Human cytochrome P450 1A2

evidence_span

{"source_cache": "artifacts/dim-research/19770484.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b5956f74860b0cd89114dab4179908bae1a59aab65220ac0421f4c5365bed6ba", "start_char": 0, "end_char": 1446, "text_sha256": "b5956f74860b0cd89114dab4179908bae1a59aab65220ac0421f4c5365bed6ba"}

experimental_model

Pretreatment versus cotreatment, adduct and recombinant-enzyme assays

exposure

DIM pretreatment for 48 hours; direct catalytic assays separately

limitations

Induction over time and direct inhibition are distinct mechanisms. Aflatoxin assay effects do not establish human cancer incidence or net disposition of unrelated drugs.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Primary human hepatocytes and human enzyme preparations

plain_language

Competing activation and conjugation routes may explain the net effect.

primary_references

[dim-p19770484] Modulation of aflatoxin B1-mediated genotoxicity in primary cultures of human hepatocytes by diindolylmethane, curcumin, and xanthohumols. (2009). https://pubmed.ncbi.nlm.nih.gov/19770484/ DOI: 10.1093/toxsci/kfp206

tissue_or_cell_type

Aflatoxin metabolism and CYP catalytic activity

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 480–491

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pretreatment versus cotreatment, adduct and recombinant-enzyme assays · source_derived_draft · unverified_draft

### dim-aflatoxin-explanation The authors linked the DIM-associated adduct increase to CYP1A2 induction and/or GSTM1 downregulation. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Competing activation and conjugation routes may explain the net effect. organism: Primary human hepatocytes and human enzyme preparations tissue_or_cell_type: Aflatoxin metabolism and CYP catalytic activity experimental_model: Pretreatment versus cotreatment, adduct and recombinant-enzyme assays limitations: Induction over time and direct inhibition are distinct mechanisms. Aflatoxin assay effects do not establish human cancer incidence or net disposition of unrelated drugs. exposure: DIM pretreatment for 48 hours; direct catalytic assays separately evidence_span: {"source_cache": "artifacts/dim-research/19770484.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b5956f74860b0cd89114dab4179908bae1a59aab65220ac0421f4c5365bed6ba", "start_char": 0, "end_char": 1446, "text_sha256": "b5956f74860b0cd89114dab4179908bae1a59aab65220ac0421f4c5365bed6ba"} [dim-p19770484] Modulation of aflatoxin B1-mediated genotoxicity in primary cultures of human hepatocytes by diindolylmethane, curcumin, and xanthohumols. (2009). https://pubmed.ncbi.nlm.nih.gov/19770484/ DOI: 10.1093/toxsci/kfp206

evidence_span

{"source_cache": "artifacts/dim-research/15289794.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "90eb96e72afdbbb53c322c2be9a34e5aa523c27f2fd0995a8eb224e2ec6e35e2", "start_char": 0, "end_char": 1753, "text_sha256": "90eb96e72afdbbb53c322c2be9a34e5aa523c27f2fd0995a8eb224e2ec6e35e2"}

experimental_model

Repeated caffeine phenotyping after smoking cessation

exposure

Abrupt cessation after run-in; repeated 148-mg caffeine probe doses

limitations

Smoking-cessation kinetics cannot be assigned to starting or stopping DIM. Clinical dose management requires drug-specific monitoring.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

12 heavy smokers

plain_language

Caffeine provides a measurable probe of enzyme activity.

primary_references

[dim-p15289794] Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. (2004). https://pubmed.ncbi.nlm.nih.gov/15289794/ DOI: 10.1016/j.clpt.2004.04.003

tissue_or_cell_type

CYP1A2 activity and caffeine clearance

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 831–842

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Repeated caffeine phenotyping after smoking cessation · source_derived_draft · unverified_draft

### dim-caffeine-1a2 The paraxanthine-to-caffeine ratio was used to phenotype CYP1A2 during smoking cessation. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Caffeine provides a measurable probe of enzyme activity. organism: 12 heavy smokers tissue_or_cell_type: CYP1A2 activity and caffeine clearance experimental_model: Repeated caffeine phenotyping after smoking cessation limitations: Smoking-cessation kinetics cannot be assigned to starting or stopping DIM. Clinical dose management requires drug-specific monitoring. exposure: Abrupt cessation after run-in; repeated 148-mg caffeine probe doses evidence_span: {"source_cache": "artifacts/dim-research/15289794.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "90eb96e72afdbbb53c322c2be9a34e5aa523c27f2fd0995a8eb224e2ec6e35e2", "start_char": 0, "end_char": 1753, "text_sha256": "90eb96e72afdbbb53c322c2be9a34e5aa523c27f2fd0995a8eb224e2ec6e35e2"} [dim-p15289794] Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. (2004). https://pubmed.ncbi.nlm.nih.gov/15289794/ DOI: 10.1016/j.clpt.2004.04.003

evidence_span

{"source_cache": "artifacts/dim-research/9384460.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "eb481193bb0d7564d728a25a9ddd63678e8234e628edca3f13ece910770279b6", "start_char": 0, "end_char": 1794, "text_sha256": "eb481193bb0d7564d728a25a9ddd63678e8234e628edca3f13ece910770279b6"}

experimental_model

Recombinant enzymes, antibodies and human liver microsomes

exposure

Enzyme-specific inhibition and metabolite formation

limitations

Identifies metabolic routes, not a trial of DIM with clozapine. Do not infer a dose change or magnitude of interaction.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human CYP enzymes

plain_language

Clozapine shares an enzyme that DIM can induce in laboratory systems; its response to DIM was not measured.

primary_references

[dim-p9384460] The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. (1997). https://pubmed.ncbi.nlm.nih.gov/9384460/ DOI: 10.1046/j.1365-2125.1997.t01-1-00605.x

tissue_or_cell_type

Clozapine oxidation

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 662–673

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

### dim-clozapine-1a2 CYP1A2 contributed to clozapine demethylation. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Clozapine shares an enzyme that DIM can induce in laboratory systems; its response to DIM was not measured. organism: Human CYP enzymes tissue_or_cell_type: Clozapine oxidation experimental_model: Recombinant enzymes, antibodies and human liver microsomes limitations: Identifies metabolic routes, not a trial of DIM with clozapine. Do not infer a dose change or magnitude of interaction. exposure: Enzyme-specific inhibition and metabolite formation evidence_span: {"source_cache": "artifacts/dim-research/9384460.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "eb481193bb0d7564d728a25a9ddd63678e8234e628edca3f13ece910770279b6", "start_char": 0, "end_char": 1794, "text_sha256": "eb481193bb0d7564d728a25a9ddd63678e8234e628edca3f13ece910770279b6"} [dim-p9384460] The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. (1997). https://pubmed.ncbi.nlm.nih.gov/9384460/ DOI: 10.1046/j.1365-2125.1997.t01-1-00605.x

evidence_span

{"source_cache": "artifacts/dim-research/17311915.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4c3f047d0ee4583ca15aae2c7059d2237b02105371fda21bf32639cbaad2d318", "start_char": 0, "end_char": 1400, "text_sha256": "4c3f047d0ee4583ca15aae2c7059d2237b02105371fda21bf32639cbaad2d318"}

experimental_model

X-ray crystallography

exposure

Alpha-naphthoflavone-bound structure at 1.95 angstrom resolution

limitations

Structural enzyme requirement; not proof that DIM depletes iron or that iron supplementation changes DIM response.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Purified human CYP1A2

plain_language

The induced enzyme still needs its iron-containing catalytic machinery.

primary_references

[dim-p17311915] Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2. (2007). https://pubmed.ncbi.nlm.nih.gov/17311915/ DOI: 10.1074/jbc.m611692200

tissue_or_cell_type

Catalytic pocket

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 259–270

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

### dim-cyp1a2-heme The CYP1A2 structure places its ligand above the heme prosthetic group. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: The induced enzyme still needs its iron-containing catalytic machinery. organism: Purified human CYP1A2 tissue_or_cell_type: Catalytic pocket experimental_model: X-ray crystallography limitations: Structural enzyme requirement; not proof that DIM depletes iron or that iron supplementation changes DIM response. exposure: Alpha-naphthoflavone-bound structure at 1.95 angstrom resolution evidence_span: {"source_cache": "artifacts/dim-research/17311915.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4c3f047d0ee4583ca15aae2c7059d2237b02105371fda21bf32639cbaad2d318", "start_char": 0, "end_char": 1400, "text_sha256": "4c3f047d0ee4583ca15aae2c7059d2237b02105371fda21bf32639cbaad2d318"} [dim-p17311915] Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2. (2007). https://pubmed.ncbi.nlm.nih.gov/17311915/ DOI: 10.1074/jbc.m611692200

evidence_span

{"source_cache": "artifacts/dim-research/18307373.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2705ee887855e9dbe738ece57d4ad9d4b3d8cc0d67de45e63c01497a4a215149", "start_char": 0, "end_char": 2879, "text_sha256": "2705ee887855e9dbe738ece57d4ad9d4b3d8cc0d67de45e63c01497a4a215149"}

experimental_model

Enzyme phenotyping and clinical drug-interaction studies

exposure

Fluvoxamine with oral or intravenous duloxetine

limitations

The clinical exposure change was caused by fluvoxamine, not DIM. The study tests inhibition, not the inverse size of induction.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human enzyme systems and healthy adults

plain_language

A shared enzyme is a reason to investigate an interaction, not proof DIM lowers the drug level.

primary_references

[dim-p18307373] In vitro and in vivo evaluations of cytochrome P450 1A2 interactions with duloxetine. (2008). https://pubmed.ncbi.nlm.nih.gov/18307373/ DOI: 10.2165/00003088-200847030-00005

tissue_or_cell_type

Duloxetine metabolism and exposure

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 792–803

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme phenotyping and clinical drug-interaction studies · source_derived_draft · unverified_draft

