Affinage

CYP1A2

Cytochrome P450 1A2 · UniProt P05177

Length
516 aa
Mass
58.4 kDa
Annotated
2026-06-09
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CYP1A2 is a constitutively expressed hepatic cytochrome P450 monooxygenase that uses a heme-iron active site, with cysteine 456 serving as the thiolate ligand, to catalyze oxidative metabolism of structurally diverse xenobiotics and drugs (PMID:6324134, PMID:8274012). Its substrate spectrum established by reconstituted-enzyme and knockout-mouse studies includes aflatoxin B1 (4-hydroxylation to aflatoxin M1) (PMID:3137222), heterocyclic amines IQ and MeIQx (N-hydroxylation to mutagens) (PMID:8200083), caffeine, zoxazolamine, clozapine, lidocaine, propranolol, and pentoxifylline (PMID:8643688, PMID:8873215, PMID:9384460, PMID:10901707, PMID:10945865, PMID:15194011); for several of these CYP1A2 dominates at low therapeutic concentrations while other P450s (CYP3A4, CYP2D6) contribute at higher concentrations (PMID:9384460, PMID:10901707, PMID:10945865). CYP1A2 is the selective catalyst of methoxyresorufin O-demethylation, distinguishing it from CYP1A1 (PMID:8274012, PMID:31147315). Beyond metabolism, CYP1A2 limits microsomal reactive oxygen production by acting as an electron sink that suppresses CYP2E1/CYP1A1-mediated H2O2 generation (PMID:14980704), is required for hepatic uroporphyrin accumulation through uroporphyrinogen oxidation in murine uroporphyria (PMID:10631128), and acts as a tumor suppressor in hepatocellular carcinoma by binding HIF-1α and promoting its ubiquitin-mediated degradation to antagonize HGF/MET signaling (PMID:33500715). CYP1A2 transcription is induced through AhR-dependent binding to dioxin responsive elements shared with CYP1A1 at a conserved head-to-head genomic locus, by ligands including 3-methylcholanthrene, beta-naphthoflavone, omeprazole, and psoralen/isopsoralen (PMID:18502397, PMID:19026991, PMID:35872289), but pyrene-induced expression is mediated by the constitutive androstane receptor rather than AhR (PMID:17618724). Expression is further controlled by DNA methylation of a proximal CpG island (PMID:19274061) and is suppressed in sepsis via Kupffer cell-derived TNF-α/IL-1β acting through downregulation of AhR/ARNT (PMID:16820944). The enzyme is absent in fetal and neonatal liver with delayed postnatal ontogenesis (PMID:9490065), and human expression is highly variable, partly through splice-site mutations and amino acid variants that abolish or alter activity (PMID:8287062, PMID:12919186, PMID:26022657).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1984 High

    Established the primary structure and the heme-iron coordination chemistry of the CYP1A2 ortholog, identifying cysteine 456 as the active-site thiolate ligand and mapping the gene physically next to CYP1A1.

    Evidence cDNA cloning/sequencing and cysteinyl peptide analysis plus somatic cell hybrid chromosome mapping in mouse

    PMID:6324134 PMID:6328503

    Open questions at the time
    • Cysteine 456 thiolate assignment was sequence-based, not validated by mutagenesis
    • No catalytic activity demonstrated at this stage
  2. 1988 High

    Resolved which enzyme detoxifies aflatoxin B1 by showing CYP1A2 itself catalyzes AFB1 4-hydroxylation, establishing direct enzyme-substrate function.

    Evidence Recombinant vaccinia virus expression of CYP1A2 cDNA with in vitro AFB1 metabolic assay

    PMID:3137222

    Open questions at the time
    • Did not address relative contribution versus other P450s in vivo
    • No structural basis for substrate selectivity
  3. 1993 High

    Defined the catalytic fingerprint that distinguishes CYP1A2 from CYP1A1 and provided isoform-selective chemical tools (furafylline), enabling all later attribution of activities to CYP1A2.

    Evidence Vaccinia cDNA expression with enzyme kinetics and selective inhibition (MROD vs EROD/BaP hydroxylase)

    PMID:8274012

    Open questions at the time
    • Inhibitor selectivity is partial (alpha-naphthoflavone inhibits both isoforms)
    • Mouse enzyme; human equivalence assumed
  4. 1994 High

    Linked CYP1A2's constitutive hepatic expression to procarcinogen activation, showing it is the primary enzyme bioactivating heterocyclic amines IQ and MeIQx to mutagens.

    Evidence Human/primate liver microsomes, Ames mutagenicity assay, CYP-level correlation, and TCDD induction in marmoset

    PMID:8200083

    Open questions at the time
    • PhIP activation shared with CYP1A1, not CYP1A2-specific
    • Correlative attribution rather than purified enzyme for all activities
  5. 1996 High

    Established in vivo physiological substrate dependence using genetic knockouts, proving CYP1A2 is rate-determining for zoxazolamine and caffeine clearance while other P450s partially compensate.

    Evidence Cyp1a2−/− knockout mice with paralysis test and pharmacokinetic/metabolite profiling

    PMID:8643688 PMID:8873215

    Open questions at the time
    • Identity of compensating caffeine-metabolizing P450s not determined
    • Mouse pharmacokinetics may differ from human
  6. 1997 High

    Clarified clinically relevant drug metabolism by showing CYP1A2 dominates clozapine demethylation at therapeutic concentrations through its low Km, with CYP3A4 dominating at higher concentrations.

    Evidence Human liver microsomes with chemical inhibitors, anti-CYP antibodies, expression systems, and kinetics

    PMID:9384460

    Open questions at the time
    • Relative in vivo contribution depends on hepatic enzyme abundance not measured here
  7. 1998 High

    Defined the developmental trajectory of CYP1A2, establishing its absence in fetal/neonatal liver and delayed postnatal onset, explaining pediatric drug-handling differences.

