061549

availability_state

biomarker_context Imported condition classification; unverified.

experimental_model

Randomized placebo-controlled trial: 271 nondemented diabetic outpatients aged at least 70, plasma B12 150–300 pmol/L.

exposure

Oral methylcobalamin 1000 micrograms/day versus placebo for 27 months.

limitations

No direct cellular flux measurement and no head-to-head form comparison.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

This B12 form improved the measured metabolic markers.

primary_references

[b12-kwok2017] A randomized placebo controlled trial of vitamin B12 supplementation to prevent cognitive decline in older diabetic people with borderline low serum vitamin B12 (2017). https://pubmed.ncbi.nlm.nih.gov/27823800/ DOI: 10.1016/j.clnu.2016.10.018

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1561–1571

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized placebo-controlled trial: 271 nondemented diabetic outpatients aged at least 70, plasma B12 150–300 pmol/L. · source_derived_draft · unverified_draft

### b12-methylcobalamin-diabetes-metabolites MMA and homocysteine were significantly lower with methylcobalamin than placebo at months 9 and 27. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This B12 form improved the measured metabolic markers. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Randomized placebo-controlled trial: 271 nondemented diabetic outpatients aged at least 70, plasma B12 150–300 pmol/L. limitations: No direct cellular flux measurement and no head-to-head form comparison. exposure: Oral methylcobalamin 1000 micrograms/day versus placebo for 27 months. [b12-kwok2017] A randomized placebo controlled trial of vitamin B12 supplementation to prevent cognitive decline in older diabetic people with borderline low serum vitamin B12 (2017). https://pubmed.ncbi.nlm.nih.gov/27823800/ DOI: 10.1016/j.clnu.2016.10.018

cross_nutrient

true

evidence_location

Primary abstract; indexed article Introduction/Figure 1

experimental_model

Purified human MMACHC thiol substitution assays

exposure

GSH versus cysteine or homocysteine

limitations

No implication that cysteine availability is irrelevant to cellular GSH synthesis; that upstream pathway was not tested here.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Having a thiol group was not enough; the enzyme required glutathione in these assays.

primary_references

[kim-2009-gsh-dealkylation] A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins (2009). https://pubmed.ncbi.nlm.nih.gov/19801555/ DOI: 10.1074/jbc.M109.057877

tissue_or_cell_type

Cell-free assay

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 739–751

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

### b12-mmachc-thiol-specificity In the human MMACHC dealkylation study, cysteine and homocysteine did not substitute for glutathione as the thiol co-substrate. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Having a thiol group was not enough; the enzyme required glutathione in these assays. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Purified human MMACHC thiol substitution assays limitations: No implication that cysteine availability is irrelevant to cellular GSH synthesis; that upstream pathway was not tested here. exposure: GSH versus cysteine or homocysteine cross_nutrient: true evidence_location: Primary abstract; indexed article Introduction/Figure 1 [kim-2009-gsh-dealkylation] A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins (2009). https://pubmed.ncbi.nlm.nih.gov/19801555/ DOI: 10.1074/jbc.M109.057877

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Randomized oral-versus-intramuscular study: 38 allocated; five subsequently identified as folate deficient excluded, leaving 18 oral and 15 injection participants.

exposure

Cyanocobalamin 2 mg orally each day for 120 days versus 1 mg IM on days 1, 3, 7, 10, 14, 21, 30, 60 and 90. Unequal cumulative exposures.

limitations

Different cumulative exposures prevent interpreting the result as inherent route superiority.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The biochemical response was recorded separately from the clinical response.

primary_references

[b12-kuzminski1998] Effective treatment of cobalamin deficiency with oral cobalamin (1998). https://pubmed.ncbi.nlm.nih.gov/9694707/ DOI: 10.1182/blood.v92.4.1191

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1697–1707

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized oral-versus-intramuscular study: 38 allocated; five subsequently identified as folate deficient excluded, leaving 18 oral and 15 injection participants. · source_derived_draft · unverified_draft

### b12-oral-im-metabolic-response At four months, mean MMA was 169 nmol/L with oral versus 265 with IM treatment; homocysteine was 10.6 versus 12.2 micromol/L. Oral-group MMA was significantly lower. Condition category: nutrient_deficiency nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The biochemical response was recorded separately from the clinical response. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Randomized oral-versus-intramuscular study: 38 allocated; five subsequently identified as folate deficient excluded, leaving 18 oral and 15 injection participants. limitations: Different cumulative exposures prevent interpreting the result as inherent route superiority. exposure: Cyanocobalamin 2 mg orally each day for 120 days versus 1 mg IM on days 1, 3, 7, 10, 14, 21, 30, 60 and 90. Unequal cumulative exposures. [b12-kuzminski1998] Effective treatment of cobalamin deficiency with oral cobalamin (1998). https://pubmed.ncbi.nlm.nih.gov/9694707/ DOI: 10.1182/blood.v92.4.1191