### dim-duloxetine-1a2 CYP1A2 catalyzed duloxetine metabolism in the in-vitro experiments. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: A shared enzyme is a reason to investigate an interaction, not proof DIM lowers the drug level. organism: Human enzyme systems and healthy adults tissue_or_cell_type: Duloxetine metabolism and exposure experimental_model: Enzyme phenotyping and clinical drug-interaction studies limitations: The clinical exposure change was caused by fluvoxamine, not DIM. The study tests inhibition, not the inverse size of induction. exposure: Fluvoxamine with oral or intravenous duloxetine evidence_span: {"source_cache": "artifacts/dim-research/18307373.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2705ee887855e9dbe738ece57d4ad9d4b3d8cc0d67de45e63c01497a4a215149", "start_char": 0, "end_char": 2879, "text_sha256": "2705ee887855e9dbe738ece57d4ad9d4b3d8cc0d67de45e63c01497a4a215149"} [dim-p18307373] In vitro and in vivo evaluations of cytochrome P450 1A2 interactions with duloxetine. (2008). https://pubmed.ncbi.nlm.nih.gov/18307373/ DOI: 10.2165/00003088-200847030-00005

evidence_span

{"source_cache": "artifacts/dim-research/11317475.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "503f4e9d299c6c978aa1e867a32cdc7b4f5c191290b74415f0f152d3b2f0d87d", "start_char": 0, "end_char": 1580, "text_sha256": "503f4e9d299c6c978aa1e867a32cdc7b4f5c191290b74415f0f152d3b2f0d87d"}

experimental_model

Human microsomes, expressed enzymes and inhibition assays

exposure

Substrate range 1-1000 micromolar

limitations

In-vitro pathway identification; no DIM coadministration, sleep outcome or proof that DIM lowers nighttime melatonin.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human liver CYP systems

plain_language

Melatonin shares the enzyme; a DIM effect on sleep cannot be read directly from this edge.

primary_references

[dim-p11317475] Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes. (2001). https://pubmed.ncbi.nlm.nih.gov/11317475/ DOI: 10.1007/s002280000245

tissue_or_cell_type

Melatonin 6-hydroxylation

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 818–829

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human microsomes, expressed enzymes and inhibition assays · source_derived_draft · unverified_draft

### dim-melatonin-1a2 CYP1A2 was the principal high-affinity, but not exclusive, enzyme for melatonin 6-hydroxylation. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Melatonin shares the enzyme; a DIM effect on sleep cannot be read directly from this edge. organism: Human liver CYP systems tissue_or_cell_type: Melatonin 6-hydroxylation experimental_model: Human microsomes, expressed enzymes and inhibition assays limitations: In-vitro pathway identification; no DIM coadministration, sleep outcome or proof that DIM lowers nighttime melatonin. exposure: Substrate range 1-1000 micromolar evidence_span: {"source_cache": "artifacts/dim-research/11317475.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "503f4e9d299c6c978aa1e867a32cdc7b4f5c191290b74415f0f152d3b2f0d87d", "start_char": 0, "end_char": 1580, "text_sha256": "503f4e9d299c6c978aa1e867a32cdc7b4f5c191290b74415f0f152d3b2f0d87d"} [dim-p11317475] Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes. (2001). https://pubmed.ncbi.nlm.nih.gov/11317475/ DOI: 10.1007/s002280000245

evidence_span

{"source_cache": "artifacts/dim-research/26329789.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1f2f35be434034ef4788653d084a6b184b1b5a109d445591c4fd0fc94b36e543", "start_char": 0, "end_char": 1657, "text_sha256": "1f2f35be434034ef4788653d084a6b184b1b5a109d445591c4fd0fc94b36e543"}

experimental_model

Human liver microsomes and recombinant enzyme phenotyping

exposure

Metabolite-specific assays including albumin effects

limitations

In-vitro relative contributions; no DIM coadministration. Multiple routes limit prediction from CYP1A2 alone.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human CYP, FMO and UGT enzymes

plain_language

This independently identified route also contributes to olanzapine handling.

primary_references

[dim-p26329789] In Vitro Characterization of the Human Liver Microsomal Kinetics and Reaction Phenotyping of Olanzapine Metabolism. (2015). https://pubmed.ncbi.nlm.nih.gov/26329789/ DOI: 10.1124/dmd.115.064790

tissue_or_cell_type

Olanzapine oxidation and conjugation

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 701–712

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human liver microsomes and recombinant enzyme phenotyping · source_derived_draft · unverified_draft

### dim-olanzapine-1a2 CYP1A2 played a major role in olanzapine 7-hydroxylation and also contributed to N-demethylation. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: This independently identified route also contributes to olanzapine handling. organism: Human CYP, FMO and UGT enzymes tissue_or_cell_type: Olanzapine oxidation and conjugation experimental_model: Human liver microsomes and recombinant enzyme phenotyping limitations: In-vitro relative contributions; no DIM coadministration. Multiple routes limit prediction from CYP1A2 alone. exposure: Metabolite-specific assays including albumin effects evidence_span: {"source_cache": "artifacts/dim-research/26329789.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1f2f35be434034ef4788653d084a6b184b1b5a109d445591c4fd0fc94b36e543", "start_char": 0, "end_char": 1657, "text_sha256": "1f2f35be434034ef4788653d084a6b184b1b5a109d445591c4fd0fc94b36e543"} [dim-p26329789] In Vitro Characterization of the Human Liver Microsomal Kinetics and Reaction Phenotyping of Olanzapine Metabolism. (2015). https://pubmed.ncbi.nlm.nih.gov/26329789/ DOI: 10.1124/dmd.115.064790

evidence_span

{"source_cache": "artifacts/dim-research/8591723.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "04a615c551d95089eb1a966d88d8be011687d658f383e81af5b651845427b66e", "start_char": 0, "end_char": 1460, "text_sha256": "04a615c551d95089eb1a966d88d8be011687d658f383e81af5b651845427b66e"}

experimental_model

Human microsomes and individually expressed enzymes

exposure

Enzyme-specific inhibitors and radiolabeled substrate

limitations

CYP3A is identified at subfamily level, without an exclusive isoform assignment. Multiple CYP pathways contribute; no DIM coadministration or clinically measured DIM effect.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human CYP systems

plain_language

A substrate list alone omits other routes that can limit a single-enzyme interaction.

primary_references

[dim-p8591723] Multiple forms of cytochrome P450 are involved in the metabolism of ondansetron in humans. (1995). https://pubmed.ncbi.nlm.nih.gov/8591723/ DOI: 10.1016/s0090-9556(25)06820-5

tissue_or_cell_type

Ondansetron oxidation

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 948–959

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human microsomes and individually expressed enzymes · source_derived_draft · unverified_draft

### dim-ondansetron-cyp1a2 CYP1A2 contributed to ondansetron metabolism in the studied human systems. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: A substrate list alone omits other routes that can limit a single-enzyme interaction. organism: Human CYP systems tissue_or_cell_type: Ondansetron oxidation experimental_model: Human microsomes and individually expressed enzymes limitations: CYP3A is identified at subfamily level, without an exclusive isoform assignment. Multiple CYP pathways contribute; no DIM coadministration or clinically measured DIM effect. exposure: Enzyme-specific inhibitors and radiolabeled substrate evidence_span: {"source_cache": "artifacts/dim-research/8591723.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "04a615c551d95089eb1a966d88d8be011687d658f383e81af5b651845427b66e", "start_char": 0, "end_char": 1460, "text_sha256": "04a615c551d95089eb1a966d88d8be011687d658f383e81af5b651845427b66e"} [dim-p8591723] Multiple forms of cytochrome P450 are involved in the metabolism of ondansetron in humans. (1995). https://pubmed.ncbi.nlm.nih.gov/8591723/ DOI: 10.1016/s0090-9556(25)06820-5

evidence_span

{"source_cache": "artifacts/dim-research/7640150.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "368198090ed645914a14e9d365b48030bcfd8a67e4d5bc4f9f6d1476e8340247", "start_char": 0, "end_char": 2428, "text_sha256": "368198090ed645914a14e9d365b48030bcfd8a67e4d5bc4f9f6d1476e8340247"}

experimental_model

Human microsomes and recombinant enzyme phenotyping

exposure

N-desisopropylation versus ring hydroxylation

limitations

Route- and enantiomer-specific biochemistry; total propranolol exposure cannot be predicted from one route.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human CYP isoforms

plain_language

This is one route through a drug with several clearance mechanisms.

primary_references

[dim-p7640150] Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers--N-desisopropylation is mediated mainly by CYP1A2. (1995). https://pubmed.ncbi.nlm.nih.gov/7640150/ DOI: 10.1111/j.1365-2125.1995.tb04472.x

tissue_or_cell_type

Propranolol enantiomer metabolism

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 909–920

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human microsomes and recombinant enzyme phenotyping · source_derived_draft · unverified_draft

### dim-propranolol-1a2 CYP1A2 contributed prominently to propranolol N-desisopropylation. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: This is one route through a drug with several clearance mechanisms. organism: Human CYP isoforms tissue_or_cell_type: Propranolol enantiomer metabolism experimental_model: Human microsomes and recombinant enzyme phenotyping limitations: Route- and enantiomer-specific biochemistry; total propranolol exposure cannot be predicted from one route. exposure: N-desisopropylation versus ring hydroxylation evidence_span: {"source_cache": "artifacts/dim-research/7640150.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "368198090ed645914a14e9d365b48030bcfd8a67e4d5bc4f9f6d1476e8340247", "start_char": 0, "end_char": 2428, "text_sha256": "368198090ed645914a14e9d365b48030bcfd8a67e4d5bc4f9f6d1476e8340247"} [dim-p7640150] Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers--N-desisopropylation is mediated mainly by CYP1A2. (1995). https://pubmed.ncbi.nlm.nih.gov/7640150/ DOI: 10.1111/j.1365-2125.1995.tb04472.x

evidence_span

{"source_cache": "artifacts/dim-research/20478852.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0b04ad3560e6db88e29df6793283d7571c2e7bba1d499b30a5675e49bc17434e", "start_char": 0, "end_char": 1696, "text_sha256": "0b04ad3560e6db88e29df6793283d7571c2e7bba1d499b30a5675e49bc17434e"}

experimental_model

Microsomal metabolism and drug-interaction prediction

exposure

CYP1A2, CYP2C19 and CYP3A4 assays

limitations

In-vitro estimated shares vary by pathway and model. Fluvoxamine inhibits multiple routes; its large interaction cannot be inverted into a DIM prediction.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human liver and intestinal microsomes

plain_language

Ramelteon has several metabolic routes; none here measures a DIM interaction.

