Affinage

CYP2C9

Cytochrome P450 2C9 · UniProt P11712

Length
490 aa
Mass
55.6 kDa
Annotated
2026-06-09
100 papers in source corpus 23 papers cited in narrative 23 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

CYP2C9 is a hepatic cytochrome P450 monooxygenase that hydroxylates a broad range of clinical drugs—including S-warfarin, diclofenac, tolbutamide, phenytoin, losartan, and NSAIDs—as well as endogenous arachidonic acid to epoxyeicosatrienoic acids (EETs) (PMID:10761997, PMID:30012669, PMID:11408373). Substrate handling is governed by discrete active-site subsites: systematic mutagenesis at Phe100, Phe114, Leu208, and Phe476 shows that distinct substrates occupy different binding locations, with the F-G loop region dictating substrate orientation, so that single substitutions can selectively enhance or abolish turnover of one substrate without affecting others (PMID:19258521). Common coding variants degrade function by mechanistically distinct routes: CYP2C9*3 (Ile359Leu) and *5 (Asp360Glu) raise Km and lower intrinsic clearance across multiple substrates (PMID:10761997, PMID:11455026), *13 (Leu90Pro) and *3 reduce protein abundance (PMID:15764711), and *2/*3 specifically impair reduction by NADPH-P450 reductase (PMID:30012669); massively parallel variant profiling generalizes this, showing that nearly two-thirds of missense variants reduce activity and that protein stability accounts for roughly half of functional variation (PMID:34314704). Allelic loss-of-function carries direct clinical consequence, as homozygous *3 produces severely diminished S-warfarin clearance (PMID:9352571). Transcription is controlled by a nuclear-receptor regulatory network: GR, CAR, PXR, and VDR act through promoter elements including a glucocorticoid palindrome at -1662/-1676 and a DR4 motif at -1803/-1818, for which these receptors compete (PMID:11679585, PMID:11991950, PMID:16749864), ERα regulates the gene through an ERE half-site at -149/-145 in a ligand-dependent manner (PMID:21493749), and miR-130b suppresses CYP2C9 both directly via the 3'-UTR and indirectly by repressing CAR and FXRα (PMID:25802328). Post-translationally, CYP2C9 forms a heteromeric complex with CYP3A4 via their N-terminal membrane anchors, which inhibits CYP2C9 activity in a manner relieved by increasing reductase (PMID:20215413, PMID:25157098). Beyond xenobiotic metabolism, CYP2C9-derived EETs drive proliferation and angiogenesis in tumor cells through a Ras-JNK signaling axis (PMID:30012669, PMID:21167292, PMID:38103405).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1993 Medium

    Established the genomic architecture and regulatory landscape of CYP2C9, framing where transcriptional control would later be mapped.

    Evidence Genomic cloning and sequencing of the gene and 2200 bp upstream region

    PMID:8333835

    Open questions at the time
    • Regulatory elements inferred from sequence homology, not functionally validated
    • No protein-level functional data
  2. 1997 Medium

    Connected a defined CYP2C9 genotype to a clinical metabolic phenotype, showing homozygous *3 selectively impairs S-warfarin clearance.

    Evidence PCR genotyping and chiral-phase HPLC of warfarin enantiomers in a homozygous *3 patient

    PMID:9352571

    Open questions at the time
    • Single-subject case
    • Does not isolate the enzymatic mechanism of impairment
  3. 2000 High

    Defined the enzymatic basis of the *3 loss-of-function allele as a broad increase in Km/decrease in intrinsic clearance across substrates.

    Evidence Site-directed mutagenesis, yeast cDNA expression, kinetics with seven substrates

    PMID:10761997

    Open questions at the time
    • Does not address protein abundance contribution
    • Yeast system may not reflect hepatic reductase coupling
  4. 2001 High

    Identified the nuclear-receptor promoter elements (GR palindrome, DR4 for CAR/PXR) controlling CYP2C9 induction, defining the xenobiotic transcriptional axis.

    Evidence Promoter deletion, mutagenesis, EMSA, co-transfection in hepatocytes with antagonists

    PMID:11679585

    Open questions at the time
    • Endogenous physiological inducers not enumerated
    • Cross-talk between receptors not resolved here
  5. 2001 High

    Characterized the *5 variant as another Km-increasing loss-of-function allele and established CYP2C9 as the major losartan-activating enzyme.

    Evidence Baculovirus expression and purification, kinetics; microsome inhibitor studies and variant expression for losartan

    PMID:11408373 PMID:11455026

    Open questions at the time
    • Substrate-specific magnitude of *5 effect varies
    • Reductase coupling not measured
  6. 2002 High

    Extended the regulatory network by showing VDR competes with PXR/CAR for the same response elements, integrating vitamin D signaling into CYP2C9 control.