    Evidence Immunoblot and MROD/imipramine activity assays across a developmental human liver bank

    PMID:9490065

    Open questions at the time
    • Molecular trigger of postnatal induction not identified
    • Antibody is anti-rat CYP1A, cross-reactivity caveats
  8. 2000 High

    Extended the CYP1A2 substrate map to lidocaine and propranolol, quantifying its concentration-dependent and fractional contributions relative to CYP3A4 and CYP2D6.

    Evidence Human liver microsomes, recombinant isoform screening, selective inhibition, and kinetics

    PMID:10901707 PMID:10945865

    Open questions at the time
    • In vivo metabolic partitioning in humans not directly measured
  9. 2000 High

    Revealed a non-xenobiotic physiological role: CYP1A2 is required for hepatic uroporphyrinogen oxidation and uroporphyria, linking the enzyme to porphyrin metabolism.

    Evidence Cyp1a2−/− mice with HCBZ/iron treatment, uroporphyrin quantification, and microsomal oxidation assay

    PMID:10631128

    Open questions at the time
    • Catalytic mechanism of uroporphyrinogen oxidation not reconstituted
    • Human relevance not directly shown
  10. 1999 High

    Tested but did not confirm CYP1A2 as a rate-limiting carcinogen activator in vivo, showing it is not the sole enzyme for 4-aminobiphenyl N-hydroxylation in mice.

    Evidence Cyp1a2−/− neonatal hepatocarcinogenesis bioassay plus in vitro microsomal N-hydroxylation

    PMID:10469630

    Open questions at the time
    • Identity of the alternative N-hydroxylating P450 unknown
    • Negative result; may not extrapolate to humans
  11. 2004 High

    Identified a protective antioxidant function whereby CYP1A2 acts as an electron sink limiting CYP2E1/CYP1A1-mediated microsomal H2O2 production.

    Evidence Cyp1a2−/− microsomes, NADPH-dependent H2O2 and TBARS assays, furafylline inhibition

    PMID:14980704

    Open questions at the time
    • Molecular mechanism of electron-sink behavior not biochemically resolved
    • In vivo physiological significance not quantified
  12. 2006 Medium

    Defined an inflammatory suppression mechanism, showing Kupffer cell TNF-α/IL-1β downregulate hepatocyte CYP1A2 via AhR/ARNT during sepsis, requiring direct cell contact.

    Evidence Kupffer cell–hepatocyte co-culture with transwells and anti-cytokine antibodies plus CLP rat sepsis model

    PMID:16820944

    Open questions at the time
    • Contact-dependent signal beyond cytokines not identified
    • AhR/ARNT downregulation mechanism not resolved at transcriptional level
  13. 2007 High

    Distinguished receptor-specific induction routes, demonstrating pyrene induces CYP1A2 through CAR rather than AhR.

    Evidence AhR knockout vs wild-type mice with mRNA, protein, and EROD/MROD activity plus CAR/CYP2B10 readouts

    PMID:17618724

    Open questions at the time
    • Direct CAR binding to CYP1A2 regulatory elements not shown
    • Generality across other CAR ligands untested
  14. 2008 High

    Mapped the cis-regulatory architecture of AhR-mediated induction, identifying a shared CYP1A1/CYP1A2 regulatory region with dioxin responsive elements and a conserved head-to-head genomic locus.

    Evidence Dual reporter deletion constructs in hepatoma cells (omeprazole/BNF/3MC) and comparative genomic DRE analysis across mammals

    PMID:18502397 PMID:19026991

    Open questions at the time
    • Lack of proximal CYP1A2 DREs leaves the precise enhancer driving CYP1A2 unresolved
    • Genomic DRE analysis lacks functional reporter validation
  15. 2009 High

    Established epigenetic control of CYP1A2, showing CpG island methylation inversely controls hepatic expression and underlies allele-specific expression variability.

    Evidence Methylation-expression correlation in 65 human livers and 5-aza-2'-deoxycytidine induction in hepatoma cells

    PMID:19274061

    Open questions at the time
    • Transcription factors recruited to the methylated region not identified
    • Causal direction at single CpG sites inferred from correlation plus pharmacology
  16. 2003 Medium

    Provided a genetic mechanism for interindividual deficiency, identifying splice-site and abnormal-splicing variants causing low CYP1A2 activity and altered drug response.

    Evidence Direct sequencing with caffeine phenotyping and population screening; earlier exon-4 deletion variant

    PMID:12919186 PMID:8287062

    Open questions at the time
    • Functional translation/protein products of truncated transcripts not validated
    • Single-patient observations require population confirmation
  17. 2015 High

    Systematically defined the functional consequences of coding variants, identifying null, reduced-function, and gain-of-function CYP1A2 alleles.

    Evidence Heterologous expression of 20 variants in COS-7 cells with kinetics on two substrates

    PMID:26022657

    Open questions at the time
    • In vivo pharmacokinetic consequences of variants not measured
    • Substrate-dependence implies activity calls may vary for other substrates
  18. 2019 High

    Quantitatively partitioned hepatic CYP1A1 vs CYP1A2 contributions and confirmed constitutive hepatic CYP1A2 with broad inducibility using humanized and double-knockout mice.

    Evidence Humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 knockout mice with microsomal kinetics, quinidine inhibition, and TCDD tissue profiling

    PMID:31147315

    Open questions at the time
    • Humanized model may not fully recapitulate human regulatory context
  19. 2019 Medium

    Connected CYP1A2 to lipid pathophysiology, implicating it in alcohol-induced lipid dysregulation through the PTEN/AKT/SREBP-1c pathway.