primary_references

[dim-p20478852] Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics. (2010). https://pubmed.ncbi.nlm.nih.gov/20478852/ DOI: 10.1124/dmd.110.034009

tissue_or_cell_type

Ramelteon metabolism

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 870–881

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Microsomal metabolism and drug-interaction prediction · source_derived_draft · unverified_draft

### dim-ramelteon-cyp1a2 CYP1A2 catalyzed ramelteon metabolism in the tested microsomal/recombinant system. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Ramelteon has several metabolic routes; none here measures a DIM interaction. organism: Human liver and intestinal microsomes tissue_or_cell_type: Ramelteon metabolism experimental_model: Microsomal metabolism and drug-interaction prediction limitations: In-vitro estimated shares vary by pathway and model. Fluvoxamine inhibits multiple routes; its large interaction cannot be inverted into a DIM prediction. exposure: CYP1A2, CYP2C19 and CYP3A4 assays evidence_span: {"source_cache": "artifacts/dim-research/20478852.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0b04ad3560e6db88e29df6793283d7571c2e7bba1d499b30a5675e49bc17434e", "start_char": 0, "end_char": 1696, "text_sha256": "0b04ad3560e6db88e29df6793283d7571c2e7bba1d499b30a5675e49bc17434e"} [dim-p20478852] Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics. (2010). https://pubmed.ncbi.nlm.nih.gov/20478852/ DOI: 10.1124/dmd.110.034009

evidence_span

{"source_cache": "artifacts/dim-research/7619675.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0697fc53b8afe8bb59065fc098e9965c7c230ad77823bea7638cd3b8049b04fb", "start_char": 0, "end_char": 1842, "text_sha256": "0697fc53b8afe8bb59065fc098e9965c7c230ad77823bea7638cd3b8049b04fb"}

experimental_model

Recombinant human enzyme kinetics

exposure

Multiple substrate concentrations

limitations

Substrate concentration changed relative contributions. Not a DIM-theophylline study or an individual dosing rule.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human CYP isoforms expressed in lymphoblastoid cells

plain_language

Theophylline is a relevant substrate to investigate, but DIM-induced concentration changes were not measured.

primary_references

[dim-p7619675] Metabolism of theophylline by cDNA-expressed human cytochromes P-450. (1995). https://pubmed.ncbi.nlm.nih.gov/7619675/ DOI: 10.1111/j.1365-2125.1995.tb04455.x

tissue_or_cell_type

Theophylline metabolism

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 766–777

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

### dim-theophylline-1a2 CYP1A2 catalyzed theophylline demethylation and hydroxylation, with high affinity and the highest tested intrinsic clearance to dimethyluric acid. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Theophylline is a relevant substrate to investigate, but DIM-induced concentration changes were not measured. organism: Human CYP isoforms expressed in lymphoblastoid cells tissue_or_cell_type: Theophylline metabolism experimental_model: Recombinant human enzyme kinetics limitations: Substrate concentration changed relative contributions. Not a DIM-theophylline study or an individual dosing rule. exposure: Multiple substrate concentrations evidence_span: {"source_cache": "artifacts/dim-research/7619675.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0697fc53b8afe8bb59065fc098e9965c7c230ad77823bea7638cd3b8049b04fb", "start_char": 0, "end_char": 1842, "text_sha256": "0697fc53b8afe8bb59065fc098e9965c7c230ad77823bea7638cd3b8049b04fb"} [dim-p7619675] Metabolism of theophylline by cDNA-expressed human cytochromes P-450. (1995). https://pubmed.ncbi.nlm.nih.gov/7619675/ DOI: 10.1111/j.1365-2125.1995.tb04455.x

evidence_span

{"source_cache": "artifacts/dim-research/14998432.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fa9fa0887ce5587c5c1894fd10a4afa651eac8220683d06745675a72f3e1ba2f", "start_char": 0, "end_char": 1208, "text_sha256": "fa9fa0887ce5587c5c1894fd10a4afa651eac8220683d06745675a72f3e1ba2f"}

experimental_model

Human microsomes and recombinant CYP comparison

exposure

NADPH-dependent substrate consumption and selective inhibition

limitations

Enzyme phenotyping; not a trial of DIM with tizanidine.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human CYP enzymes

plain_language

Tizanidine has a strong pathway connection, while the size and direction of a DIM interaction remain unmeasured.

primary_references

[dim-p14998432] Tizanidine is mainly metabolized by cytochrome p450 1A2 in vitro. (2004). https://pubmed.ncbi.nlm.nih.gov/14998432/ DOI: 10.1046/j.1365-2125.2003.02028.x

tissue_or_cell_type

Tizanidine metabolism

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 779–790

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human microsomes and recombinant CYP comparison · source_derived_draft · unverified_draft

### dim-tizanidine-1a2 CYP1A2 was the predominant tested catalyst of tizanidine metabolism. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Tizanidine has a strong pathway connection, while the size and direction of a DIM interaction remain unmeasured. organism: Human CYP enzymes tissue_or_cell_type: Tizanidine metabolism experimental_model: Human microsomes and recombinant CYP comparison limitations: Enzyme phenotyping; not a trial of DIM with tizanidine. exposure: NADPH-dependent substrate consumption and selective inhibition evidence_span: {"source_cache": "artifacts/dim-research/14998432.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fa9fa0887ce5587c5c1894fd10a4afa651eac8220683d06745675a72f3e1ba2f", "start_char": 0, "end_char": 1208, "text_sha256": "fa9fa0887ce5587c5c1894fd10a4afa651eac8220683d06745675a72f3e1ba2f"} [dim-p14998432] Tizanidine is mainly metabolized by cytochrome p450 1A2 in vitro. (2004). https://pubmed.ncbi.nlm.nih.gov/14998432/ DOI: 10.1046/j.1365-2125.2003.02028.x

evidence_access

Primary abstract

experimental_model

Human CYP expression and liver microsomes.

limitations

Not evidence that the two oral products give equivalent exposures.

nutrient_topic

Luteolin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Luteolin / 3′,4′,5,7-tetrahydroxyflavone

plain_language

A related flavone can be converted into luteolin.

primary_references

In vitro investigation of cytochrome P450-mediated metabolism of dietary flavonoids. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11955666/ · DOI 10.1016/s0278-6915(01)00125-9

Luteolin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 140–146

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human CYP expression and liver microsomes. · source_derived_draft · unverified_draft

## luteolin-cyp1a2-apigenin A related flavone can be converted into luteolin. Recombinant human CYP1A2 supported apigenin 3′-hydroxylation to luteolin. Model: Human CYP expression and liver microsomes. Limitations: Not evidence that the two oral products give equivalent exposures. Evidence access: Primary abstract In vitro investigation of cytochrome P450-mediated metabolism of dietary flavonoids. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11955666/ · DOI 10.1016/s0278-6915(01)00125-9

evidence_access

Primary abstract

experimental_model

Recombinant human CYP comparison.

limitations

Explains a candidate source of urinary bias; not proof of drug induction.

nutrient_topic

Luteolin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Luteolin / 3′,4′,5,7-tetrahydroxyflavone

plain_language

Downstream removal can reverse the apparent product preference.

primary_references

Luteolin is a rare substrate of human catechol-O-methyltransferase favoring a para-methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23386290/ · DOI 10.1002/mnfr.201200584

Luteolin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 100–106

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human CYP comparison. · source_derived_draft · unverified_draft

## luteolin-cyp1a2-demethylation Downstream removal can reverse the apparent product preference. Human CYP1A2 demethylated diosmetin more readily than chrysoeriol in vitro. Model: Recombinant human CYP comparison. Limitations: Explains a candidate source of urinary bias; not proof of drug induction. Evidence access: Primary abstract Luteolin is a rare substrate of human catechol-O-methyltransferase favoring a para-methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23386290/ · DOI 10.1002/mnfr.201200584

evidence_span

{"source_cache": "artifacts/melatonin-research/15616152.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2", "start_char": 0, "end_char": 1733, "text_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2"}

experimental_model

Recombinant P450 screen and mouse brain comparisons

exposure

Eleven P450 isozymes; NADPH-dependent 6-hydroxylation/O-demethylation

limitations

Catalytic capacity in an enzyme assay is not whole-body contribution. CYP1B1 is an extrahepatic route; human proteins are not substituted for mouse knockout identity.

nutrient_topic

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

organism

Human recombinant enzymes; separate mouse knockout experiment

plain_language

Removing the methyl group returns a molecule with the identity of a synthetic precursor.

primary_references

[melatonin-p15616152] Metabolism of melatonin by human cytochromes p450. (2005). https://pubmed.ncbi.nlm.nih.gov/15616152/ DOI: 10.1124/dmd.104.002410

tissue_or_cell_type

Oxidative melatonin metabolism

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 617–628

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant P450 screen and mouse brain comparisons · source_derived_draft · unverified_draft