    Evidence EMSA, mutated oligonucleotides, reporter assays in HepG2 and primary hepatocytes

    PMID:11991950

    Open questions at the time
    • Physiological relevance of VDR induction in vivo not established
    • Competition dynamics quantitatively undefined
  7. 2006 Medium

    Confirmed PXR/CAR-driven induction operates in intact liver, validating the in vitro promoter model in vivo.

    Evidence Hydrodynamic reporter delivery to mouse liver with receptor co-expression and chemical inducers

    PMID:16749864

    Open questions at the time
    • Mouse liver context, not human
    • Precise element usage not mapped in vivo
  8. 2009 High

    Resolved the active site into substrate-specific binding subsites, explaining how single residues differentially govern turnover of distinct drugs.

    Evidence Site-directed mutagenesis of nine active-site positions with kinetic and stereochemical readouts

    PMID:19258521

    Open questions at the time
    • No co-crystal structure for most substrates
    • Does not address dynamics of substrate entry
  9. 2010 High

    Revealed a post-translational regulatory mechanism: CYP2C9 forms an inhibitory N-terminal-anchored heterocomplex with CYP3A4.

    Evidence Reconstituted system, N-terminal truncation constructs, co-IP, varied CPR/b5

    PMID:20215413

    Open questions at the time
    • Stoichiometry of the complex undefined
    • Structural basis of the interface not solved
  10. 2010 Medium

    Linked CYP2C9-derived EETs to cancer cell proliferation, opening an endogenous signaling role beyond drug metabolism.

    Evidence Pharmacological CYP2C9 inhibition in esophageal cancer lines with cell-cycle analysis and 11,12-EET rescue

    PMID:21167292

    Open questions at the time
    • Inhibitor selectivity not genetically confirmed here
    • Downstream signaling not dissected
  11. 2011 High

    Added estrogen-receptor control through an ERE half-site, with ligand-dependent up- or down-regulation.

    Evidence Reporter assays, ERE mutagenesis, EMSA/supershift, ChIP, primary hepatocytes

    PMID:21493749

    Open questions at the time
    • Physiological estrogen effect on hepatic CYP2C9 in vivo not quantified
    • Interaction with xenobiotic receptors unexplored
  12. 2013 Medium

    Broadened the catalog of loss-of-function alleles, identifying multiple null and reduced-activity variants on S-warfarin.

    Evidence Transient expression of 32 variants in COS-7 with S-warfarin kinetics

    PMID:23752738

    Open questions at the time
    • Single substrate tested
    • Protein abundance vs catalytic effects not separated
  13. 2014 Medium

    Demonstrated the CYP3A4-CYP2C9 interaction operates in physiological hepatocytes, with CYP3A4 levels inversely tuning CYP2C9 activity.

    Evidence CYP3A4 siRNA knockdown in HepatoPac culture with activity, mRNA, and protein readouts

    PMID:25157098

    Open questions at the time
    • Endogenous regulators of CYP3A4 abundance not addressed
    • Quantitative interplay across genotypes unknown
  14. 2015 Medium

    Identified miR-130b as a direct and indirect post-transcriptional repressor of CYP2C9, linking expression to cholestasis and inflammation.

    Evidence miRNA mimic transfection in HepaRG, 3'-UTR reporter, qRT-PCR, LC-MS/MS activity

    PMID:25802328

    Open questions at the time
    • In vivo regulation by miR-130b not demonstrated
    • Relative weight of direct vs indirect (CAR/FXRα) effects unclear
  15. 2018 High

    Established the EET-tumor angiogenesis axis mechanistically and showed reduced-function variants impair it via defective reductase coupling.

    Evidence Purified protein kinetics, reductase assays, NSCLC xenografts, endothelial assays, EET quantification

    PMID:30012669

    Open questions at the time
    • Generalizability across tumor types not shown
    • Contribution of EETs vs other CYP2C9 products not isolated
  16. 2021 High

    Provided a genome-scale functional map showing protein stability accounts for about half of CYP2C9 functional variation.

    Evidence Click-seq pooled yeast activity assay plus VAMP-seq abundance in human cells across thousands of variants

    PMID:34314704

    Open questions at the time
    • Single substrate context for activity assay
    • Clinical translation of variant scores not validated
  17. 2023 Medium

    Generalized the CYP2C9-EET-Ras-JNK signaling axis to stress-induced ferroptosis, defining it as unidirectional from enzyme to signaling.