    Evidence siRNA knockdown and fluvoxamine inhibition in L02 cells with PTEN manipulation and Western blots

    PMID:30979496

    Open questions at the time
    • In vitro single cell line only; no in vivo confirmation
    • Direct enzymatic link between CYP1A2 catalysis and PTEN/AKT not established
  20. 2021 Medium

    Defined a non-catalytic tumor-suppressor function: CYP1A2 binds HIF-1α and drives its ubiquitin-mediated degradation to suppress HGF/MET signaling in hepatocellular carcinoma.

    Evidence Co-immunoprecipitation, overexpression/knockdown in HCC cell lines, and in vivo xenografts

    PMID:33500715

    Open questions at the time
    • Ubiquitination mechanism not reconstituted; E3 ligase not identified
    • Co-IP without reciprocal structural validation of the CYP1A2–HIF-1α interface
  21. 2022 Medium

    Extended induction and bioactivation roles to herbal/agricultural toxicants, showing AhR-mediated induction by psoralen/isopsoralen and CYP1A2-dependent bioactivation of carbendazim to reactive adduct-forming metabolites.

    Evidence Thermal shift, docking, AhR translocation imaging, microsomal trapping/LC-MS, and in vivo rat metabolite detection

    PMID:35316061 PMID:35872289

    Open questions at the time
    • Direct AhR-DRE engagement for psoralen not demonstrated by ChIP
    • Single-lab bioactivation studies for carbendazim
  22. 2023 Low

    Provided a computational mechanistic model of CYP1A2 catalysis on melatonin, predicting 6-hydroxylation and O-demethylation via the heme-iron oxo intermediate.

    Evidence Molecular dynamics and DFT quantum chemical calculations on the CYP1A2 crystal structure with docked melatonin

    PMID:36835057

    Open questions at the time
    • Computational-only; no experimental validation in this study
    • Predicted product distribution not biochemically confirmed here

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CYP1A2's catalytic monooxygenase function mechanistically integrates with its non-catalytic regulatory roles (HIF-1α degradation, electron-sink antioxidant activity, lipid signaling) remains unresolved.
  • No structural definition of the CYP1A2–HIF-1α interaction
  • E3 ligase mediating HIF-1α degradation unidentified
  • Biochemical basis of electron-sink behavior not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 6 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-9748784 Drug ADME 4 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 2
Partners
AHRARNTHIF1A

