Affinage

CYP3A4

Cytochrome P450 3A4 · UniProt P08684

Length
503 aa
Mass
57.3 kDa
Annotated
2026-06-09
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CYP3A4 is a heme-dependent microsomal monooxygenase that oxidizes a broad range of drug and endogenous substrates, including steroids such as testosterone, clinical drugs (midazolam, atorvastatin, paclitaxel, irinotecan, quetiapine, vinorelbine), and the antiviral prodrug pradefovir, often as the predominant or sole catalyzing isoform relative to CYP3A5 (PMID:11714865, PMID:20847137, PMID:16940083, PMID:23780963). Catalysis proceeds through substrate binding, NADPH-dependent reduction of cytochrome P450 reductase, and interflavin/interprotein electron transfer; these steps and overall monooxygenase rate are stimulated by anionic phospholipid-mimetic citrate ions that bind near a site where the N-terminus splits from the protein core (PMID:26066995), while cytochrome b5 can modulate isoform-specific intrinsic clearance (PMID:19022943). The enzyme metabolizes endogenous vitamin D metabolites, and a gain-of-function substrate-recognition-site mutation (I301T) accelerates 1,25-dihydroxyvitamin D inactivation and causes vitamin D-dependent rickets type 3 (PMID:29461981). CYP3A4 is also subject to mechanism-based inactivation, forming a metabolic-intermediate complex with verapamil/norverapamil and apoprotein adducts from a raloxifene diquinone methide intermediate (PMID:15689501, PMID:20405834). Transcription is governed by an interlocking nuclear-receptor network — PXR, CAR, GR, and VDR acting through proximal and distal (XREM, −7.2 to −7.8 kb) elements, with HNF4α binding required to license PXR/CAR activation and a distal regulatory region physically looping to the promoter as a shared CYP3A enhancer (PMID:12514743, PMID:12130689, PMID:10772626, PMID:12815159, PMID:36045613) — and is further tuned by circadian DBP/E4BP4, p53, and post-transcriptional miR-27b targeting of the 3'-UTR (PMID:18004209, PMID:23054612, PMID:19581388). Functionally important variation includes the splicing-defective CYP3A4*22 allele that lowers hepatic expression and the heme-null, catalytically dead CYP3A4*20 allele that reduces in vivo drug clearance (PMID:20386561, PMID:26488616, PMID:16580902).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 Medium

    Established that CYP3A4 induction is driven by ligand-activated nuclear receptors, resolving how xenobiotics and glucocorticoids upregulate the enzyme.

    Evidence Reporter assays with the −1 kb CYP3A4 promoter and separate/combined GR and PXR transfection in HepG2 cells

    PMID:10772626

    Open questions at the time
    • Did not localize the GR/PXR response elements within the promoter
    • Receptor cooperativity in vivo not addressed
  2. 2001 High

    Defined how coding variants alter catalytic competence, linking specific residues to turnover and heme incorporation.

    Evidence Site-directed mutagenesis with bacterial heterologous expression and steroid/midazolam/chlorpyrifos activity assays

    PMID:11470997 PMID:11714865

    Open questions at the time
    • Allele frequencies and in vivo clinical impact not established
    • Structural basis of altered kinetics not resolved
  3. 2002 High

    Mapped CAR response elements in the CYP3A4 5'-flanking region and showed CAR/PXR share these motifs, revealing cooperative receptor regulation.

    Evidence Reporter assays and binding-motif identification at −7720 and −150, with in vivo confirmation

    PMID:12130689

    Open questions at the time
    • Quantitative contribution of each motif to inducibility not resolved
    • Cofactor requirements not addressed here
  4. 2003 High

    Identified HNF4α as a required gatekeeper licensing PXR/CAR-mediated activation, and defined the distal (>−3.2 kb / XREM) region needed for constitutive and inducible expression.