    Evidence siRNA, sulfaphenazole, Ras inhibitor epistasis, ferroptosis markers in porcine Sertoli cells

    PMID:38103405

    Open questions at the time
    • Porcine model; human relevance untested
    • Molecular link between EETs and Ras activation not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How transcriptional, post-transcriptional (miR-130b), and post-translational (CYP3A4 complex) layers are jointly coordinated to set hepatic CYP2C9 activity in vivo remains unresolved.
  • No integrated in vivo model combining the regulatory layers
  • Structural basis of the CYP3A4 interface unsolved
  • Relative contribution of each layer to interindividual drug-response variability unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0008289 lipid binding 3 GO:0016787 hydrolase activity 3
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-9748784 Drug ADME 3 R-HSA-1430728 Metabolism 2
Partners
CYP3A4

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Transcriptional regulation of CYP2C9 by glucocorticoid receptor (GR) and constitutive androstane receptor (CAR): a glucocorticoid-responsive imperfect palindrome was identified at -1662/-1676 and a DR4 motif at -1803/-1818 in the CYP2C9 promoter. The DR4 motif is recognized and transactivated by CAR and pregnane X receptor (PXR). These elements were characterized by deletional analysis, co-transfection experiments, directed mutagenesis, gel shift assays, and response to specific antagonists (RU486, androstanol). Promoter deletion analysis, site-directed mutagenesis, co-transfection in hepatocytes, electrophoretic mobility shift assay (EMSA), specific receptor antagonists The Journal of biological chemistry High 11679585
2002 Vitamin D receptor (VDR) binds and transactivates xenobiotic-responsive elements (ER6, DR3, DR4) in the CYP2C9 promoter previously identified as PXR/CAR targets, inducing CYP2C9 expression in primary human hepatocytes. VDR, PXR, and CAR compete for the same response elements in the CYP3A4/CYP2C9 promoter region. EMSA, co-transfection in HepG2 cells using wild-type and mutated oligonucleotides, reporter-gene assays in primary human hepatocytes The Journal of biological chemistry High 11991950
1993 Structural characterization of the CYP2C9 gene: nine coding exons spanning ~55 kb, with intron-exon organization similar to other CYP2C subfamily members. The 5'-upstream region contains TATA boxes, multiple glucocorticoid regulatory element consensus sequences, and a 15-base sequence with homology to a barbiturate-inducible element from P450BM-3 in Bacillus megaterium. Genomic cloning, restriction mapping, DNA sequencing of 2200 bp upstream region Biochemical and biophysical research communications Medium 8333835
2000 The CYP2C9*3 allele (Ile359Leu substitution) significantly reduces catalytic activity for all seven CYP2C9 substrates tested (S-warfarin, diclofenac, tolbutamide, phenytoin, piroxicam, and others). The Leu359 variant shows higher Km values for all substrates and reduced Vmax/Km (intrinsic clearance) ranging from 3.4- to 26.9-fold lower than wild-type. The substitution also decreases enantiomeric selectivity for phenytoin hydroxylation. Site-directed mutagenesis, cDNA expression in yeast, enzyme kinetic assays with seven substrates Pharmacogenetics High 10761997
2001 CYP2C9*5 variant (Asp360Glu substitution) was identified in African Americans and expressed in insect cells. Comparative kinetic studies showed that Asp360Glu primarily increases Km (12-fold for S-warfarin 7-hydroxylation, 5-fold for diclofenac 4'-hydroxylation, 3-fold for lauric acid ω-1 hydroxylation) relative to wild-type CYP2C9*1, with in vitro intrinsic clearances 8–18% of CYP2C9*1 values. Single-strand conformational polymorphism, RFLP, baculovirus expression, purification from insect cells, comparative kinetic studies with three substrates Molecular pharmacology High 11455026
1997 CYP2C9*3 (homozygous) is associated with severely diminished clearance of S-warfarin. A patient homozygous for CYP2C9*3 who could tolerate only 0.5 mg/day warfarin showed a plasma S:R warfarin ratio of 3.9:1 (versus 0.50 ± 0.25 in controls), indicating selective impairment of S-warfarin metabolism. Urinary 7-hydroxywarfarin S:R ratio was normal (4:1), suggesting the defect is in clearance not in stereospecificity of available enzyme. PCR genotyping, restriction digest, chiral-phase HPLC measurement of plasma warfarin enantiomers and urinary metabolites Pharmacogenetics Medium 9352571
2010 CYP2C9 and CYP3A4 physically interact via their hydrophobic N-terminal membrane-anchoring domains to form a heteromeric complex. This interaction inhibits CYP2C9-mediated metabolism (up to 80% inhibition of S-naproxen and S-flurbiprofen hydroxylation) without changing Km values, while CYP2C9 does not alter CYP3A4 testosterone metabolism. Truncation of either enzyme's N-terminus abolishes the inhibition. Increasing CPR concentrations relieves the inhibition. Reconstituted system incubations, truncated protein constructs, co-immunoprecipitation, varied CPR and cytochrome b5 concentrations Drug metabolism and disposition: the biological fate of chemicals High 20215413