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 Mouse cytochrome P3-450 (CYP1A2 ortholog) cDNA was fully sequenced, revealing a 513-residue protein with six cysteine residues; analysis of cysteinyl peptide-coding regions identified cysteine 456 as the likely thiolate ligand to the heme iron in the active site. cDNA cloning and sequencing; sequence homology analysis of cysteinyl peptide-coding regions Nucleic acids research Medium 6324134
1984 Mouse Cyp1a1 and Cyp1a2 (P1-450 and P3-450) structural genes were mapped to mouse chromosome 9 by Southern blot analysis of hamster-mouse somatic cell hybrids. Somatic cell hybrid Southern blot chromosome segregation analysis Proceedings of the National Academy of Sciences of the United States of America High 6328503
1988 CYP1A2 (cytochrome P3-450) cDNA encodes aflatoxin B1-4-hydroxylase activity, establishing CYP1A2 as the enzyme responsible for detoxification of AFB1 to aflatoxin M1; demonstrated by expression in mammalian cells via recombinant vaccinia virus. Recombinant vaccinia virus expression system; in vitro metabolic assay with AFB1 substrate The Journal of biological chemistry High 3137222
1993 CYP1A2 protein is highly variably expressed in human liver (>40-fold variation in mRNA); hepatic CYP1A2 mRNA levels significantly correlate with CYP1A2 protein levels by immunoblot. An abnormally spliced variant lacking exon 4 was identified in one individual with very low CYP1A2 protein, suggesting aberrant splicing as one mechanism of reduced expression. Quantitative PCR; immunoblot; cDNA cloning and sequencing; PCR splice variant analysis Pharmacogenetics Medium 8287062
1993 Mouse CYP1A2 preferentially catalyzes MROD (7-methoxyresorufin O-demethylase) activity, while CYP1A1 preferentially catalyzes benzo[a]pyrene hydroxylase and EROD activities; furafylline is a CYP1A2-selective inhibitor of MROD and EROD, whereas alpha-naphthoflavone equally inhibits AHH activity of CYP1A1 and CYP1A2. Vaccinia virus cDNA expression system; enzyme kinetics (kcat, Km); selective chemical inhibition; immunoblot Archives of biochemistry and biophysics High 8274012
1994 Human CYP1A2 (constitutively expressed in liver) is the primary enzyme responsible for N-hydroxylation and metabolic activation of heterocyclic amines IQ and MeIQx to mutagens; PhIP activation is shared with CYP1A1. This was established by correlation of CYP1A2 constitutive expression with activation rates in human and primate liver microsomes and by TCDD-induced CYP1A2 induction in marmoset with proportional increases in IQ and MeIQx activation. Human/primate liver microsomal incubations; Ames mutagenicity assay; correlation of CYP levels with activation rates; TCDD induction experiments Carcinogenesis High 8200083
1996 CYP1A2-deficient (Cyp1a2−/−) mice develop normally and are fertile, but exhibit dramatically prolonged zoxazolamine-induced paralysis (a CYP1A2 substrate), demonstrating that CYP1A2 is required for in vivo metabolism of this substrate. Cyp1a2(+/−) heterozygotes show intermediate paralysis times. Homologous recombination knockout mouse; zoxazolamine paralysis test; Northern blot; histological examination Proceedings of the National Academy of Sciences of the United States of America High 8643688
1996 CYP1A2 is the primary determinant of caffeine clearance in mice: Cyp1a2−/− mice show 7-fold longer caffeine half-life and 8-fold slower clearance compared to wild-type. Caffeine 3-demethylated metabolites (1-methylxanthine, 1-methylurate) are still formed in Cyp1a2−/− mice at 40% of wild-type levels, indicating additional P450s contribute. CYP1A2 knockout mouse pharmacokinetic study; blood caffeine measurement; urine metabolite analysis; liver function tests; Western blot for other P450s Pharmacogenetics High 8873215
1997 CYP1A2 and CYP3A4 are both involved in demethylation of clozapine (CLZ) to desmethylclozapine (DCLZ); CYP3A4 is primarily responsible for N-oxidation of CLZ. CYP1A2 has lower Km and Vmax than CYP3A4 for demethylation, suggesting CYP1A2 is more important at low (therapeutic) CLZ concentrations. Demonstrated by chemical inhibitors (fluvoxamine, triacetyloleandomycin, ketoconazole), specific antibodies, and heterologous expression systems. Human liver microsomal incubations; chemical inhibitors; anti-CYP antibody inhibition; CYP expression systems; correlation analysis; enzyme kinetics (Km, Vmax) British journal of clinical pharmacology High 9384460
1998 CYP1A2 protein is absent in human fetal and neonatal livers and shows delayed ontogenesis, with levels increasing from 1–3 months postnatal and reaching 50% of adult values at one year. Methoxyresorufin demethylase activity (CYP1A2-selective) follows this ontogenic profile. In early neonates, CYP3A mediates the low residual imipramine demethylation before CYP1A2 onset. Immunoblot with polyclonal anti-rat CYP1A antibody; enzymatic activity assays (methoxyresorufin demethylase, imipramine demethylation); human liver bank analysis across developmental stages European journal of biochemistry High 9490065