### melatonin-cyp-1a2-demethylation Human CYP1A2 catalyzed melatonin O-demethylation to a lesser extent than CYP2C19 in the study. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing the methyl group returns a molecule with the identity of a synthetic precursor. organism: Human recombinant enzymes; separate mouse knockout experiment tissue_or_cell_type: Oxidative melatonin metabolism experimental_model: Recombinant P450 screen and mouse brain comparisons limitations: Catalytic capacity in an enzyme assay is not whole-body contribution. CYP1B1 is an extrahepatic route; human proteins are not substituted for mouse knockout identity. exposure: Eleven P450 isozymes; NADPH-dependent 6-hydroxylation/O-demethylation evidence_span: {"source_cache": "artifacts/melatonin-research/15616152.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2", "start_char": 0, "end_char": 1733, "text_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2"} [melatonin-p15616152] Metabolism of melatonin by human cytochromes p450. (2005). https://pubmed.ncbi.nlm.nih.gov/15616152/ DOI: 10.1124/dmd.104.002410

evidence_span

{"source_cache": "artifacts/coumarin-research/11950775.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "98a03fafa68ef4d55593a3b725af646175a11b42ce02b1dfe02be84ff49d4861", "start_char": 0, "end_char": 1158, "text_sha256": "98a03fafa68ef4d55593a3b725af646175a11b42ce02b1dfe02be84ff49d4861"}

experimental_model

Recombinant CYP enzymes, immunoinhibition and mouse lung inhibitor experiments

exposure

CYP1A/2E antibody inhibition and 5-phenyl-pentyne lung experiments

limitations

Relative contributions depend on species and tissue; this is not a clinical drug-interaction study.

nutrient_topic

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

organism

Human, rat and mouse; each claim specifies enzyme origin

plain_language

CYP1A2 provides another route to the reactive intermediate.

primary_references

[coumarin-p11950775] Identification of the cytochromes P450 that catalyze coumarin 3,4-epoxidation and 3-hydroxylation. (2002). https://pubmed.ncbi.nlm.nih.gov/11950775/ DOI: 10.1124/dmd.30.5.483

tissue_or_cell_type

Liver and lung microsomes

Coumarin: metabolism, signaling and nutrient connections (2026-09-17) · lines 228–239

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant CYP enzymes, immunoinhibition and mouse lung inhibitor experiments · source_derived_draft · unverified_draft

### coumarin-1a2-epoxide Recombinant human CYP1A2 catalyzed coumarin 3,4-epoxide formation. Condition category: normal nutrient_topic: Coumarin research collection; topical membership is not evidence of a direct dietary effect. plain_language: CYP1A2 provides another route to the reactive intermediate. organism: Human, rat and mouse; each claim specifies enzyme origin tissue_or_cell_type: Liver and lung microsomes experimental_model: Recombinant CYP enzymes, immunoinhibition and mouse lung inhibitor experiments limitations: Relative contributions depend on species and tissue; this is not a clinical drug-interaction study. exposure: CYP1A/2E antibody inhibition and 5-phenyl-pentyne lung experiments evidence_span: {"source_cache": "artifacts/coumarin-research/11950775.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "98a03fafa68ef4d55593a3b725af646175a11b42ce02b1dfe02be84ff49d4861", "start_char": 0, "end_char": 1158, "text_sha256": "98a03fafa68ef4d55593a3b725af646175a11b42ce02b1dfe02be84ff49d4861"} [coumarin-p11950775] Identification of the cytochromes P450 that catalyze coumarin 3,4-epoxidation and 3-hydroxylation. (2002). https://pubmed.ncbi.nlm.nih.gov/11950775/ DOI: 10.1124/dmd.30.5.483

evidence_span

{"source_cache": "artifacts/dim-research/19770484.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b5956f74860b0cd89114dab4179908bae1a59aab65220ac0421f4c5365bed6ba", "start_char": 0, "end_char": 1446, "text_sha256": "b5956f74860b0cd89114dab4179908bae1a59aab65220ac0421f4c5365bed6ba"}

experimental_model

Pretreatment versus cotreatment, adduct and recombinant-enzyme assays

exposure

DIM pretreatment for 48 hours; direct catalytic assays separately

limitations

Induction over time and direct inhibition are distinct mechanisms. Aflatoxin assay effects do not establish human cancer incidence or net disposition of unrelated drugs.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Primary human hepatocytes and human enzyme preparations

plain_language

Direct enzyme inhibition can oppose a slower increase in enzyme production.

primary_references

[dim-p19770484] Modulation of aflatoxin B1-mediated genotoxicity in primary cultures of human hepatocytes by diindolylmethane, curcumin, and xanthohumols. (2009). https://pubmed.ncbi.nlm.nih.gov/19770484/ DOI: 10.1093/toxsci/kfp206

tissue_or_cell_type

Aflatoxin metabolism and CYP catalytic activity

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 441–452

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pretreatment versus cotreatment, adduct and recombinant-enzyme assays · source_derived_draft · unverified_draft

### dim-cyp1a2-direct-inhibition DIM directly inhibited CYP1A2 catalytic activity in the tested enzyme assay. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Direct enzyme inhibition can oppose a slower increase in enzyme production. organism: Primary human hepatocytes and human enzyme preparations tissue_or_cell_type: Aflatoxin metabolism and CYP catalytic activity experimental_model: Pretreatment versus cotreatment, adduct and recombinant-enzyme assays limitations: Induction over time and direct inhibition are distinct mechanisms. Aflatoxin assay effects do not establish human cancer incidence or net disposition of unrelated drugs. exposure: DIM pretreatment for 48 hours; direct catalytic assays separately evidence_span: {"source_cache": "artifacts/dim-research/19770484.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b5956f74860b0cd89114dab4179908bae1a59aab65220ac0421f4c5365bed6ba", "start_char": 0, "end_char": 1446, "text_sha256": "b5956f74860b0cd89114dab4179908bae1a59aab65220ac0421f4c5365bed6ba"} [dim-p19770484] Modulation of aflatoxin B1-mediated genotoxicity in primary cultures of human hepatocytes by diindolylmethane, curcumin, and xanthohumols. (2009). https://pubmed.ncbi.nlm.nih.gov/19770484/ DOI: 10.1093/toxsci/kfp206

evidence_span

{"source_cache": "artifacts/dim-research/15672752.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ccf97f305e0f4d5b98b172cef3a0875729e44b8f65420d87a6d725ec7207ca63", "start_char": 0, "end_char": 1560, "text_sha256": "ccf97f305e0f4d5b98b172cef3a0875729e44b8f65420d87a6d725ec7207ca63"}

experimental_model

Quantitative gene expression and protein assessment

exposure

DIM 10-50 micromolar

limitations

Cell-culture concentrations; fold mRNA induction is not the fold change in drug clearance in people.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Primary human hepatocytes

plain_language

This establishes a mechanism to investigate drug interactions, not their clinical size.

primary_references

[dim-p15672752] Phytochemical-induced changes in gene expression of carcinogen-metabolizing enzymes in cultured human primary hepatocytes. (2004). https://pubmed.ncbi.nlm.nih.gov/15672752/ DOI: 10.1080/00498250412331285481

tissue_or_cell_type

CYP and phase-II enzyme expression

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 389–400

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Quantitative gene expression and protein assessment · source_derived_draft · unverified_draft

### dim-hepatocyte-cyp1a2 DIM increased CYP1A2 mRNA dose-dependently, with induction also reflected in protein measurements. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: This establishes a mechanism to investigate drug interactions, not their clinical size. organism: Primary human hepatocytes tissue_or_cell_type: CYP and phase-II enzyme expression experimental_model: Quantitative gene expression and protein assessment limitations: Cell-culture concentrations; fold mRNA induction is not the fold change in drug clearance in people. exposure: DIM 10-50 micromolar evidence_span: {"source_cache": "artifacts/dim-research/15672752.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ccf97f305e0f4d5b98b172cef3a0875729e44b8f65420d87a6d725ec7207ca63", "start_char": 0, "end_char": 1560, "text_sha256": "ccf97f305e0f4d5b98b172cef3a0875729e44b8f65420d87a6d725ec7207ca63"} [dim-p15672752] Phytochemical-induced changes in gene expression of carcinogen-metabolizing enzymes in cultured human primary hepatocytes. (2004). https://pubmed.ncbi.nlm.nih.gov/15672752/ DOI: 10.1080/00498250412331285481

evidence_span

{"source_cache": "artifacts/dim-research/16103443.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ece0ac1a0c31053cdc1ec3eefbf9c78887018e0eddf2db36c3a1a07c998e15c4", "start_char": 0, "end_char": 1706, "text_sha256": "ece0ac1a0c31053cdc1ec3eefbf9c78887018e0eddf2db36c3a1a07c998e15c4"}

experimental_model

Phase I placebo run-in and dose escalation

exposure

I3C 400 mg/day then 800 mg/day for four weeks each

limitations

The administered compound was I3C, not DIM. Multiple acid-condensation products and nonrandomized sequential periods prevent assigning the observed fold change specifically to DIM.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

17 women at elevated breast-cancer risk

plain_language

There is human evidence for the precursor, but it must not be silently relabeled as a DIM trial.

primary_references

[dim-p16103443] A phase I study of indole-3-carbinol in women: tolerability and effects. (2005). https://pubmed.ncbi.nlm.nih.gov/16103443/ DOI: 10.1158/1055-9965.epi-05-0121

tissue_or_cell_type

Caffeine CYP1A2 phenotype and estrogen metabolites

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 1026–1037

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phase I placebo run-in and dose escalation · source_derived_draft · unverified_draft

### dim-i3c-human-1a2 I3C increased caffeine-probed CYP1A2 activity in 94% of participants in the phase I study. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: There is human evidence for the precursor, but it must not be silently relabeled as a DIM trial. organism: 17 women at elevated breast-cancer risk tissue_or_cell_type: Caffeine CYP1A2 phenotype and estrogen metabolites experimental_model: Phase I placebo run-in and dose escalation limitations: The administered compound was I3C, not DIM. Multiple acid-condensation products and nonrandomized sequential periods prevent assigning the observed fold change specifically to DIM. exposure: I3C 400 mg/day then 800 mg/day for four weeks each evidence_span: {"source_cache": "artifacts/dim-research/16103443.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ece0ac1a0c31053cdc1ec3eefbf9c78887018e0eddf2db36c3a1a07c998e15c4", "start_char": 0, "end_char": 1706, "text_sha256": "ece0ac1a0c31053cdc1ec3eefbf9c78887018e0eddf2db36c3a1a07c998e15c4"} [dim-p16103443] A phase I study of indole-3-carbinol in women: tolerability and effects. (2005). https://pubmed.ncbi.nlm.nih.gov/16103443/ DOI: 10.1158/1055-9965.epi-05-0121

evidence_span

{"source_cache": "artifacts/dim-research/9741959.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "11eec60fad1ec0e18085a59f90fa3237235bb0614b5ee2b29058757e3b45ba47", "start_char": 0, "end_char": 1338, "text_sha256": "11eec60fad1ec0e18085a59f90fa3237235bb0614b5ee2b29058757e3b45ba47"}

experimental_model

Precision-cut liver-slice induction and immunoblotting

exposure

DIM 50 micromolar for 72 hours

limitations

Ex-vivo exposure; not a measured oral DIM effect on a patient drug concentration. Four donors showed variable responses.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human donor liver slices

plain_language

Human liver tissue can make more of this enzyme after DIM exposure.