2014 Modulation of CYP3A4 protein levels in human hepatocytes (HepatoPac long-term culture) inversely affects CYP2C9 activity: siRNA-mediated CYP3A4 knockdown (60% decrease) caused a 74% increase in CYP2C9 activity with no change in CYP2C9 mRNA, confirming post-translational protein-protein interaction between CYP3A4 and CYP2C9 in a physiological in vitro system. siRNA knockdown of CYP3A4 in HepatoPac long-term human hepatocyte culture, activity assays, mRNA and protein quantification Drug metabolism and disposition: the biological fate of chemicals Medium 25157098
2015 miR-130b directly targets the CYP2C9 3'-UTR and negatively regulates CYP2C9 activity. Transfection of miR-130b mimics in HepaRG cells significantly reduced CYP2C9 mRNA expression and decreased CYP2C9 enzyme activity by at least 30%. miR-130b also indirectly downregulates CYP2C9 by suppressing nuclear receptors CAR and FXRα. miR-130b levels are elevated in cholestasis and inflammation. miRNA mimic transfection in HepaRG cells, quantitative RT-PCR, LC-MS/MS cocktail P450 activity assay, 3'-UTR reporter gene assay Drug metabolism and disposition: the biological fate of chemicals Medium 25802328
2011 Estrogen receptor α (ERα) regulates CYP2C9 transcription through a functionally relevant ERE half-site at position -149/-145 in the CYP2C9 promoter. ERα binds this site (confirmed by EMSA and antibody supershift). ERα ligands differentially regulate CYP2C9 promoter activity: 4-hydroxytamoxifen and raloxifene upregulate, while 17α-ethinylestradiol suppresses, CYP2C9 promoter activity. Mutations in the ERE half-site abolish these effects. ChIP confirmed ERα association with the CYP2C9 promoter in cells. Luciferase reporter assay, site-directed mutagenesis of ERE half-site, EMSA with antibody supershift, chromatin immunoprecipitation (ChIP), primary hepatocyte experiments The Journal of pharmacology and experimental therapeutics High 21493749
2006 PXR and CAR activate CYP2C9 gene expression in mouse liver through elements residing in the -2000 to -1000 bp region of the 5'-flanking sequence. Chemical inducers of PXR (rifampicin, PCN) and CAR (phenobarbital, TCPOBOP) significantly enhanced CYP2C9 promoter-driven luciferase expression when cotransfected with respective receptor expression vectors in vivo in mouse liver. Hydrodynamic delivery of reporter constructs to mouse liver, co-transfection with PXR or CAR expression vectors, luciferase reporter assay Molecular pharmaceutics Medium 16749864
2009 Active-site mutagenesis at Phe100, Phe114, Leu208, and Phe476 in CYP2C9 reveals substrate-specific binding locations: F100L and F114W mutants show 4-5-fold increased catalytic efficiency for phenytoin, while F100W, F114L, F476L, and F476W mutants lose >90% phenytoin hydroxylation capacity. The pattern differs from S-warfarin and S-flurbiprofen, indicating these substrates occupy discrete locations within the active site. L208V and F114L mutants alter phenytoin's catalytic orientation. L208V uniquely enhances 6-hydroxylation of S-warfarin, providing experimental evidence for the F-G loop region in dictating substrate orientation. Site-directed mutagenesis of nine active-site positions, in vitro kinetic analysis, stereochemical analysis of hydroxylated metabolites The Journal of pharmacology and experimental therapeutics High 19258521
2013 Functional characterization of 32 CYP2C9 allelic variants expressed in COS-7 cells using S-warfarin as substrate revealed that CYP2C9.18, .21, .24, .26, .33, and .35 exhibit no enzyme activity, and 12 additional variants show significantly decreased activity, establishing the molecular basis for loss-of-function alleles. Transient expression of variant CYP2C9 proteins in COS-7 cells, S-warfarin hydroxylation kinetic assay The pharmacogenomics journal Medium 23752738
2021 Massively parallel activity profiling of 6,142 CYP2C9 missense variants using a pooled yeast-based click-seq assay, combined with VAMP-seq abundance measurement in human cells for 6,370 variants, revealed that almost two-thirds of CYP2C9 variants show decreased activity and that protein abundance (stability) accounts for approximately half of the variation in CYP2C9 function. Click-seq pooled yeast activity assay, VAMP-seq (variant abundance by massively parallel sequencing) in human cells American journal of human genetics High 34314704
2018 CYP2C9 metabolizes arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs), and the CYP2C9*2 and CYP2C9*3 variants metabolize AA less efficiently than CYP2C9*1, primarily due to impaired reduction of these variant proteins by NADPH-P450 reductase. Expression of CYP2C9*2 or *3 in NSCLC cells produced lower EET levels, smaller/less vascularized tumors in mice, and reduced endothelial cell proliferation and migration, establishing a direct mechanistic link between CYP2C9 variant activity, EET biosynthesis, and tumor angiogenesis. In vitro kinetic assays with purified CYP2C9*1, *2, *3 proteins, NADPH-P450 reductase activity assays, NSCLC cell tumor xenograft mouse model, endothelial cell proliferation/migration assays, EET quantification Cancer research High 30012669