1999 CYP1A2 is not the sole enzyme responsible for 4-aminobiphenyl (4-ABP) N-hydroxylation in mice; in vivo hepatocarcinogenesis in Cyp1a2−/− mice showed no significant difference in overall tumor incidence compared to wild-type. In vitro studies confirmed another unidentified P450 contributes to 4-ABP N-hydroxylation in mice. Cyp1a2 knockout mouse neonatal bioassay; histological analysis of hepatic tumors and preneoplastic foci; in vitro microsomal N-hydroxylation assays with Cyp1a2−/− and wild-type microsomes Carcinogenesis High 10469630
2000 CYP1A2 is the major CYP isoform catalyzing lidocaine N-deethylation (MEGX formation) at low (therapeutically relevant) lidocaine concentrations (~60% inhibition by furafylline, >75% by anti-CYP1A1/2 antibodies), while CYP3A4 contribution increases at high lidocaine concentrations. CYP1A2 also almost exclusively catalyzes lidocaine 3-hydroxylation. Human liver microsomes; selective chemical inhibitors (furafylline, troleandomycin); immunoinhibition with anti-CYP antibodies; recombinant human CYP isoforms; enzyme kinetics Drug metabolism and disposition: the biological fate of chemicals High 10901707
2000 Both CYP1A2 and CYP2D6 catalyze propranolol 4-hydroxylation in human liver microsomes, with CYP1A2 contributing ~45% and CYP2D6 ~55% of total activity. Enzyme kinetics showed CYP1A2 Km of ~21 µM and CYP2D6 Km of ~8.5 µM for (S)-4-hydroxypropranolol formation. Human liver microsomes; recombinant CYP enzyme screening (11 isoforms); correlation analysis with CYP1A2 marker activity; selective chemical inhibitors (furafylline, quinidine); enzyme kinetics The Journal of pharmacology and experimental therapeutics High 10945865
2000 CYP1A2 is essential for hepatic uroporphyrin accumulation in hexachlorobenzene (HCBZ) and iron-induced murine uroporphyria: Cyp1a2−/− mice show no hepatic uroporphyrin accumulation even after additional HCBZ doses, while wild-type mice accumulate 300 nmol/g liver. HCBZ-induced uroporphyrinogen oxidation in microsomes was CYP1A2-dependent. Cyp1a2 knockout mouse; hepatic uroporphyrin measurement; Western immunoblotting for CYP proteins; microsomal uroporphyrinogen oxidation assay Toxicology and applied pharmacology High 10631128
2003 A heterozygous point mutation in the donor splice site of intron 6 (3534G>A) of CYP1A2 was identified as the likely cause of very low CYP1A2 activity (and high clozapine plasma concentrations) in a patient; this mutation is predicted to cause abnormal RNA splicing and a truncated nonfunctional enzyme. This is the first reported splice-site mutation in CYP1A2. Direct sequencing of all 7 exons, exon-intron boundaries, and 5'-flanking region; caffeine phenotyping; population screen of 100 Caucasians British journal of clinical pharmacology Medium 12919186
2004 CYP1A2 decreases microsomal reactive oxygen production (H2O2) possibly by acting as an 'electron sink,' reducing CYP2E1- and CYP1A1-mediated oxidative stress. Cyp1a2−/− mice showed significantly higher NADPH-dependent H2O2 production in microsomes compared to wild-type, and CYP1A2 inhibitor furafylline exacerbated H2O2 production proportional to degree of CYP1A2 inhibition. Cyp1a2 knockout mouse liver microsomes; NADPH-dependent H2O2 measurement; TCDD induction; furafylline inhibition; TBARS assay; membrane polarization anisotropy Free radical biology & medicine High 14980704
2004 CYP1A2 mediates pentoxifylline (PTX) metabolism in mice: Cyp1a2 knockout mice have significantly elevated serum PTX levels compared to wild-type at 20 minutes post-injection. Furafylline (selective CYP1A2 inhibitor) inhibits PTX metabolism in murine hepatic microsomes, and ciprofloxacin inhibits PTX metabolism without downregulating CYP1A2 protein. Cyp1a2 knockout mouse; furafylline inhibition; in vitro hepatic microsomal incubation; serum PTX measurement; Western blot for CYP1A2 and CYP2E1 Biochemical pharmacology High 15194011
2007 Pyrene-induced CYP1A2 expression (protein, mRNA, and EROD/pyrene 1-hydroxylation activities) occurs in both AhR(+/+) and AhR(−/−) mice, demonstrating that pyrene-induced CYP1A2 is regulated by constitutive androstane receptor (CAR) rather than AhR. Pyrene simultaneously induced CAR and its target CYP2B10 in both genotypes. AhR knockout and wild-type mouse in vivo exposure; hepatic protein and mRNA expression by Western blot and RT-PCR; enzyme activity assays (EROD, MROD); CAR and CYP2B10 expression analysis Toxicology High 17618724
2008 Omeprazole induces both CYP1A1 and CYP1A2 transcription through a common regulatory region containing multiple AhR-binding motifs (nucleotides −464 to −1829 of human CYP1A1), identical to the region for beta-naphthoflavone and 3-methylcholanthrene induction, but omeprazole activates both CYP1A1 and CYP1A2 to similar extents while BNF and 3MC prefer CYP1A1. Transient transfection of dual reporter gene constructs with deletion constructs in human hepatoma cells; AhR-dependence confirmed Biochemical pharmacology High 18502397
2008 Mouse Cyp1a1 and Cyp1a2 genes are arranged in head-to-head orientation separated by ~13.9 kb; eight consensus dioxin responsive elements (DREs) are present in this junction, with seven located within 1.4 kb upstream of Cyp1a1 but no conserved DREs in the proximal Cyp1a2 upstream region. This genomic architecture is conserved across human, mouse, cattle, dog, and rat. Comparative genomic DNA sequence analysis; identification of DRE motifs; evolutionary conservation analysis across mammalian genomes Biochemical pharmacology Medium 19026991