    Evidence Reporter assays, EMSA, Hnf4α conditional knockout mice, and CYP3A4/lacZ transgenic mice with deletion analysis

    PMID:12514743 PMID:12815159

    Open questions at the time
    • Mechanism by which HNF4α permits receptor action not detailed
    • Chromatin architecture of the XREM not resolved at this stage
  5. 2005 High

    Demonstrated isoform-selective mechanism-based inhibition, showing verapamil metabolites trap CYP3A4 (but not CYP3A5) as a metabolic-intermediate complex.

    Evidence Dual-beam spectrophotometry detecting the 455 nm MIC and time-dependent inactivation kinetics with recombinant CYP3A4/CYP3A5 and liver microsomes

    PMID:15689501

    Open questions at the time
    • Structural basis of CYP3A4 vs CYP3A5 selectivity not resolved
    • In vivo drug-interaction magnitude not quantified
  6. 2006 Medium

    Connected a null allele to clinical phenotype and confirmed CYP3A4 as a bioactivating enzyme for a prodrug.

    Evidence CYP3A4*20 expression in yeast/HEK293 showing no heme incorporation plus in vivo midazolam pharmacokinetics; CYP isoform panel and antibody inhibition for pradefovir activation

    PMID:16580902 PMID:16940083

    Open questions at the time
    • *20 carrier numbers very small
    • Determinants of heme incorporation failure not defined
  7. 2007 Medium

    Revealed circadian control of CYP3A4, explaining ~24 h oscillation in drug-metabolizing capacity.

    Evidence Reporter assays, EMSA confirming DBP binding near the TSS, and E4BP4 repression in serum-shocked HepG2 cells

    PMID:18004209

    Open questions at the time
    • In vivo rhythmicity of human CYP3A4 not directly demonstrated here
    • Integration with nuclear-receptor inputs unresolved
  8. 2009 Medium

    Added a post-transcriptional layer, showing miR-27b directly and indirectly (via VDR) suppresses CYP3A4.

    Evidence Luciferase 3'-UTR reporters with MRE mutagenesis, immunoblot, qPCR, and miR-27b overexpression

    PMID:19581388

    Open questions at the time
    • Physiological miR-27b levels required for regulation not defined
    • Single-lab reporter-based mechanism without in vivo confirmation
  9. 2010 High

    Established CYP3A4*22 as an expression-reducing regulatory allele acting through aberrant splicing, and quantified substrate-dependent effects of other coding alleles.

    Evidence Allelic expression in human liver, minigene transfection, clinical pharmacokinetics, plus Sf21 recombinant kinetics for *16 and *18 across seven substrates

    PMID:20386561 PMID:20847137

    Open questions at the time
    • Splice mechanism tissue-specificity not yet shown at this stage
    • Generalizability of substrate-dependent effects across all substrates unclear
  10. 2010 High

    Resolved the chemical mechanism of raloxifene-mediated inactivation, distinguishing dehydrogenation from oxygenation.

    Evidence 18O-incorporation tracing and mass spectrometry in reconstituted CYP3A4

    PMID:20405834

    Open questions at the time
    • Identity of the modified apoprotein carboxylate residue not defined
    • Quantitative contribution to clinical inactivation not assessed
  11. 2012 Medium

    Expanded the regulatory network to stress and intestinal/seasonal signals, implicating p53 and VDR in CYP3A4 expression.

    Evidence ChIP and reporter assays for p53 binding in hepatocytes; VDR genotyping with intestinal biopsy expression and midazolam pharmacokinetics

    PMID:22484315 PMID:23054612

    Open questions at the time
    • Physiological relevance of chemotherapy-induced p53 effect uncertain
    • Causality of VDR genotype-expression association not proven
  12. 2015 High

    Provided a structural and mechanistic account of allosteric stimulation by anionic effectors, mapping rate-limiting electron-transfer steps.