primary_references

[dim-p9741959] 3,3'-Diindolylmethane induces CYP1A2 in cultured precision-cut human liver slices. (1998). https://pubmed.ncbi.nlm.nih.gov/9741959/ DOI: 10.1080/004982598239227

tissue_or_cell_type

CYP1A proteins and catalytic assays

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 350–361

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Precision-cut liver-slice induction and immunoblotting · source_derived_draft · unverified_draft

### dim-liver-cyp1a2 DIM increased CYP1A2 protein in cultured human liver slices. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human liver tissue can make more of this enzyme after DIM exposure. organism: Human donor liver slices tissue_or_cell_type: CYP1A proteins and catalytic assays experimental_model: Precision-cut liver-slice induction and immunoblotting limitations: Ex-vivo exposure; not a measured oral DIM effect on a patient drug concentration. Four donors showed variable responses. exposure: DIM 50 micromolar for 72 hours evidence_span: {"source_cache": "artifacts/dim-research/9741959.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "11eec60fad1ec0e18085a59f90fa3237235bb0614b5ee2b29058757e3b45ba47", "start_char": 0, "end_char": 1338, "text_sha256": "11eec60fad1ec0e18085a59f90fa3237235bb0614b5ee2b29058757e3b45ba47"} [dim-p9741959] 3,3'-Diindolylmethane induces CYP1A2 in cultured precision-cut human liver slices. (1998). https://pubmed.ncbi.nlm.nih.gov/9741959/ DOI: 10.1080/004982598239227

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/dim-research/19884324.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3f702cc9af1528241d8572b8bcafc23dacb5ed3cacf6bb77403e8aa40d21a214", "start_char": 0, "end_char": 1738, "text_sha256": "3f702cc9af1528241d8572b8bcafc23dacb5ed3cacf6bb77403e8aa40d21a214"}

experimental_model

Recombinant protein and engineered bacterial coexpression

exposure

POR mutation and added FMN

limitations

In-vitro rescue of one mutant; not a dietary-riboflavin deficiency experiment or evidence that FMN reverses a DIM-drug interaction.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human POR Y181D and human CYP1A2 in engineered systems

plain_language

Inducing an enzyme is not enough if its electron-supply machinery fails.

primary_references

[dim-p19884324] Human cytochrome P450 oxidoreductase deficiency caused by the Y181D mutation: molecular consequences and rescue of defect. (2010). https://pubmed.ncbi.nlm.nih.gov/19884324/ DOI: 10.1124/dmd.109.030445

tissue_or_cell_type

FMN-dependent electron transfer

trigger_kind

machinery_impairment Imported condition classification; unverified.

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 272–283

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant protein and engineered bacterial coexpression · source_derived_draft · unverified_draft

### dim-por-fmn-loss POR Y181D lacked bound FMN and poorly supported CYP1A2-catalyzed reactions despite retaining FAD binding and NADPH utilization. Condition category: machinery_impairment nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Inducing an enzyme is not enough if its electron-supply machinery fails. organism: Human POR Y181D and human CYP1A2 in engineered systems tissue_or_cell_type: FMN-dependent electron transfer experimental_model: Recombinant protein and engineered bacterial coexpression limitations: In-vitro rescue of one mutant; not a dietary-riboflavin deficiency experiment or evidence that FMN reverses a DIM-drug interaction. exposure: POR mutation and added FMN evidence_span: {"source_cache": "artifacts/dim-research/19884324.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3f702cc9af1528241d8572b8bcafc23dacb5ed3cacf6bb77403e8aa40d21a214", "start_char": 0, "end_char": 1738, "text_sha256": "3f702cc9af1528241d8572b8bcafc23dacb5ed3cacf6bb77403e8aa40d21a214"} [dim-p19884324] Human cytochrome P450 oxidoreductase deficiency caused by the Y181D mutation: molecular consequences and rescue of defect. (2010). https://pubmed.ncbi.nlm.nih.gov/19884324/ DOI: 10.1124/dmd.109.030445

evidence_span

{"source_cache": "artifacts/ceylon-research/39845339.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "243c3bd561d9ff4d7dfe10fa748b1aacc0941a4ec9f712615f7dd7df4e98f118", "start_char": 0, "end_char": 1463, "text_sha256": "243c3bd561d9ff4d7dfe10fa748b1aacc0941a4ec9f712615f7dd7df4e98f118"}

experimental_model

Human receptor reporters and CYP inhibition assays

exposure

Oil/parent/metabolite comparisons; PXR 0.62–20 micrograms/mL for 24 hours

limitations

Reporter activation is not demonstrated induction of clinical drug clearance. HepG2 is liver-derived; full results distinguish it from intestinal LS174T.

nutrient_topic

Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. · Ceylon cinnamon / Cinnamomum verum bark preparations

organism

Human-derived reporter cells and human CYP assay systems

plain_language

A test-tube inhibition signal does not establish a clinical caffeine or medicine interaction.

primary_references

[ceylon-p39845339] Evaluation of bioaccessibility, metabolic clearance and interaction with xenobiotic receptors (PXR and AhR) of cinnamaldehyde. (2025). https://pubmed.ncbi.nlm.nih.gov/39845339/ DOI: 10.1016/j.fochms.2024.100237

tissue_or_cell_type

HepG2, LS174T and AhR reporter cells

Ceylon cinnamon: metabolism, signaling and nutrient connections (2026-09-17) · lines 857–868

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human receptor reporters and CYP inhibition assays · source_derived_draft · unverified_draft

### ceylon-ca-cyp1a2 Cinnamaldehyde inhibited CYP1A2 catalytic activity in the study enzyme assay. Condition category: normal nutrient_topic: Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. plain_language: A test-tube inhibition signal does not establish a clinical caffeine or medicine interaction. organism: Human-derived reporter cells and human CYP assay systems tissue_or_cell_type: HepG2, LS174T and AhR reporter cells experimental_model: Human receptor reporters and CYP inhibition assays limitations: Reporter activation is not demonstrated induction of clinical drug clearance. HepG2 is liver-derived; full results distinguish it from intestinal LS174T. exposure: Oil/parent/metabolite comparisons; PXR 0.62–20 micrograms/mL for 24 hours evidence_span: {"source_cache": "artifacts/ceylon-research/39845339.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "243c3bd561d9ff4d7dfe10fa748b1aacc0941a4ec9f712615f7dd7df4e98f118", "start_char": 0, "end_char": 1463, "text_sha256": "243c3bd561d9ff4d7dfe10fa748b1aacc0941a4ec9f712615f7dd7df4e98f118"} [ceylon-p39845339] Evaluation of bioaccessibility, metabolic clearance and interaction with xenobiotic receptors (PXR and AhR) of cinnamaldehyde. (2025). https://pubmed.ncbi.nlm.nih.gov/39845339/ DOI: 10.1016/j.fochms.2024.100237

evidence_span

{"source_cache": "artifacts/ceylon-research/39845339.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "243c3bd561d9ff4d7dfe10fa748b1aacc0941a4ec9f712615f7dd7df4e98f118", "start_char": 0, "end_char": 1463, "text_sha256": "243c3bd561d9ff4d7dfe10fa748b1aacc0941a4ec9f712615f7dd7df4e98f118"}

experimental_model

Human receptor reporters and CYP inhibition assays

exposure

Oil/parent/metabolite comparisons; PXR 0.62–20 micrograms/mL for 24 hours

limitations

Reporter activation is not demonstrated induction of clinical drug clearance. HepG2 is liver-derived; full results distinguish it from intestinal LS174T.

nutrient_topic

Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. · Ceylon cinnamon / Cinnamomum verum bark preparations

organism

Human-derived reporter cells and human CYP assay systems

plain_language

The oil preparation also inhibited this enzyme under the assay conditions.

primary_references

[ceylon-p39845339] Evaluation of bioaccessibility, metabolic clearance and interaction with xenobiotic receptors (PXR and AhR) of cinnamaldehyde. (2025). https://pubmed.ncbi.nlm.nih.gov/39845339/ DOI: 10.1016/j.fochms.2024.100237

tissue_or_cell_type

HepG2, LS174T and AhR reporter cells

Ceylon cinnamon: metabolism, signaling and nutrient connections (2026-09-17) · lines 883–894

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human receptor reporters and CYP inhibition assays · source_derived_draft · unverified_draft