2009 CYP1A2 gene expression in human liver is regulated by DNA methylation: extent of methylation of a CpG island near the translation start site inversely correlates with hepatic CYP1A2 mRNA levels. Methylation of two core CpG sites is strongly associated with CYP1A2 mRNA levels and allele-specific expression phenotype. CYP1A2 expression in hepatoma cells was induced by the demethylating agent 5-aza-2'-deoxycytidine. 65 human liver samples; allele-specific expression analysis; CpG island methylation analysis; 5-aza-2'-deoxycytidine treatment of hepatoma cells; correlation analysis The pharmacogenomics journal High 19274061
2015 Functional characterization of 20 CYP1A2 amino acid substitution variants showed that CYP1A2*4, *6, *8, *15, *16, and *21 are completely inactive toward both phenacetin and 7-ethoxyresorufin. CYP1A2*11 shows markedly reduced activity with substrate-dependent changes in Km. CYP1A2*14 and *20 exhibit increased enzymatic activity compared to wild-type CYP1A2*1. Heterologous expression in COS-7 cells; enzyme kinetics (Km, Vmax) with two substrates (phenacetin O-deethylation, 7-ethoxyresorufin O-deethylation) Drug metabolism and pharmacokinetics High 26022657
2019 Using mice humanized for human CYP1A1/CYP1A2 combined with Cyp1a1/Cyp1a2 double knockout mice, CYP1A2 was shown to be constitutively expressed in the liver while both proteins are highly inducible by TCDD in liver, lung, kidney, and small intestine. Both CYP1A1 and CYP1A2 contribute to hepatic metabolism of 7-methoxy and 7-ethoxyresorufin; differential inhibition by quinidine allows quantitative partitioning of their respective contributions. Humanized CYP1A1/1A2 mice; Cyp1a1/Cyp1a2 knockout mice; microsomal enzyme kinetics; selective inhibition by quinidine; TCDD induction; tissue expression profiling Drug metabolism and disposition: the biological fate of chemicals High 31147315
2021 CYP1A2 acts as a tumor suppressor in hepatocellular carcinoma by directly binding to HIF-1α (confirmed by Co-immunoprecipitation), inducing ubiquitin-mediated degradation of HIF-1α, thereby inhibiting HIF-1α-mediated transcription of MET and reducing HGF/MET signaling pathway activation and MMP expression. Co-immunoprecipitation; Western blot; overexpression and knockdown in HCC cell lines; in vivo xenograft; Western blot; qRT-PCR; immunohistochemistry Theranostics Medium 33500715
2006 Kupffer cell-derived proinflammatory cytokines (TNF-α and IL-1β) suppress hepatocyte CYP1A2 expression in sepsis via downregulation of AhR/ARNT; anti-TNF-α and anti-IL-1β antibodies attenuated CYP1A2 downregulation in co-culture. LPS alone did not suppress CYP1A2 without direct Kupffer cell–hepatocyte contact. Primary Kupffer cell and hepatocyte co-culture (with and without transwells); anti-cytokine antibodies; CLP rat sepsis model; curcumin pretreatment; CYP1A2, AhR, ARNT expression analysis International journal of molecular medicine Medium 16820944
2019 CYP1A2 contributes to alcohol-induced abnormal lipid metabolism through the PTEN/AKT/SREBP-1c pathway: siRNA-mediated knockdown or fluvoxamine inhibition of CYP1A2 in L02 cells reduced ethanol-induced ALT, triglycerides, and SREBP-1c expression, while modulation of PTEN/AKT upstream of SREBP-1c confirmed pathway involvement. siRNA knockdown; pharmacological inhibition with fluvoxamine; PTEN siRNA; bpv (PTEN inhibitor); Western blot for PTEN, p-AKT, SREBP-1c; ALT and triglyceride measurement in cell culture Biochemical and biophysical research communications Medium 30979496
2022 CYP1A2 is induced by psoralen and isopsoralen via AhR-mediated transcriptional activation: both compounds bind AhR and activate its translocation from cytoplasm to nucleus, leading to transcriptional upregulation of CYP1A2, which mediates their hepatotoxicity. Shown in vitro and in vivo by AhR binding, nucleocytoplasmic shuttling, and CYP1A2 activity assays. HepG2 cells and mouse in vivo; cellular thermal shift assay; molecular docking; immunofluorescence (AhR translocation); CYP1A2 mRNA, protein, and phenacetin metabolism assays Journal of ethnopharmacology Medium 35872289
2022 CYP1A2 is the major enzyme responsible for metabolic activation (N-hydroxylation/oxidation) of the fungicide carbendazim to a reactive electrophilic metabolite that forms glutathione conjugates and protein adducts, contributing to hepatotoxicity. Biliary and urinary conjugate metabolites were detected in rats, and protein adduction in primary hepatocytes correlated with cytotoxicity. Human and rat liver microsomal incubation; GSH and NAC trapping; LC-MS/MS metabolite identification; in vivo rat biliary/urinary metabolite detection; protein adduction in rat primary hepatocytes Journal of agricultural and food chemistry Medium 35316061
2023 Molecular dynamics and quantum chemical calculations on CYP1A2 crystal structure with docked melatonin predict that CYP1A2 catalyzes melatonin 6-hydroxylation (aromatic hydroxylation) and O-demethylation (forming N-acetylserotonin) via the heme-iron oxo intermediate; calculated barrier heights are consistent with experimental product distributions and explain species differences with CYP1A1. Molecular dynamics simulation (up to 1 µs); density functional theory (DFT) quantum chemical cluster models; starting from crystal structure coordinates; substrate docking International journal of molecular sciences Low 36835057