    Evidence X-ray co-crystallization of CYP3A4 with progesterone and citrate plus functional reconstitution of soluble CYP3A4/CPR

    PMID:26066995

    Open questions at the time
    • Physiological identity of the in vivo anionic activator not established
    • Quantitative contribution to hepatic activity unknown
  13. 2018 High

    Demonstrated a gain-of-function disease mechanism, linking an SRS-4 mutation to accelerated vitamin D inactivation and Mendelian rickets.

    Evidence Whole exome sequencing and in vitro activity comparison of I301T mutant vs wild-type toward vitamin D metabolites

    PMID:29461981

    Open questions at the time
    • Structural mechanism described from modeling, not solved structure
    • Single-case basis for the disease association
  14. 2022 High

    Established physical promoter-enhancer looping at a distal regulatory region shared across the CYP3A locus and tied DRR SNPs to expression.

    Evidence 4C chromatin conformation capture, CRISPR deletion, reporter assays, and human liver cohort (n=246)

    PMID:36045613

    Open questions at the time
    • Trans-factors binding the DRR not identified
    • Mechanism connecting DRR to nuclear-receptor inputs unresolved
  15. 2022 Medium

    Refined the mechanism of small-molecule modulation of PXR-driven CYP3A4 induction via chaperone exchange and coactivator interactions.

    Evidence Co-IP of PXR with HSP90α and RXRα, immunofluorescence for nuclear translocation, qPCR/western with hCAR siRNA

    PMID:35417848

    Open questions at the time
    • Single-lab co-IP without orthogonal interaction validation
    • Generalization beyond the tested ligand unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory inputs (HNF4α, PXR/CAR, GR, VDR, p53, circadian DBP/E4BP4, miRNAs, and the distal regulatory region) are integrated at chromatin to set CYP3A4 expression in a given hepatocyte remains unresolved.
  • No unified model linking enhancer looping to specific trans-factor occupancy
  • Quantitative hierarchy among regulatory inputs unknown
  • In vivo human dynamics of post-transcriptional vs transcriptional control undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0016787 hydrolase activity 2
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-9748784 Drug ADME 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1430728 Metabolism 2
Partners
CARCYB5AHNF4AHSP90AA1PORPXRRXRAVDR