2001 CYP2C9 is the major enzyme responsible for losartan oxidation to the active carboxylic acid metabolite E-3174. CYP2C9 inhibitor sulfaphenazole blocked E-3174 formation at low losartan concentrations, while CYP3A4 inhibitor triacetyloleandomycin was effective only at high concentrations. CYP2C9.2 and CYP2C9.3 yeast-expressed variants showed significantly reduced losartan oxidation, primarily due to lower Vmax. CYP2C9*3 liver microsomes also showed lower oxidation rates. Human liver microsome incubations with selective inhibitors, yeast expression of CYP2C9 variants, HPLC metabolite analysis, kinetic analysis across 25 individual liver microsome samples with genotype correlation Drug metabolism and disposition: the biological fate of chemicals High 11408373
2005 CYP2C9*13 (Leu90Pro substitution) reduces lornoxicam 5'-hydroxylation in COS-7 cells (Vmax/Km 12% of wild-type CYP2C9*1; compared to 28% for CYP2C9*3). Protein levels of both CYP2C9*3 and *13 were lower than CYP2C9*1. In a clinical study, CYP2C9*1/*13 subjects showed 1.9-fold higher lornoxicam AUC and 44% lower oral clearance versus CYP2C9*1/*1. Transient transfection expression in COS-7 cells, enzyme kinetic assays, clinical pharmacokinetic study in CYP2C9*1/*13 heterozygotes Drug metabolism and disposition: the biological fate of chemicals Medium 15764711
2018 Dicloxacillin induces CYP2C9 expression and activity through activation of pregnane X receptor (PXR): dicloxacillin treatment in primary human hepatocytes produced a statistically significant dose-dependent increase in CYP2C9 expression and activity, and luciferase assays confirmed PXR activation as the mechanism. Open-label randomized clinical crossover study with tolbutamide as CYP2C9 probe, primary human hepatocyte gene expression and activity assays, luciferase-based nuclear receptor activation assay British journal of clinical pharmacology Medium 29105855
2017 Crystal structure of CYP2C9 in complex with a TCA1 antitubercular thiophene analog revealed interaction patterns within the CYP2C9 active site; structure-guided optimization enabled generation of molecules with differential inhibitory activities against DprE1 and CYP2C9, providing structural basis for CYP2C9 inhibitor selectivity. X-ray crystallography of CYP2C9 in complex with TCA1 analog, structure-guided analog synthesis Angewandte Chemie (International ed. in English) Medium 28815830
2023 Heat stress increases CYP2C9 expression and EET production in porcine Sertoli cells, activating the Ras-JNK signaling pathway and inducing ferroptosis. Pharmacological inhibition of CYP2C9 with sulfaphenazole or siRNA knockdown of CYP2C9 reduced EET content, suppressed Ras-JNK activation, and alleviated ferroptosis. Ras inhibitor (salirasib) did not affect CYP2C9 expression or EET levels, indicating unidirectional signaling from CYP2C9-EETs to Ras-JNK. CYP2C9 siRNA knockdown, sulfaphenazole pharmacological inhibition, Ras inhibitor, flow cytometry (apoptosis/ROS), Western blotting (GPX4, TFR1, Ferritin, p-JNK), EET quantification in porcine Sertoli cells Theriogenology Medium 38103405
2010 CYP2C9 promotes esophageal cancer cell proliferation through EET production. Selective pharmacological inhibition of CYP2C9 decreased tumor cell proliferation in esophageal cancer cell lines (KYSE30, PT1590, OE19), and this anti-proliferative effect was reversed by exogenous addition of 11,12-EET. CYP2C9 inhibition caused G0/G1 cell-cycle arrest. CYP2C9 inhibitor treatment of cancer cell lines, cell cycle analysis by FACS, EET rescue experiment Prostaglandins & other lipid mediators Medium 21167292
2004 Active-site probing with hydantoin and barbiturate inhibitors established that CYP2C9 active site differs from CYP2C19 in stereochemical requirements: inhibitor stereochemistry does not markedly influence Ki toward CYP2C9, and log P adequately predicts inhibitor potency for CYP2C9, contrasting with CYP2C19 where stereochemistry is a major factor. All tested compounds were competitive inhibitors of CYP2C9. Synthesis of N-3 alkyl-substituted phenytoin, nirvanol, and barbiturate derivatives; Ki determination against recombinant CYP2C9 and CYP2C19; CoMFA modeling Archives of biochemistry and biophysics Medium 15288804
2010 CYP2C9*3 (Ile359Leu) and CYP2C9*13 (Leu90Pro) variants reduce diclofenac 4'-hydroxylation in yeast-expressed enzyme. Both variants also alter the inhibitory potency of clinical drugs against diclofenac metabolism; in particular, CYP2C9*13 significantly weakens inhibition by sulfaphenazole, fluvastatin, fluvoxamine, and tranylcypromine, demonstrating that active-site substitutions alter drug-drug interaction profiles. Yeast expression of CYP2C9*1, *3, *13, kinetic analysis of diclofenac 4'-hydroxylation, Ki determination for nine inhibitors against each variant Drug metabolism and pharmacokinetics Medium 20814155