### ceylon-oil-cyp1a2 The C. verum oil inhibited CYP1A2 catalytic activity in the study assay. Condition category: normal nutrient_topic: Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. plain_language: The oil preparation also inhibited this enzyme under the assay conditions. organism: Human-derived reporter cells and human CYP assay systems tissue_or_cell_type: HepG2, LS174T and AhR reporter cells experimental_model: Human receptor reporters and CYP inhibition assays limitations: Reporter activation is not demonstrated induction of clinical drug clearance. HepG2 is liver-derived; full results distinguish it from intestinal LS174T. exposure: Oil/parent/metabolite comparisons; PXR 0.62–20 micrograms/mL for 24 hours evidence_span: {"source_cache": "artifacts/ceylon-research/39845339.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "243c3bd561d9ff4d7dfe10fa748b1aacc0941a4ec9f712615f7dd7df4e98f118", "start_char": 0, "end_char": 1463, "text_sha256": "243c3bd561d9ff4d7dfe10fa748b1aacc0941a4ec9f712615f7dd7df4e98f118"} [ceylon-p39845339] Evaluation of bioaccessibility, metabolic clearance and interaction with xenobiotic receptors (PXR and AhR) of cinnamaldehyde. (2025). https://pubmed.ncbi.nlm.nih.gov/39845339/ DOI: 10.1016/j.fochms.2024.100237

evidence_span

{"source_cache": "artifacts/mangiferin-research/22815239.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e85ebd0af89f030dbeda45ed922e93a8a616c51f5ce1b64badc44d90791716c0", "start_char": 0, "end_char": 1728, "text_sha256": "e85ebd0af89f030dbeda45ed922e93a8a616c51f5ce1b64badc44d90791716c0"}

experimental_model

Primary human hepatocyte exposure

exposure

Mangiferin 50-250 micrograms/mL for 48 hours

limitations

High in vitro concentrations; decreased enzyme activity is not proof of human drug-level changes. Extract and isolated mangiferin are distinct.

nutrient_topic

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

organism

Homo sapiens

plain_language

A drug-metabolizing enzyme was inhibited under the tested exposure.

primary_references

[mangiferin-p22815239] Mangifera indica L. extract and mangiferin modulate cytochrome P450 and UDP-glucuronosyltransferase enzymes in primary cultures of human hepatocytes. (2013). https://pubmed.ncbi.nlm.nih.gov/22815239/ DOI: 10.1002/ptr.4782

tissue_or_cell_type

Cultured hepatocytes

Mangiferin: metabolism, signaling and nutrient connections (2026-09-17) · lines 770–781

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

### mangiferin-cyp1a2-activity Mangiferin reduced measured CYP1A2 activity in the hepatocyte experiment. Condition category: normal nutrient_topic: Mangiferin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A drug-metabolizing enzyme was inhibited under the tested exposure. organism: Homo sapiens tissue_or_cell_type: Cultured hepatocytes experimental_model: Primary human hepatocyte exposure limitations: High in vitro concentrations; decreased enzyme activity is not proof of human drug-level changes. Extract and isolated mangiferin are distinct. exposure: Mangiferin 50-250 micrograms/mL for 48 hours evidence_span: {"source_cache": "artifacts/mangiferin-research/22815239.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e85ebd0af89f030dbeda45ed922e93a8a616c51f5ce1b64badc44d90791716c0", "start_char": 0, "end_char": 1728, "text_sha256": "e85ebd0af89f030dbeda45ed922e93a8a616c51f5ce1b64badc44d90791716c0"} [mangiferin-p22815239] Mangifera indica L. extract and mangiferin modulate cytochrome P450 and UDP-glucuronosyltransferase enzymes in primary cultures of human hepatocytes. (2013). https://pubmed.ncbi.nlm.nih.gov/22815239/ DOI: 10.1002/ptr.4782

evidence_access

Primary full text PMC3513969, CYP methods and results

experimental_model

Human liver microsomes; product concentrations normalized to 0.5–25 micromolar lovastatin, with an NADPH-generating system.

limitations

In-vitro inhibition is not a measured interaction with every drug using this enzyme; the additional responsible constituent was not identified.

nutrient_topic

Red yeast rice collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Red yeast rice

plain_language

The mixture changed an enzyme assay beyond its lovastatin content.

primary_references

[23227093] Interaction between Red Yeast Rice and CYP450 Enzymes/P-Glycoprotein and Its Implication for the Clinical Pharmacokinetics of Lovastatin. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23227093/ · DOI 10.1155/2012/127043

Red yeast rice: constituents, mevalonate, CoQ and product-specific interactions (2026-09-20) · lines 108–114

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human liver microsomes; product concentrations normalized to 0.5–25 micromolar lovastatin, with an NADPH-generating system. · source_derived_draft · unverified_draft

## red-yeast-rice-extract-cyp1a2 The mixture changed an enzyme assay beyond its lovastatin content. The three 2012 red yeast rice product extracts inhibited human microsomal CYP1A2 more potently than pure lovastatin at matched nominal lovastatin concentrations. Model: Human liver microsomes; product concentrations normalized to 0.5–25 micromolar lovastatin, with an NADPH-generating system. Limitations: In-vitro inhibition is not a measured interaction with every drug using this enzyme; the additional responsible constituent was not identified. Evidence access: Primary full text PMC3513969, CYP methods and results [23227093] Interaction between Red Yeast Rice and CYP450 Enzymes/P-Glycoprotein and Its Implication for the Clinical Pharmacokinetics of Lovastatin. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23227093/ · DOI 10.1155/2012/127043

evidence_access

Primary full text

experimental_model

42 initiated; enzyme activities assessed in 40; before/after pharmacological-dose study.

limitations

Probe indices are not proof of transcriptional induction or a quantified interaction with every substrate; no medication adjustment follows.

nutrient_topic

Resveratrol collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Resveratrol

plain_language

A human drug-metabolism interaction was measured with a specific probe.

primary_references

Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20716633/ · DOI 10.1158/1940-6207.CAPR-09-0155

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 414–420

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 42 initiated; enzyme activities assessed in 40; before/after pharmacological-dose study. · source_derived_draft · unverified_draft

## resveratrol-human-cyp1a2 A human drug-metabolism interaction was measured with a specific probe. After 1 g/day resveratrol for four weeks, the healthy-volunteer study found increased CYP1A2 phenotypic activity using caffeine as the probe. Model: 42 initiated; enzyme activities assessed in 40; before/after pharmacological-dose study. Limitations: Probe indices are not proof of transcriptional induction or a quantified interaction with every substrate; no medication adjustment follows. Evidence access: Primary full text Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20716633/ · DOI 10.1158/1940-6207.CAPR-09-0155

acting_entity

s-allylcysteine

dose

SAC 0.01–1 mM; N-acetyl-SAC 1 mM

duration

Probe-specific incubation

evidence_access

Primary full-text HTML, methods/results

experimental_comparison

Test compound versus probe reaction without compound

experimental_model

Pooled human liver microsomes; probe substrate metabolism

interpretation_status

Source-derived research curation; not independent primary verification

limitations

Microsomal assay; not a clinical interaction or induction study.

nutrient_topic

S-allylcysteine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · S-allyl-L-cysteine / SAC

organism

Human liver preparation

plain_language

A negative enzyme-interaction result is retained.

primary_references

[27725449] Evaluation of the Effects of S-Allyl-L-cysteine, S-Methyl-L-cysteine, trans-S-1-Propenyl-L-cysteine, and Their N-Acetylated and S-Oxidized Metabolites on Human CYP Activities. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27725449/ · DOI 10.1248/bpb.b16-00449

route

In vitro

tissue_or_cell_type

Pooled human liver microsomes; probe substrate metabolism

S-allylcysteine: sulfur signaling, redox responses and cross-nutrient mechanisms (2026-09-20) · lines 383–390

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Pooled human liver microsomes; probe substrate metabolism · source_derived_draft · unverified_draft

## s-allylcysteine-cyp-null-cyp1a2 A negative enzyme-interaction result is retained. SAC showed little effect on tested human CYP1A2 activity over 0.01–1 mM. Model: Pooled human liver microsomes; probe substrate metabolism Limitations: Microsomal assay; not a clinical interaction or induction study. Evidence access: Primary full-text HTML, methods/results [27725449] Evaluation of the Effects of S-Allyl-L-cysteine, S-Methyl-L-cysteine, trans-S-1-Propenyl-L-cysteine, and Their N-Acetylated and S-Oxidized Metabolites on Human CYP Activities. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27725449/ · DOI 10.1248/bpb.b16-00449 Structured context: {"organism": "Human liver preparation", "tissue_or_cell_type": "Pooled human liver microsomes; probe substrate metabolism", "dose": "SAC 0.01–1 mM; N-acetyl-SAC 1 mM", "duration": "Probe-specific incubation", "route": "In vitro", "experimental_comparison": "Test compound versus probe reaction without compound", "acting_entity": "s-allylcysteine", "interpretation_status": "Source-derived research curation; not independent primary verification"}

evidence_access

Primary abstract

experimental_model

Human liver microsomes; metabolite HPLC.

limitations

Not all three demethylations are exclusively CYP1A2-dependent.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

An enzyme experiment supports the observed clearance interaction.

primary_references

Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9868741/ · DOI 10.1111/j.1600-0773.1998.tb01476.x

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 212–218

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human liver microsomes; metabolite HPLC. · source_derived_draft · unverified_draft

## caf-cyp1a2-inhibition An enzyme experiment supports the observed clearance interaction. In human liver microsomes, fluvoxamine inhibited caffeine demethylated-metabolite formation with Ki values of 0.08–0.28 micromolar. Model: Human liver microsomes; metabolite HPLC. Limitations: Not all three demethylations are exclusively CYP1A2-dependent. Evidence access: Primary abstract Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9868741/ · DOI 10.1111/j.1600-0773.1998.tb01476.x

evidence_span

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experimental_model

Enzyme phenotyping and clinical drug-interaction studies

exposure

Fluvoxamine with oral or intravenous duloxetine

limitations

The clinical exposure change was caused by fluvoxamine, not DIM. The study tests inhibition, not the inverse size of induction.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human enzyme systems and healthy adults

plain_language

Blocking metabolism increased exposure; this measured result must not be relabeled as a DIM study.

primary_references

[dim-p18307373] In vitro and in vivo evaluations of cytochrome P450 1A2 interactions with duloxetine. (2008). https://pubmed.ncbi.nlm.nih.gov/18307373/ DOI: 10.2165/00003088-200847030-00005

tissue_or_cell_type

Duloxetine metabolism and exposure

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 805–816

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme phenotyping and clinical drug-interaction studies · source_derived_draft · unverified_draft