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 HNF4α is required for PXR- and CAR-mediated transcriptional activation of CYP3A4. A specific cis-acting element in the CYP3A4 gene enhancer confers HNF4α binding, which then permits PXR- and CAR-mediated gene activation. Conditional hepatic deletion of Hnf4α in mice reduced basal and inducible CYP3A expression. Reporter gene assays, electrophoretic mobility shift assay (EMSA), conditional knockout mice (Hnf4α deletion), cell-based transfection Nature medicine High 12514743
2002 CAR (constitutive androstane receptor) trans-activates CYP3A4 expression both in vitro and in vivo. CAR responsiveness is mediated by two high-affinity binding motifs at approximately −7720 and −150 bases upstream of the transcription start site. These same CAR response elements also mediate PXR-mediated trans-activation, indicating cooperative interplay between CAR and PXR in CYP3A4 regulation. Reporter gene assays in cell lines, in vivo studies, identification of CAR binding motifs in CYP3A4 5'-flanking region Molecular pharmacology High 12130689
2010 An intronic SNP in CYP3A4 (rs35599367, C>T in intron 6; designated CYP3A4*22) causes allelic expression imbalance in human liver. Livers with CC genotype have 1.7-fold higher mRNA and 2.5-fold higher enzyme activity compared to CT/TT carriers, with functional consequences for statin metabolism. Allelic CYP3A4 hnRNA and mRNA expression measurement in 76 human liver samples, minigene transfection in cell culture, pharmacokinetic analysis in 235 patients The pharmacogenomics journal High 20386561
2016 CYP3A4*22 (rs35599367 C>T in intron 6) reduces mRNA/protein expression by promoting formation of a nonfunctional alternative splice variant with partial intron 6 retention in liver but not in small intestines, demonstrating tissue-specific splicing as the mechanism of reduced expression. Human liver RNA analysis, CYP3A4 minigene transfection in HepG2 (liver) and LS-174T (intestinal) cell lines Pharmacogenetics and genomics High 26488616
2001 CYP3A4 variant F189S exhibits lower turnover numbers for testosterone and chlorpyrifos, while L293P has higher turnover numbers for both substrates, compared to wild-type CYP3A4*1. Variants M445T and P467S showed no significant difference from wild-type in catalytic activity. Site-directed mutagenesis of cDNA, heterologous expression in E. coli, in vitro enzyme activity assay with testosterone and chlorpyrifos as substrates The Journal of pharmacology and experimental therapeutics High 11714865
2001 Two CYP3A4 protein variants (R130Q and P416L) fail to produce detectable P450 holoprotein when expressed in bacteria. T363M is expressed at significantly lower levels than wild-type. L373F displays a significantly altered testosterone metabolite profile and a four-fold increase in Km for 1'-OH midazolam formation. Heterologous bacterial expression system, steroid hydroxylase activity assays, midazolam hydroxylation kinetics Pharmacogenetics High 11470997
2006 CYP3A4*20 contains a premature stop codon yielding a truncated protein that does not incorporate heme and is completely devoid of catalytic activity. The heterozygous carrier showed low systemic midazolam clearance in vivo, confirming genotype-phenotype correlation. DNA sequencing, heterologous expression in yeast and HEK293 cells, in vivo midazolam pharmacokinetics (phenotyping) Clinical pharmacology and therapeutics High 16580902
2018 A de novo missense mutation c.902T>C (p.I301T) in CYP3A4 alters substrate recognition site 4 (SRS-4) conformation. The mutant CYP3A4 oxidizes 1,25-dihydroxyvitamin D with 10-fold greater activity than wild-type CYP3A4, and 2-fold greater activity than CYP24A1, causing accelerated vitamin D inactivation and vitamin D-dependent rickets type 3. Whole exome sequencing, in vitro enzyme activity assay comparing mutant vs wild-type CYP3A4 activity toward vitamin D metabolites The Journal of clinical investigation High 29461981
2009 miR-27b directly targets the 3'-UTR of CYP3A4 and suppresses its protein expression by >30%. miR-27b also indirectly regulates CYP3A4 transcription by targeting the VDR 3'-UTR, reducing VDR levels. Disruption of the miRNA response element (MRE) within CYP3A4 3'UTR led to 2- to 3-fold increase in reporter activity. Luciferase reporter assays with CYP3A4 3'UTR, site-directed mutagenesis of MRE, immunoblot analysis, qPCR, overexpression of miR-27b in cell lines Drug metabolism and disposition Medium 19581388