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 807 11926893
2007 Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. Journal of thrombosis and haemostasis : JTH 603 17900275
2002 Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes. The Journal of biological chemistry 288 11991950
2002 CYP2C9 allelic variants: ethnic distribution and functional significance. Advanced drug delivery reviews 272 12406644
2003 The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors. Biochimica et biophysica acta 267 12573484
2002 Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clinical pharmacology and therapeutics 266 12496751
1996 Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 254 8946475
1997 Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 253 9352571
2003 Developmental expression of human hepatic CYP2C9 and CYP2C19. The Journal of pharmacology and experimental therapeutics 236 14634042
2000 CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates. Pharmacogenetics 234 10761997
2001 Transcriptional regulation of CYP2C9 gene. Role of glucocorticoid receptor and constitutive androstane receptor. The Journal of biological chemistry 218 11679585
2001 Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans. Molecular pharmacology 214 11455026
2005 Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics. Annual review of pharmacology and toxicology 185 15822186
2004 Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. Pharmacological research 165 15177309
2017 Pharmacogenomics of CYP2C9: Functional and Clinical Considerations. Journal of personalized medicine 163 29283396
2006 Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 - rationale and perspectives. Thrombosis research 157 17161452
2002 Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kinetics and the insulin and glucose response in healthy volunteers. Pharmacogenetics 152 11875364
2001 Role of CYP2C9 polymorphism in losartan oxidation. Drug metabolism and disposition: the biological fate of chemicals 140 11408373
2007 Detection of human CYP2C8, CYP2C9, and CYP2J2 in cardiovascular tissues. Drug metabolism and disposition: the biological fate of chemicals 133 17220242
2003 Clinical relevance of genetic polymorphisms in the human CYP2C9 gene. European journal of clinical investigation 115 14641553
2006 CYP2C9 inhibition: impact of probe selection and pharmacogenetics on in vitro inhibition profiles. Drug metabolism and disposition: the biological fate of chemicals 97 16963489
2005 Impact of CYP2C9 genotype on pharmacokinetics: are all cyclooxygenase inhibitors the same? Drug metabolism and disposition: the biological fate of chemicals 90 16118328
2021 Massively parallel characterization of CYP2C9 variant enzyme activity and abundance. American journal of human genetics 85 34314704
2003 Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Pharmacogenetics 84 12893985
2005 Genetic polymorphism of CYP2C9 and CYP2C19 in a Bolivian population: an investigative and comparative study. European journal of clinical pharmacology 81 15776277
2004 CYP2C9 genotypes and the pharmacokinetics of tenoxicam in Brazilians. Clinical pharmacology and therapeutics 72 15229460
2013 Functional characterization of 32 CYP2C9 allelic variants. The pharmacogenomics journal 70 23752738
2004 QTc interval, CYP2D6 and CYP2C9 genotypes and risperidone plasma concentrations. Journal of psychopharmacology (Oxford, England) 70 15260906
1993 Gene structure and upstream regulatory regions of human CYP2C9 and CYP2C18. Biochemical and biophysical research communications 68 8333835
2005 Role of CYP2C9 and its variants (CYP2C9*3 and CYP2C9*13) in the metabolism of lornoxicam in humans. Drug metabolism and disposition: the biological fate of chemicals 66 15764711
2015 Inflammation-associated microRNA-130b down-regulates cytochrome P450 activities and directly targets CYP2C9. Drug metabolism and disposition: the biological fate of chemicals 65 25802328
2007 Current pharmacogenetic developments in oral anticoagulation therapy: the influence of variant VKORC1 and CYP2C9 alleles. Thrombosis and haemostasis 65 17849045
2004 Effect of CYP2D6 and CYP2C9 genotypes on fluoxetine and norfluoxetine plasma concentrations during steady-state conditions. European journal of clinical pharmacology 64 14726986
2021 PharmVar GeneFocus: CYP2C9. Clinical pharmacology and therapeutics 58 34109627
2001 Association of CYP2C9 genotypes leading to high enzyme activity and colorectal cancer risk. Carcinogenesis 56 11470765
2004 The inhibitory effects of herbal components on CYP2C9 and CYP3A4 catalytic activities in human liver microsomes. American journal of therapeutics 55 15133536