### dim-duloxetine-inhibition Fluvoxamine increased oral duloxetine AUC by 460% and peak concentration by 141% in the clinical study. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Blocking metabolism increased exposure; this measured result must not be relabeled as a DIM study. organism: Human enzyme systems and healthy adults tissue_or_cell_type: Duloxetine metabolism and exposure experimental_model: Enzyme phenotyping and clinical drug-interaction studies limitations: The clinical exposure change was caused by fluvoxamine, not DIM. The study tests inhibition, not the inverse size of induction. exposure: Fluvoxamine with oral or intravenous duloxetine evidence_span: {"source_cache": "artifacts/dim-research/18307373.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2705ee887855e9dbe738ece57d4ad9d4b3d8cc0d67de45e63c01497a4a215149", "start_char": 0, "end_char": 2879, "text_sha256": "2705ee887855e9dbe738ece57d4ad9d4b3d8cc0d67de45e63c01497a4a215149"} [dim-p18307373] In vitro and in vivo evaluations of cytochrome P450 1A2 interactions with duloxetine. (2008). https://pubmed.ncbi.nlm.nih.gov/18307373/ DOI: 10.2165/00003088-200847030-00005

evidence_span

{"source_cache": "artifacts/dim-research/21599724.publisher-preview.txt", "locator": "Primary public publisher preview, reference superscripts removed; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2a31ba5c71ba785b8fc6cdec21ed2dfa37686cb6d44dbf22616b0ab9b585a940", "start_char": 0, "end_char": 537, "text_sha256": "2a31ba5c71ba785b8fc6cdec21ed2dfa37686cb6d44dbf22616b0ab9b585a940"}

experimental_model

Randomized crossover nicotine-patch study; full-text extract

exposure

42 mg/day transdermal nicotine or placebo; caffeine probe on day eight

limitations

Nicotine-only exposure differs from smoke exposure; this short study does not test every tissue or nicotine product.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

12 healthy smokers abstinent from tobacco during study

plain_language

Smoking and nicotine alone are not interchangeable CYP1A2 exposures.

primary_references

[dim-p21599724] Effect of nicotine on cytochrome P450 1A2 activity. (2011). https://pubmed.ncbi.nlm.nih.gov/21599724/ DOI: 10.1111/j.1365-2125.2011.04023.x

tissue_or_cell_type

Caffeine-based hepatic CYP1A2 phenotyping

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 857–868

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized crossover nicotine-patch study; full-text extract · source_derived_draft · unverified_draft

### dim-nicotine-not-smoke Nicotine patches did not significantly change caffeine pharmacokinetics or metabolite formation in the crossover study. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Smoking and nicotine alone are not interchangeable CYP1A2 exposures. organism: 12 healthy smokers abstinent from tobacco during study tissue_or_cell_type: Caffeine-based hepatic CYP1A2 phenotyping experimental_model: Randomized crossover nicotine-patch study; full-text extract limitations: Nicotine-only exposure differs from smoke exposure; this short study does not test every tissue or nicotine product. exposure: 42 mg/day transdermal nicotine or placebo; caffeine probe on day eight evidence_span: {"source_cache": "artifacts/dim-research/21599724.publisher-preview.txt", "locator": "Primary public publisher preview, reference superscripts removed; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2a31ba5c71ba785b8fc6cdec21ed2dfa37686cb6d44dbf22616b0ab9b585a940", "start_char": 0, "end_char": 537, "text_sha256": "2a31ba5c71ba785b8fc6cdec21ed2dfa37686cb6d44dbf22616b0ab9b585a940"} [dim-p21599724] Effect of nicotine on cytochrome P450 1A2 activity. (2011). https://pubmed.ncbi.nlm.nih.gov/21599724/ DOI: 10.1111/j.1365-2125.2011.04023.x

evidence_span

{"source_cache": "artifacts/dim-research/15289794.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "90eb96e72afdbbb53c322c2be9a34e5aa523c27f2fd0995a8eb224e2ec6e35e2", "start_char": 0, "end_char": 1753, "text_sha256": "90eb96e72afdbbb53c322c2be9a34e5aa523c27f2fd0995a8eb224e2ec6e35e2"}

experimental_model

Repeated caffeine phenotyping after smoking cessation

exposure

Abrupt cessation after run-in; repeated 148-mg caffeine probe doses

limitations

Smoking-cessation kinetics cannot be assigned to starting or stopping DIM. Clinical dose management requires drug-specific monitoring.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

12 heavy smokers

plain_language

Stopping an established inducer can raise exposure to its substrates, but these numbers describe smoking.

primary_references

[dim-p15289794] Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. (2004). https://pubmed.ncbi.nlm.nih.gov/15289794/ DOI: 10.1016/j.clpt.2004.04.003

tissue_or_cell_type

CYP1A2 activity and caffeine clearance

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 844–855

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Repeated caffeine phenotyping after smoking cessation · source_derived_draft · unverified_draft

### dim-smoking-cessation Caffeine clearance fell by 36.1% after cessation; the fitted half-life of CYP1A2 activity decline was 38.6 hours. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Stopping an established inducer can raise exposure to its substrates, but these numbers describe smoking. organism: 12 heavy smokers tissue_or_cell_type: CYP1A2 activity and caffeine clearance experimental_model: Repeated caffeine phenotyping after smoking cessation limitations: Smoking-cessation kinetics cannot be assigned to starting or stopping DIM. Clinical dose management requires drug-specific monitoring. exposure: Abrupt cessation after run-in; repeated 148-mg caffeine probe doses evidence_span: {"source_cache": "artifacts/dim-research/15289794.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "90eb96e72afdbbb53c322c2be9a34e5aa523c27f2fd0995a8eb224e2ec6e35e2", "start_char": 0, "end_char": 1753, "text_sha256": "90eb96e72afdbbb53c322c2be9a34e5aa523c27f2fd0995a8eb224e2ec6e35e2"} [dim-p15289794] Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. (2004). https://pubmed.ncbi.nlm.nih.gov/15289794/ DOI: 10.1016/j.clpt.2004.04.003

evidence_span

{"source_cache": "artifacts/melatonin-research/14616429.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6a8b06b9e1bcb570dca49735b73c2c7360a77381ae6fa25744bcccee7ceb52d8", "start_char": 0, "end_char": 1070, "text_sha256": "6a8b06b9e1bcb570dca49735b73c2c7360a77381ae6fa25744bcccee7ceb52d8"}

experimental_model

Concurrent caffeine interaction study

exposure

6 mg melatonin alone or with three 200 mg caffeine doses

limitations

Caffeine schedule and amount were study-specific. CYP1A2 inhibition was the proposed mechanism; higher melatonin exposure does not imply better sleep while using caffeine.

nutrient_topic

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

organism

Twelve humans, six smokers and six nonsmokers

plain_language

One substance can promote wakefulness while increasing blood exposure to another substance.

primary_references

[melatonin-p14616429] Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. (2003). https://pubmed.ncbi.nlm.nih.gov/14616429/ DOI: 10.1046/j.1365-2125.2003.01933.x

tissue_or_cell_type

Oral melatonin pharmacokinetics

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 708–719

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Concurrent caffeine interaction study · source_derived_draft · unverified_draft

### melatonin-caffeine-exposure Concurrent caffeine raised melatonin peak concentration by 142% and AUC by 120% on average. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: One substance can promote wakefulness while increasing blood exposure to another substance. organism: Twelve humans, six smokers and six nonsmokers tissue_or_cell_type: Oral melatonin pharmacokinetics experimental_model: Concurrent caffeine interaction study limitations: Caffeine schedule and amount were study-specific. CYP1A2 inhibition was the proposed mechanism; higher melatonin exposure does not imply better sleep while using caffeine. exposure: 6 mg melatonin alone or with three 200 mg caffeine doses evidence_span: {"source_cache": "artifacts/melatonin-research/14616429.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6a8b06b9e1bcb570dca49735b73c2c7360a77381ae6fa25744bcccee7ceb52d8", "start_char": 0, "end_char": 1070, "text_sha256": "6a8b06b9e1bcb570dca49735b73c2c7360a77381ae6fa25744bcccee7ceb52d8"} [melatonin-p14616429] Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. (2003). https://pubmed.ncbi.nlm.nih.gov/14616429/ DOI: 10.1046/j.1365-2125.2003.01933.x

evidence_span

{"source_cache": "artifacts/melatonin-research/18490497.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ab9a91b566e88a73ccbd20d9152934f6a048348bc18ec0c2535ec5a9142dc0e4", "start_char": 0, "end_char": 927, "text_sha256": "ab9a91b566e88a73ccbd20d9152934f6a048348bc18ec0c2535ec5a9142dc0e4"}

experimental_model

Pharmacokinetic comparison by contraceptive use and genotype

exposure

6 mg melatonin; oral contraceptive users versus nonusers

limitations

Formulations were not universal across all contraceptives. Exposure comparison is not proof all hormone treatments behave identically; genotype effects were nonsignificant.

nutrient_topic

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

organism

29 human participants

plain_language

Medication context changes how a dose appears in the bloodstream.

primary_references

[melatonin-p18490497] The effect of oral contraceptives on the pharmacokinetics of melatonin in healthy subjects with CYP1A2 g.-163C>A polymorphism. (2008). https://pubmed.ncbi.nlm.nih.gov/18490497/ DOI: 10.1177/0091270008318669

tissue_or_cell_type

Melatonin clearance

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 721–732

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pharmacokinetic comparison by contraceptive use and genotype · source_derived_draft · unverified_draft