2007 The circadian transcription factor DBP activates CYP3A4 transcription by binding to a DNA sequence near the transcription start site, driving rhythmic (~24 h) oscillation in CYP3A4 mRNA and metabolic activity. The negative circadian clock component E4BP4 represses DBP-mediated CYP3A4 transcription. Luciferase reporter gene analysis, electrophoretic mobility shift assay (EMSA), serum-shocked HepG2 cells as circadian model Pharmacogenetics and genomics Medium 18004209
2000 Both the glucocorticoid receptor (GR) and pregnane X receptor (PXR) mediate hydrocortisone-dependent induction of CYP3A4 via the −1 kb promoter region. PXR decreases the EC50 for hydrocortisone-dependent induction by 3.3-fold. Rifampicin-dependent activation favors PXR over GR. Reporter gene system with −1 kb CYP3A4 promoter in HepG2 cells, separate and combined transfection of hGR and hPXR expression plasmids Drug metabolism and disposition Medium 10772626
2003 Transgenic mice carrying the human CYP3A4 upstream regulatory region linked to lacZ show that sequences beyond −3.2 kb are required for both constitutive expression and xenobiotic induction. PXR/CAR-activating reagents (dexamethasone, pregnenolone 16α-carbonitrile, phenobarbital) induce expression through the xenobiotic-responsive enhancer module (XREM, −7.2 to −7.8 kb). Induction operates primarily through zonal recruitment of more hepatocytes to expression. CYP3A4/lacZ transgenic mice, histochemical staining for β-galactosidase, deletion construct analysis Molecular pharmacology Medium 12815159
2005 Verapamil and its metabolite N-desalkylverapamil (D617) form a metabolic-intermediate complex (MIC) with CYP3A4 (characteristic 455 nm peak) but not with CYP3A5, demonstrating differential mechanism-based inhibition. Norverapamil inactivates CYP3A4 with kinact = 0.30 min−1 and KI = 10.3 μM, but inactivates CYP3A5 ~45-fold less efficiently. Dual beam spectrophotometry for MIC detection, time-dependent inhibition assays with cDNA-expressed CYP3A4 and CYP3A5, human liver microsomes Drug metabolism and disposition High 15689501
2010 CYP3A4*16 (T185S, found in East Asians) exhibits considerably reduced intrinsic clearance (by 60–84%) for midazolam, carbamazepine, atorvastatin, paclitaxel, and irinotecan due to increased Km values, while CYP3A4*18 (L293P) shows reduced Vmax for midazolam, paclitaxel, docetaxel, and irinotecan with unchanged Km values. Both alleles show substrate-dependent effects. Heterologous expression in Sf21 insect cell microsomes with human NADPH-P450 reductase, kinetic assays with seven substrates Drug metabolism and disposition High 20847137
2015 Citrate ions, which mimic anionic phospholipids of the microsomal membrane, bind CYP3A4 at a site near the N-terminus where it splits from the protein core, and stimulate CYP3A4 monooxygenase activity in a concentration-dependent manner. CYP3A4-substrate binding, NADPH-dependent reduction of CPR, and interflavin and interprotein electron transfer were identified as citrate-sensitive steps. X-ray co-crystallization of CYP3A4 with progesterone and citrate, functional assays of soluble CYP3A4/CPR reconstituted system, comparative analysis of anions Biochemistry High 26066995
2010 Raloxifene undergoes CYP3A4-mediated dehydrogenation to a reactive diquinone methide intermediate (not via arene oxide), which forms adducts with a carboxylic acid moiety of CYP3A4 apoprotein, causing mechanism-based inactivation. 7-Hydroxyraloxifene is produced by hydrolysis from the putative ester conjugate rather than direct oxygenation. 18O-incorporation studies with isotopically labeled substrates in reconstituted CYP3A4 system, mass spectrometry metabolite analysis Biochemistry High 20405834
2012 p53 directly binds p53-responsive elements in CYP3A4 regulatory DNA and enhances CYP3A4 transcription. Activation of p53 by chemotherapeutic agents (cisplatin, etoposide, doxorubicin) induces CYP3A4 expression and enzymatic activity in a p53-dependent manner in human hepatocytes. Microarray screen, chromatin immunoprecipitation (ChIP) for p53 binding to CYP3A4 regulatory regions, reporter gene assays, qPCR, enzymatic activity assays in HepG2, Huh6, and primary human hepatocytes Carcinogenesis Medium 23054612