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA 320 16522833
1992 Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities. Clinical pharmacology and therapeutics 269 1458773
2005 Assessment of CYP1A2 activity in clinical practice: why, how, and when? Basic & clinical pharmacology & toxicology 222 16128905
2008 Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms. Pharmacogenomics 205 18466106
2007 Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans. European journal of clinical pharmacology 202 17370067
1997 The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. British journal of clinical pharmacology 193 9384460
1998 Delayed ontogenesis of CYP1A2 in the human liver. European journal of biochemistry 157 9490065
1998 Evolutionary conserved light regulation of Calvin cycle activity by NADPH-mediated reversible phosphoribulokinase/CP12/ glyceraldehyde-3-phosphate dehydrogenase complex dissociation. Proceedings of the National Academy of Sciences of the United States of America 145 9689144
1993 Expression of CYP1A1 and CYP1A2 genes in human liver. Pharmacogenetics 145 8287062
2018 Caffeine, CYP1A2 Genotype, and Endurance Performance in Athletes. Medicine and science in sports and exercise 140 29509641
1994 Contribution of CYP1A1 and CYP1A2 to the activation of heterocyclic amines in monkeys and human. Carcinogenesis 135 8200083
1997 CP12 provides a new mode of light regulation of Calvin cycle activity in higher plants. Proceedings of the National Academy of Sciences of the United States of America 126 9294236
1996 Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism. Proceedings of the National Academy of Sciences of the United States of America 122 8643688
2011 Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption. Human molecular genetics 107 21357676
2003 The small protein CP12: a protein linker for supramolecular complex assembly. Biochemistry 99 12846565
2004 Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene. Journal of clinical psychopharmacology 95 15206669
2004 Emergence of new regulatory mechanisms in the Benson-Calvin pathway via protein-protein interactions: a glyceraldehyde-3-phosphate dehydrogenase/CP12/phosphoribulokinase complex. Journal of experimental botany 92 15047759
2011 Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease. European journal of neurology 87 21281405
1997 Lifestyle and nutritional correlates of cytochrome CYP1A2 activity: inverse associations with plasma lutein and alpha-tocopherol. Pharmacogenetics 83 9110357
2000 Involvement of CYP1A2 and CYP3A4 in lidocaine N-deethylation and 3-hydroxylation in humans. Drug metabolism and disposition: the biological fate of chemicals 80 10901707
2014 The CP12 protein family: a thioredoxin-mediated metabolic switch? Frontiers in plant science 74 24523724
2006 Search for an association between the human CYP1A2 genotype and CYP1A2 metabolic phenotype. Pharmacogenetics and genomics 74 16609368
2004 Genetic polymorphism of CYP1A2 increases the risk of myocardial infarction. Journal of medical genetics 67 15466009
2012 Associations between polymorphisms in the AHR and CYP1A1-CYP1A2 gene regions and habitual caffeine consumption. The American journal of clinical nutrition 60 22854411
2012 An intrinsically disordered protein, CP12: jack of all trades and master of the Calvin cycle. Biochemical Society transactions 60 22988853
1996 Role of CYP1A2 in caffeine pharmacokinetics and metabolism: studies using mice deficient in CYP1A2. Pharmacogenetics 60 8873215
2012 Measurement of CYP1A2 activity: a focus on caffeine as a probe. Current drug metabolism 59 22554278
2008 Omeprazole transactivates human CYP1A1 and CYP1A2 expression through the common regulatory region containing multiple xenobiotic-responsive elements. Biochemical pharmacology 59 18502397
1984 Mouse cytochrome P3-450: complete cDNA and amino acid sequence. Nucleic acids research 57 6324134
2003 Polymorphisms in the CYP1A2 gene and theophylline metabolism in patients with asthma. Clinical pharmacology and therapeutics 55 12732846
1999 CYP1A2 is not the primary enzyme responsible for 4-aminobiphenyl-induced hepatocarcinogenesis in mice. Carcinogenesis 55 10469630
1988 Cytochrome P3-450 cDNA encodes aflatoxin B1-4-hydroxylase. The Journal of biological chemistry 53 3137222
2007 Association of CYP1A1, CYP1A2, GSTM1 and NAT2 gene polymorphisms with colorectal cancer and smoking. Asian Pacific journal of cancer prevention : APJCP 52 18159984
1999 Simultaneous assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and caffeine. Pharmacogenetics 52 10634135
2012 Caffeine intake and CYP1A2 variants associated with high caffeine intake protect non-smokers from hypertension. Human molecular genetics 51 22492992
2000 CYP1A2 and CYP2D6 4-hydroxylate propranolol and both reactions exhibit racial differences. The Journal of pharmacology and experimental therapeutics 50 10945865
2003 Identification of a novel splice-site mutation in the CYP1A2 gene. British journal of clinical pharmacology 49 12919186
1993 Enzyme-kinetic and immunochemical characteristics of mouse cDNA-expressed, microsomal, and purified CYP1A1 and CYP1A2. Archives of biochemistry and biophysics 48 8274012
2012 Comparative analysis of 126 cyanobacterial genomes reveals evidence of functional diversity among homologs of the redox-regulated CP12 protein. Plant physiology 47 23184231
2009 Allele-specific expression and gene methylation in the control of CYP1A2 mRNA level in human livers. The pharmacogenomics journal 47 19274061
2004 Cyp1a2 protects against reactive oxygen production in mouse liver microsomes. Free radical biology & medicine 47 14980704
2002 Induction of CYP1A1 and CYP1A2 expressions by prototypic and atypical inducers in the human lung. Cancer letters 47 11849738
2000 CYP1A2 is essential in murine uroporphyria caused by hexachlorobenzene and iron. Toxicology and applied pharmacology 47 10631128
2013 CP12-mediated protection of Calvin-Benson cycle enzymes from oxidative stress. Biochimie 46 24211189
1984 Localization of cytochrome P1-450 and P3-450 genes to mouse chromosome 9. Proceedings of the National Academy of Sciences of the United States of America 46 6328503
2020 Effects of CYP1A2 and ADORA2A Genotypes on the Ergogenic Response to Caffeine in Professional Handball Players. Genes 43 32823594
2021 Novel insights on caffeine supplementation, CYP1A2 genotype, physiological responses and exercise performance. European journal of applied physiology 42 33403509
2019 Defining the Contribution of CYP1A1 and CYP1A2 to Drug Metabolism Using Humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 Knockout Mice. Drug metabolism and disposition: the biological fate of chemicals 42 31147315
2017 PXR mediated induction of CYP3A4, CYP1A2, and P-gp by Mitragyna speciosa and its alkaloids. Phytotherapy research : PTR 42 29071751
2010 CYP1A1, CYP1A2 and CYBA gene polymorphisms associated with oxidative stress in COPD. Clinica chimica acta; international journal of clinical chemistry 42 20080081
2007 NAT2 and CYP1A2 polymorphisms and lung cancer risk in relation to smoking status. Asian Pacific journal of cancer prevention : APJCP 42 17477782
2019 Polymorphisms in CYP1A2, CYP2C9 and ABCB1 affect agomelatine pharmacokinetics. Journal of psychopharmacology (Oxford, England) 41 30789308
2010 CYP1A2 polymorphisms, occupational and environmental exposures and risk of bladder cancer. European journal of epidemiology 41 20559687