### melatonin-contraceptive-exposure Melatonin AUC and peak concentrations were about four- to fivefold higher in oral-contraceptive users than nonusers. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Medication context changes how a dose appears in the bloodstream. organism: 29 human participants tissue_or_cell_type: Melatonin clearance experimental_model: Pharmacokinetic comparison by contraceptive use and genotype limitations: Formulations were not universal across all contraceptives. Exposure comparison is not proof all hormone treatments behave identically; genotype effects were nonsignificant. exposure: 6 mg melatonin; oral contraceptive users versus nonusers evidence_span: {"source_cache": "artifacts/melatonin-research/18490497.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ab9a91b566e88a73ccbd20d9152934f6a048348bc18ec0c2535ec5a9142dc0e4", "start_char": 0, "end_char": 927, "text_sha256": "ab9a91b566e88a73ccbd20d9152934f6a048348bc18ec0c2535ec5a9142dc0e4"} [melatonin-p18490497] The effect of oral contraceptives on the pharmacokinetics of melatonin in healthy subjects with CYP1A2 g.-163C>A polymorphism. (2008). https://pubmed.ncbi.nlm.nih.gov/18490497/ DOI: 10.1177/0091270008318669

evidence_span

{"source_cache": "artifacts/melatonin-research/10668847.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0f3c51771fcf28fd453299490bdedee5088501fb2447e3683edd68b93590d544", "start_char": 0, "end_char": 1563, "text_sha256": "0f3c51771fcf28fd453299490bdedee5088501fb2447e3683edd68b93590d544"}

experimental_model

Single-dose drug interaction study

exposure

5 mg melatonin with or without 50 mg fluvoxamine

limitations

Very small study; one CYP2D6 poor metabolizer affected fluvoxamine exposure. Increased melatonin exposure is consistent with inhibited elimination, not proof of increased pineal synthesis.

nutrient_topic

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

organism

Five healthy male volunteers

plain_language

Slowing clearance can sharply raise exposure to an unchanged swallowed dose.

primary_references

[melatonin-p10668847] Increased bioavailability of oral melatonin after fluvoxamine coadministration. (2000). https://pubmed.ncbi.nlm.nih.gov/10668847/ DOI: 10.1067/mcp.2000.104071

tissue_or_cell_type

Oral melatonin pharmacokinetics

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 695–706

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single-dose drug interaction study · source_derived_draft · unverified_draft

### melatonin-fluvoxamine-exposure Fluvoxamine increased melatonin AUC about 17-fold and peak concentration about 12-fold on average. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Slowing clearance can sharply raise exposure to an unchanged swallowed dose. organism: Five healthy male volunteers tissue_or_cell_type: Oral melatonin pharmacokinetics experimental_model: Single-dose drug interaction study limitations: Very small study; one CYP2D6 poor metabolizer affected fluvoxamine exposure. Increased melatonin exposure is consistent with inhibited elimination, not proof of increased pineal synthesis. exposure: 5 mg melatonin with or without 50 mg fluvoxamine evidence_span: {"source_cache": "artifacts/melatonin-research/10668847.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0f3c51771fcf28fd453299490bdedee5088501fb2447e3683edd68b93590d544", "start_char": 0, "end_char": 1563, "text_sha256": "0f3c51771fcf28fd453299490bdedee5088501fb2447e3683edd68b93590d544"} [melatonin-p10668847] Increased bioavailability of oral melatonin after fluvoxamine coadministration. (2000). https://pubmed.ncbi.nlm.nih.gov/10668847/ DOI: 10.1067/mcp.2000.104071

evidence_span

{"source_cache": "artifacts/berberine-research/21870106.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "12e465c3c0a8ce995697a6fb9bf77c079e38b413e82c8b4f2a82e45a3dbf8ae5", "start_char": 0, "end_char": 1817, "text_sha256": "12e465c3c0a8ce995697a6fb9bf77c079e38b413e82c8b4f2a82e45a3dbf8ae5"}

experimental_model

Two-phase randomized crossover enzyme-phenotyping study

exposure

Berberine 300 mg three times daily for 14 days versus placebo

limitations

Small short-term study. Probe metabolic ratios are not percentage inhibition of every substrate. No universal dose-adjustment rule; no statistically significant effect is not equivalence.

nutrient_topic

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

organism

Healthy human male volunteers; 17 completed

plain_language

This study did not show a CYP1A2 effect matching the effects on three other enzymes.

primary_references

[berberine-p21870106] Repeated administration of berberine inhibits cytochromes P450 in humans. (2012). https://pubmed.ncbi.nlm.nih.gov/21870106/ DOI: 10.1007/s00228-011-1108-2

tissue_or_cell_type

Oral probe pharmacokinetics and urinary metabolite ratios

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 675–686

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two-phase randomized crossover enzyme-phenotyping study · source_derived_draft · unverified_draft

### berberine-human-cyp-1a2-null No statistically significant change in caffeine probe pharmacokinetics was found after berberine. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: This study did not show a CYP1A2 effect matching the effects on three other enzymes. organism: Healthy human male volunteers; 17 completed tissue_or_cell_type: Oral probe pharmacokinetics and urinary metabolite ratios experimental_model: Two-phase randomized crossover enzyme-phenotyping study limitations: Small short-term study. Probe metabolic ratios are not percentage inhibition of every substrate. No universal dose-adjustment rule; no statistically significant effect is not equivalence. exposure: Berberine 300 mg three times daily for 14 days versus placebo evidence_span: {"source_cache": "artifacts/berberine-research/21870106.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "12e465c3c0a8ce995697a6fb9bf77c079e38b413e82c8b4f2a82e45a3dbf8ae5", "start_char": 0, "end_char": 1817, "text_sha256": "12e465c3c0a8ce995697a6fb9bf77c079e38b413e82c8b4f2a82e45a3dbf8ae5"} [berberine-p21870106] Repeated administration of berberine inhibits cytochromes P450 in humans. (2012). https://pubmed.ncbi.nlm.nih.gov/21870106/ DOI: 10.1007/s00228-011-1108-2

evidence_access

Primary abstract

experimental_model

12 nonsmoking healthy men; single 12.5 mg clozapine; caffeine 400–1000 mg/day, mean 550.

limitations

Small healthy-volunteer study; patient effect size and toxicity cannot be inferred for an individual.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine changed exposure to a drug sharing its metabolic pathway.

primary_references

Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10606838/ · DOI 10.1046/j.1365-2125.2000.00111.x

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 268–274

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 12 nonsmoking healthy men; single 12.5 mg clozapine; caffeine 400–1000 mg/day, mean 550. · source_derived_draft · unverified_draft

## caf-clozapine-auc Caffeine changed exposure to a drug sharing its metabolic pathway. Caffeine coadministration increased mean clozapine AUC by 19% in the crossover experiment. Model: 12 nonsmoking healthy men; single 12.5 mg clozapine; caffeine 400–1000 mg/day, mean 550. Limitations: Small healthy-volunteer study; patient effect size and toxicity cannot be inferred for an individual. Evidence access: Primary abstract Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10606838/ · DOI 10.1046/j.1365-2125.2000.00111.x

evidence_access

Primary abstract

experimental_model

Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers.

limitations

Study used 200 mg caffeine and repeated fluvoxamine; not a prediction of the same effect size for every CYP1A2 inhibitor.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Inhibiting the metabolic pathway slowed caffeine removal.

primary_references

A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 196–202

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. · source_derived_draft · unverified_draft

## caf-fluvox-clear Inhibiting the metabolic pathway slowed caffeine removal. Median caffeine clearance fell from 107 to 21 mL/min during fluvoxamine treatment. Model: Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. Limitations: Study used 200 mg caffeine and repeated fluvoxamine; not a prediction of the same effect size for every CYP1A2 inhibitor. Evidence access: Primary abstract A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

evidence_access

Primary abstract

experimental_model

Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers.

limitations

CYP1A2 is the principal demethylating route; minor routes and individual clearance vary.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine produces a distinct metabolite that needs its own record.

primary_references

A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 172–178

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. · source_derived_draft · unverified_draft

## caf-met-px Caffeine produces a distinct metabolite that needs its own record. Caffeine N3-demethylation produced the specified dimethylxanthine; fluvoxamine reduced its formation clearance. Model: Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. Limitations: CYP1A2 is the principal demethylating route; minor routes and individual clearance vary. Evidence access: Primary abstract A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

evidence_access

Primary abstract

experimental_model

Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers.

limitations

CYP1A2 is the principal demethylating route; minor routes and individual clearance vary.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine produces a distinct metabolite that needs its own record.

primary_references

A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 180–186

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. · source_derived_draft · unverified_draft

## caf-met-tb Caffeine produces a distinct metabolite that needs its own record. Caffeine N1-demethylation produced the specified dimethylxanthine; fluvoxamine reduced its formation clearance. Model: Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. Limitations: CYP1A2 is the principal demethylating route; minor routes and individual clearance vary. Evidence access: Primary abstract A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

evidence_access

Primary abstract

experimental_model

Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers.

limitations

CYP1A2 is the principal demethylating route; minor routes and individual clearance vary.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine produces a distinct metabolite that needs its own record.

primary_references

A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 188–194

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. · source_derived_draft · unverified_draft

## caf-met-tp Caffeine produces a distinct metabolite that needs its own record. Caffeine N7-demethylation produced the specified dimethylxanthine; fluvoxamine reduced its formation clearance. Model: Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. Limitations: CYP1A2 is the principal demethylating route; minor routes and individual clearance vary. Evidence access: Primary abstract A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

evidence_access

Primary abstract

experimental_model

Same 21-person caffeine-phenotyping study.

limitations

Changed ratios do not prove corresponding changes in NAT2 or CYP1A2 catalytic activity.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

A downstream block can make another enzyme’s probe result misleading.

primary_references

Xanthine oxidase inhibition by allopurinol affects the reliability of urinary caffeine metabolic ratios as markers for N-acetyltransferase 2 and CYP1A2 activities. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10027663/ · DOI 10.1007/s002280050569

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 244–250

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Same 21-person caffeine-phenotyping study. · source_derived_draft · unverified_draft

## caf-probe-confounding A downstream block can make another enzyme’s probe result misleading. The NAT2 ratio AFMU/1MX fell to 56.7%, an alternative combined-metabolite NAT2 ratio stayed constant, and a CYP1A2 ratio transiently rose to 167%. Model: Same 21-person caffeine-phenotyping study. Limitations: Changed ratios do not prove corresponding changes in NAT2 or CYP1A2 catalytic activity. Evidence access: Primary abstract Xanthine oxidase inhibition by allopurinol affects the reliability of urinary caffeine metabolic ratios as markers for N-acetyltransferase 2 and CYP1A2 activities. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10027663/ · DOI 10.1007/s002280050569