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"}

experimental_model

Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin

exposure

850 mg metformin three times daily for 4.3 years versus placebo

limitations

The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

The lower the vitamin, the higher this metabolite climbed.

primary_references

[metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

tissue_or_cell_type

Whole body

trigger_kind

biomarker_context Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1074–1085

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin · source_derived_draft · unverified_draft

### metformin-b12-homocysteine Patients with vitamin B-12 deficiency at study end had a mean homocysteine of 23.7 micromol/l, compared with 18.1 in those with low B-12 and 14.9 in those with normal B-12. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The lower the vitamin, the higher this metabolite climbed. organism: Human tissue_or_cell_type: Whole body experimental_model: Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin limitations: The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes. exposure: 850 mg metformin three times daily for 4.3 years versus placebo evidence_span: {"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"} [metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

evidence_access

Primary abstract

experimental_model

Human and yeast CBS kinetics, with human enzyme kept as this record’s subject.

limitations

Relative pathway dominance in a tissue cannot be read directly from purified-enzyme substrate tests.

nutrient_topic

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

plain_language

An enzyme that helps synthesize cysteine can also use it in sulfur-gas production.

primary_references

Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19531479/ · DOI 10.1074/jbc.M109.010868

L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 284–290

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human and yeast CBS kinetics, with human enzyme kept as this record’s subject. · source_derived_draft · unverified_draft

## l-cysteine-cbs-h2s-branch An enzyme that helps synthesize cysteine can also use it in sulfur-gas production. Purified human CBS favored H2S production through replacement of cysteine by homocysteine over the tested alternative cysteine reactions. Model: Human and yeast CBS kinetics, with human enzyme kept as this record’s subject. Limitations: Relative pathway dominance in a tissue cannot be read directly from purified-enzyme substrate tests. Evidence access: Primary abstract Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19531479/ · DOI 10.1074/jbc.M109.010868

evidence_access

Primary abstract

experimental_model

Simulation based on purified CBS/CSE kinetics with assumed equimolar enzyme concentrations.

limitations

A modeled 25–70% contribution is not a directly measured universal human tissue fraction.

nutrient_topic

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

plain_language

Methylation-cycle chemistry can influence a sulfur-signaling branch.

primary_references

Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19531479/ · DOI 10.1074/jbc.M109.010868

L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 292–298

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Simulation based on purified CBS/CSE kinetics with assumed equimolar enzyme concentrations. · source_derived_draft · unverified_draft

## l-cysteine-sam-sulfur-partition Methylation-cycle chemistry can influence a sulfur-signaling branch. Kinetic simulations predicted that SAM-dependent activation changes the relative CBS contribution to H2S generation at specified substrate concentrations. Model: Simulation based on purified CBS/CSE kinetics with assumed equimolar enzyme concentrations. Limitations: A modeled 25–70% contribution is not a directly measured universal human tissue fraction. Evidence access: Primary abstract Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19531479/ · DOI 10.1074/jbc.M109.010868

cross_nutrient

Betaine/choline and folate routes meet at homocysteine.

experimental_model

Recombinant human BHMT and human liver-derived BHMT.

limitations

Does not establish complete folate substitution in vivo.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Betaine supplies another recycling route.

primary_references

[millian-1998] Human betaine-homocysteine methyltransferase is a zinc metalloenzyme (1998). https://pubmed.ncbi.nlm.nih.gov/9681996/ DOI: 10.1006/abbi.1998.0757

tissue_or_cell_type

Recombinant and liver-derived enzyme

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 610–620

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human BHMT and human liver-derived BHMT. · source_derived_draft · unverified_draft

### folate-methyl-bhmt-reaction Purified human BHMT uses betaine and homocysteine in the alternative methionine-forming reaction. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Betaine supplies another recycling route. organism: Homo sapiens tissue_or_cell_type: Recombinant and liver-derived enzyme experimental_model: Recombinant human BHMT and human liver-derived BHMT. limitations: Does not establish complete folate substitution in vivo. cross_nutrient: Betaine/choline and folate routes meet at homocysteine. [millian-1998] Human betaine-homocysteine methyltransferase is a zinc metalloenzyme (1998). https://pubmed.ncbi.nlm.nih.gov/9681996/ DOI: 10.1006/abbi.1998.0757

cross_nutrient

Folate methyl transfer requires B12.

experimental_model

Human MTR/MTRR expressed in insect cells; purified enzymes and extracts.

limitations

Chemistry, not dietary response.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

B12-dependent MTR recycles both homocysteine and folate.

primary_references

[yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103

tissue_or_cell_type

Purified protein

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 482–492

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. · source_derived_draft · unverified_draft

### folate-methyl-mtr-methyl-transfer Reconstituted human MTR transfers methylfolate-derived methyl groups through cobalamin to homocysteine, producing methionine and THF. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: B12-dependent MTR recycles both homocysteine and folate. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. limitations: Chemistry, not dietary response. cross_nutrient: Folate methyl transfer requires B12. [yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103