2006 Association of CYP2D6 and CYP1A2 gene polymorphism with tardive dyskinesia in Chinese schizophrenic patients. Acta pharmacologica Sinica 40 16490169
2008 Exploring CP12 binding proteins revealed aldolase as a new partner for the phosphoribulokinase/glyceraldehyde 3-phosphate dehydrogenase/CP12 complex--purification and kinetic characterization of this enzyme from Chlamydomonas reinhardtii. The FEBS journal 39 18266760
2007 Ontogeny of hepatic CYP1A2 and CYP2E1 expression in rat. Journal of biochemical and molecular toxicology 39 17366540
2006 Construction of a 3D model of CP12, a protein linker. Journal of molecular graphics & modelling 38 16427344
2016 Gene-Environment Interaction in Parkinson's Disease: Coffee, ADORA2A, and CYP1A2. Neuroepidemiology 37 28135712
2012 CYP1A2 and coffee intake and the modifying effect of sex, age, and smoking. The American journal of clinical nutrition 37 22648710
2009 CP12 from Chlamydomonas reinhardtii, a permanent specific "chaperone-like" protein of glyceraldehyde-3-phosphate dehydrogenase. The Journal of biological chemistry 37 19287002
2004 Constitutive and inducible expression of cytochromes P4501A (CYP1A1 and CYP1A2) in normal prostate and prostate cancer cells. Journal of cellular biochemistry 35 14743400
2021 CYP1A2 suppresses hepatocellular carcinoma through antagonizing HGF/MET signaling. Theranostics 34 33500715
2009 Sulforaphane and its analogues inhibit CYP1A1 and CYP1A2 activity induced by benzo[a]pyrene. Journal of biochemical and molecular toxicology 34 19202560
2009 CYP1A2 genetic polymorphisms and adenocarcinoma lung cancer risk in the Tunisian population. Life sciences 34 19332078
2018 The azole fungicide tebuconazole affects human CYP1A1 and CYP1A2 expression by an aryl hydrocarbon receptor-dependent pathway. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 33 30458266
1999 Interaction of pefloxacin and enoxacin with the human cytochrome P450 enzyme CYP1A2. Clinical pharmacology and therapeutics 31 10096258
2006 Mapping of the interaction site of CP12 with glyceraldehyde-3-phosphate dehydrogenase from Chlamydomonas reinhardtii. Functional consequences for glyceraldehyde-3-phosphate dehydrogenase. The FEBS journal 30 16803460
2006 Suppression of hepatocyte CYP1A2 expression by Kupffer cells via AhR pathway: the central role of proinflammatory cytokines. International journal of molecular medicine 29 16820944
2009 Mapping of a copper-binding site on the small CP12 chloroplastic protein of Chlamydomonas reinhardtii using top-down mass spectrometry and site-directed mutagenesis. The Biochemical journal 28 19099541
2015 CYP1A2*1D and *1F polymorphisms have a significant impact on olanzapine serum concentrations. Therapeutic drug monitoring 27 25090458
2007 Pyrene-induced CYP1A2 and SULT1A1 may be regulated by CAR and not by AhR. Toxicology 27 17618724
2003 Smoking and tardive dyskinesia: lack of involvement of the CYP1A2 gene. Journal of psychiatry & neuroscience : JPN 27 12790158
2003 Constitutive and inducible levels of CYP1A1 and CYP1A2 in rat cerebral cortex and cerebellum. Archives of toxicology 27 14574441
1992 Expression and regulation of cytochrome P-450I genes (CYP1A1 and CYP1A2) in the rat alimentary tract. Biochimica et biophysica acta 27 1482679
2022 CP12 fine-tunes the Calvin-Benson cycle and carbohydrate metabolism in cyanobacteria. Frontiers in plant science 25 36330266
2012 CP12 residues involved in the formation and regulation of the glyceraldehyde-3-phosphate dehydrogenase-CP12-phosphoribulokinase complex in Chlamydomonas reinhardtii. Molecular bioSystems 25 22955105
2008 Conserved genomic structure of the Cyp1a1 and Cyp1a2 loci and their dioxin responsive elements cluster. Biochemical pharmacology 24 19026991
2020 Screening of Human CYP1A2 and CYP3A4 Inhibitors from Seaweed In Silico and In Vitro. Marine drugs 22 33260381
2012 Association between common CYP1A2 polymorphisms and theophylline metabolism in non-smoking healthy volunteers. Basic & clinical pharmacology & toxicology 21 23167834
2004 Role of CYP1A2 and CYP2E1 in the pentoxifylline ciprofloxacin drug interaction. Biochemical pharmacology 21 15194011
1995 3-Methylcholanthrene and pyridine effects on CYP1A1 and CYP1A2 expression in rat renal tissue. Drug metabolism and disposition: the biological fate of chemicals 21 7493548
2020 Relationships between CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 metabolic phenotypes and genotypes in a Nicaraguan Mestizo population. The pharmacogenomics journal 20 33024249
2018 Structural and functional insights into the unique CBS-CP12 fusion protein family in cyanobacteria. Proceedings of the National Academy of Sciences of the United States of America 20 29915055
2016 CYP1A2 and CYP2D6 Gene Polymorphisms in Schizophrenic Patients with Neuroleptic Drug-Induced Side Effects. Bulletin of experimental biology and medicine 20 27021090
2008 Comparison of CYP1A2 and NAT2 phenotypes between black and white smokers. Biochemical pharmacology 20 18703023
1997 Marmoset CYP1A2: primary structure and constitutive expression in livers. Carcinogenesis 20 9364010
1995 Regulation of cytochrome P-450 isozymes CYP1A1, CYP1A2 and CYP2B10 by three benzodioxole compounds. Chemico-biological interactions 20 7750163
2000 Parkinson's disease and CYP1A2 activity. British journal of clinical pharmacology 19 11012552
2018 Cryptic Disorder Out of Disorder: Encounter between Conditionally Disordered CP12 and Glyceraldehyde-3-Phosphate Dehydrogenase. Journal of molecular biology 18 29501381
2008 Characterization of substrate specificity of dog CYP1A2 using CYP1A2-deficient and wild-type dog liver microsomes. Drug metabolism and disposition: the biological fate of chemicals 18 18573860
2008 Purification, molecular cloning, heterologous expression and characterization of pig CYP1A2. Xenobiotica; the fate of foreign compounds in biological systems 18 18949657
2023 Melatonin Activation by Cytochrome P450 Isozymes: How Does CYP1A2 Compare to CYP1A1? International journal of molecular sciences 16 36835057
2022 First in vivo analysis of the regulatory protein CP12 of the model cyanobacterium Synechocystis PCC 6803: Biotechnological implications. Frontiers in plant science 16 36176677
2011 Isolation and compositional analysis of a CP12-associated complex of calvin cycle enzymes from Nicotiana tabacum. Protein and peptide letters 16 21271977
2009 Malaria downmodulates mRNA expression and catalytic activities of CYP1A2, 2E1 and 3A11 in mouse liver. European journal of pharmacology 16 19501084
2022 Metabolic Activation and Cytotoxicity of Fungicide Carbendazim Mediated by CYP1A2. Journal of agricultural and food chemistry 15 35316061
2022 Psoralen and isopsoralen from Psoraleae Fructus aroused hepatotoxicity via induction of aryl hydrocarbon receptor-mediated CYP1A2 expression. Journal of ethnopharmacology 15 35872289
2019 CYP1A2 contributes to alcohol-induced abnormal lipid metabolism through the PTEN/AKT/SREBP-1c pathway. Biochemical and biophysical research communications 15 30979496
2015 Functional characterization of 20 allelic variants of CYP1A2. Drug metabolism and pharmacokinetics 15 26022657
2010 Induction of immune responses in mice by a DNA vaccine encoding Cryptosporidium parvum Cp12 and Cp21 and its effect against homologous oocyst challenge. Veterinary parasitology 15 20541869

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