2011 Drug metabolism of CYP3A4, CYP2C9 and CYP2D6 substrates in pigs and humans. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 51 21447389
2002 Analysis of CYP2C9*5 in Caucasian, Oriental and black-African populations. European journal of clinical pharmacology 51 12451434
2015 Clinical significance of CYP2C9-status guided valproic acid therapy in children. Epilepsia 47 25967074
2012 Evaluation of the relationship between sex, polymorphisms in CYP2C8 and CYP2C9, and pharmacokinetics of angiotensin receptor blockers. Drug metabolism and disposition: the biological fate of chemicals 45 23118328
2010 CYP2C9-CYP3A4 protein-protein interactions: role of the hydrophobic N terminus. Drug metabolism and disposition: the biological fate of chemicals 45 20215413
2009 Global variation in CYP2C8-CYP2C9 functional haplotypes. The pharmacogenomics journal 44 19381162
2004 CYP2C9 genetic variants and losartan oxidation in a Turkish population. European journal of clinical pharmacology 44 15197523
1999 Homology modeling and substrate binding study of human CYP2C9 enzyme. Proteins 44 10584064
2011 Frequency of CYP2C9 alleles in Koreans and their effects on losartan pharmacokinetics. Acta pharmacologica Sinica 43 21841812
2016 CYP2C9 Genotype-Dependent Warfarin Pharmacokinetics: Impact of CYP2C9 Genotype on R- and S-Warfarin and Their Oxidative Metabolites. Journal of clinical pharmacology 42 27539372
2013 Association of CYP2C9*2 with bosentan-induced liver injury. Clinical pharmacology and therapeutics 42 23863877
2006 Enzyme source effects on CYP2C9 kinetics and inhibition. Drug metabolism and disposition: the biological fate of chemicals 42 16928789
2019 Polymorphisms in CYP1A2, CYP2C9 and ABCB1 affect agomelatine pharmacokinetics. Journal of psychopharmacology (Oxford, England) 41 30789308
2017 Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes. Angewandte Chemie (International ed. in English) 41 28815830
2012 Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin. Seminars in thrombosis and hemostasis 41 23041981
2004 CYP2C9 polymorphisms and the interindividual variability in pharmacokinetics and pharmacodynamics of the loop diuretic drug torsemide. Clinical pharmacology and therapeutics 39 15592327
2009 Binding of CYP2C9 with diverse drugs and its implications for metabolic mechanism. Medicinal chemistry (Shariqah (United Arab Emirates)) 38 19442216
2015 CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effects. Expert opinion on drug metabolism & toxicology 37 26037375
2005 Ethnic differences in CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu) genotypes in Japanese and Israeli populations. Life sciences 35 16111713
2004 CYP3A4, CYP2C9 and CYP2B6 expression and ifosfamide turnover in breast cancer tissue microsomes. British journal of cancer 35 14970873
2019 Relevance of CYP2C9 Function in Valproate Therapy. Current neuropharmacology 33 29119932
2014 VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children. Pediatric blood & cancer 33 24474498
2020 CYP2C9 and CYP2C19: Deep Mutational Scanning and Functional Characterization of Genomic Missense Variants. Clinical and translational science 32 32004414
2004 The CYP2C9 polymorphism: from enzyme kinetics to clinical dose recommendations. Personalized medicine 32 29793229
2020 Inhibition of CYP2C9 by natural products: insight into the potential risk of herb-drug interactions. Drug metabolism reviews 30 32406758
2009 CYP2C9 polymorphisms: considerations in NSAID therapy. Current opinion in drug discovery & development 29 19152219
2016 Genetic Polymorphisms and in Vitro Functional Characterization of CYP2C8, CYP2C9, and CYP2C19 Allelic Variants. Biological & pharmaceutical bulletin 28 27803446
2018 Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro. British journal of clinical pharmacology 27 29105855
2010 Influence of CYP2C9 polymorphism on metabolism of valproate and its hepatotoxin metabolite in Iranian patients. Toxicology mechanisms and methods 27 20602621
2009 CYP2C9 genotype and pharmacodynamic responses to losartan in patients with primary and secondary kidney diseases. European journal of clinical pharmacology 27 19669737
2018 The Cytochrome P450 Slow Metabolizers CYP2C9*2 and CYP2C9*3 Directly Regulate Tumorigenesis via Reduced Epoxyeicosatrienoic Acid Production. Cancer research 26 30012669
2013 Genotyping of CYP2C9 and VKORC1 in the Arabic population of Al-Ahsa, Saudi Arabia. BioMed research international 26 23586031
2010 Effects of CYP2C9*3 and CYP2C9*13 on Diclofenac Metabolism and Inhibition-based Drug-Drug Interactions. Drug metabolism and pharmacokinetics 26 20814155
2012 Prevalence of VKORC1 and CYP2C9 gene polymorphisms in Indian population and its effect on warfarin response. The Journal of the Association of Physicians of India 25 23781667
2010 Esophageal cancer proliferation is mediated by cytochrome P450 2C9 (CYP2C9). Prostaglandins & other lipid mediators 25 21167292
2006 Activation of human CYP2C9 promoter and regulation by CAR and PXR in mouse liver. Molecular pharmaceutics 25 16749864
2004 Association between the CYP2C9 polymorphism and the drug metabolism phenotype. Clinical chemistry and laboratory medicine 25 15061384
2013 Evaluation of the relationship between polymorphisms in CYP2C8 and CYP2C9 and the pharmacokinetics of celecoxib. Journal of clinical pharmacology 24 23996211
2020 Functional Measurement of CYP2C9 and CYP3A4 Allelic Polymorphism on Sildenafil Metabolism. Drug design, development and therapy 23 33262574
2003 CYP2C9 gene and susceptibility to major depressive disorder. The pharmacogenomics journal 23 14583800
2018 CYP2C9 and OATP1B1 genetic polymorphisms affect the metabolism and transport of glimepiride and gliclazide. Scientific reports 22 30030468
2017 Polymorphisms of CYP2C8, CYP2C9 and CYP2C19 and risk of coronary heart disease in Russian population. Gene 22 28687336
2009 CYP2C9 polymorphism: prevalence in healthy and warfarin-treated Malay and Chinese in Malaysia. Singapore medical journal 22 19495518
2015 Identification and Functional Assessment of a New CYP2C9 Allelic Variant CYP2C9*59. Drug metabolism and disposition: the biological fate of chemicals 21 25994031
2014 Altered CYP2C9 activity following modulation of CYP3A4 levels in human hepatocytes: an example of protein-protein interactions. Drug metabolism and disposition: the biological fate of chemicals 21 25157098
2012 Analysis of CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A polymorphisms in a population from South-Eastern Europe. Journal of cellular and molecular medicine 21 22863573
2009 Prevalence of CYP2C9 polymorphisms in the south of Europe. The pharmacogenomics journal 21 19381164
2007 CYP2C9 and CYP2C19 polymorphic forms are related to increased indisulam exposure and higher risk of severe hematologic toxicity. Clinical cancer research : an official journal of the American Association for Cancer Research 21 17504998
2023 Heat stress induces ferroptosis of porcine Sertoli cells by enhancing CYP2C9-Ras- JNK axis. Theriogenology 20 38103405
2020 The Effect of UGT1A9, CYP2B6 and CYP2C9 Genes Polymorphism on Propofol Pharmacokinetics in Children. Pharmacogenomics and personalized medicine 20 32021384
2020 Relationships between CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 metabolic phenotypes and genotypes in a Nicaraguan Mestizo population. The pharmacogenomics journal 20 33024249
2014 Genetic polymorphisms of CYP2C8, CYP2C9 and CYP2C19 in Ecuadorian Mestizo and Spaniard populations: a comparative study. Molecular biology reports 20 24430292
2014 Molecular functionality of CYP2C9 polymorphisms and their influence on drug therapy. Drug metabolism and drug interactions 20 24825094
2023 Butyric acid inhibits oxidative stress and inflammation injury in calcium oxalate nephrolithiasis by targeting CYP2C9. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 19 37414240
2009 CYP2C9 amino acid residues influencing phenytoin turnover and metabolite regio- and stereochemistry. The Journal of pharmacology and experimental therapeutics 19 19258521
2004 CYP2C9 genotype as a predictor of drug disposition in humans. Methods and findings in experimental and clinical pharmacology 19 15349140
2014 Genetic polymorphism of cynomolgus and rhesus macaque CYP2C9. Drug metabolism and pharmacokinetics 18 25760542
2011 The ligands of estrogen receptor α regulate cytochrome P4502C9 (CYP2C9) expression. The Journal of pharmacology and experimental therapeutics 18 21493749
2002 Effects of serum albumin and liver cytosol on CYP2C9- and CYP3A4-mediated drug metabolism. Drug metabolism and pharmacokinetics 18 15618707
2020 Impact of CYP2C19 and CYP2C9 gene polymorphisms on sodium valproate plasma concentration in patients with epilepsy. European journal of hospital pharmacy : science and practice 17 32868386
2016 CYP2C9, CYPC19 and CYP2D6 gene profiles and gene susceptibility to drug response and toxicity in Turkish population. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society 17 28344492
2014 Association of CYP2C8, CYP2C9 and CYP2J2 gene polymorphisms with myocardial infarction in South Indian population. Pharmacological reports : PR 17 25560582
2004 Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors. Archives of biochemistry and biophysics 17 15288804
2020 Influence of CYP2C9 and CYP2A6 on plasma concentrations of valproic acid: a meta-analysis. European journal of clinical pharmacology 16 32385545

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