2011 Metformin suppresses PXR-mediated CYP3A4 expression in human hepatocytes by disrupting PXR's interaction with steroid receptor coactivator-1 (SRC1), independently of the PXR ligand binding pocket. Metformin also inhibited VDR-, GR-, and CAR-mediated induction of CYP3A4. AMPK activation and SHP upregulation were not involved in this mechanism. Reporter gene assays, qRT-PCR in human hepatocytes, two-hybrid assay (PXR-SRC1 interaction), Pxr−/− mouse experiments Biochemical pharmacology Medium 21920351
2006 CYP3A4 catalyzes the metabolic activation of pradefovir to its active antiviral form PMEA. This conversion is inhibited by ketoconazole and a monoclonal antibody specific to CYP3A4. In human liver microsomes, Km = 60 μM and Vmax = 228 pmol/min/mg protein. No other cDNA-expressed CYP isoform catalyzed this conversion. cDNA-expressed CYP isoforms panel, human liver microsomes with kinetic parameters, CYP3A4-specific inhibitors (ketoconazole and monoclonal antibody 3A4) Antimicrobial agents and chemotherapy Medium 16940083
2012 VDR polymorphisms (BsmIG>A, Cdx2-3731G>A, GATA-1012A>G) are significantly associated with intestinal CYP3A4 expression and activity. Intestinal CYP3A4 expression shows seasonal variation, being significantly higher between April and September, likely related to annual changes in UV sunlight and vitamin D levels activating VDR-mediated transcription. Genotyping of VDR polymorphisms, CYP3A4 protein/mRNA measurement in intestinal biopsies, midazolam pharmacokinetics in patients Biochemical pharmacology Medium 22484315
2022 A distal regulatory region (DRR) physically interacts with the CYP3A4 promoter (detected by 4C chromatin conformation capture). CRISPR-mediated deletion of the DRR decreased expression of CYP3A4, CYP3A5, and CYP3A7, identifying it as a shared enhancer. Two SNPs (rs115025140 and rs776744/rs776742) within the DRR increase enhancer-driven transcription in reporter assays and are associated with increased CYP3A4/CYP3A5 expression in human liver. 4C chromatin conformation capture, CRISPR deletion, luciferase reporter assays, CYP3A4 mRNA and protein measurement in human liver cohort (n=246) Clinical and translational science High 36045613
2022 Panaxytriol upregulates CYP3A4 expression by promoting PXR dissociation from HSP90α and enhancing PXR binding to RXRα, facilitating PXR nuclear translocation and transcriptional activation. At high concentrations, CAR undergoes a similar mechanism but generally antagonizes PXR binding to RXRα. Co-immunoprecipitation (PXR/CAR binding to RXRα and HSP90α), immunofluorescence for nuclear translocation, qPCR, western blot, siRNA silencing of hCAR Phytomedicine Medium 35417848
2008 Quetiapine is metabolized by CYP3A4 with substantially higher intrinsic clearance than by CYP3A5 (<35% relative activity). CYP3A5 produces a different metabolic pattern, with O-desalkylquetiapine constituting a higher proportion of metabolites. Coexpressed cytochrome b5 decreases CYP3A4 intrinsic clearance for quetiapine 3-fold but has no effect on CYP3A5 clearance. In vitro metabolism assays with CYP3A4 and CYP3A5 insect cell microsomes ± cytochrome b5, substrate depletion kinetics, metabolite identification Drug metabolism and disposition Medium 19022943
2021 CYP3A4 overexpression in HepG2 cells causes resistance to docetaxel (reduced antiproliferative activity), which is reversed by co-administration of ketoconazole. This resistance is mediated at least partly through impaired activation of caspases 3/7, 8, and 9. CYP3A4 overexpression does not confer resistance to vincristine. Lentiviral transduction of CYP3A4 into HepG2 cells, MTT proliferation assay, caspase activation assay, ketoconazole inhibition rescue Chemico-biological interactions Medium 33775687
2013 CYP3A4 and CYP3A5 are both capable of oxidizing vinorelbine in vitro. CYP3A4+cytochrome b5 and CYP3A5+cytochrome b5 show equivalent Michaelis-Menten constants (Km 2.6 and 3.6 μM respectively) with common Vmax of 1.4 pmol/min/pmol. However, intrinsic clearance in human liver microsomes correlates with CYP3A4 activity, and CYP3A4 produces more of the major metabolite M2 (didehydro-vinorelbine), indicating CYP3A4 as the predominant contributor in vivo. cDNA-expressed recombinant enzymes, human liver microsomes, selective P450 inhibitors, kinetic analysis, radiolabeled substrate, NMR and mass spectrometry metabolite characterization Drug metabolism and disposition High 23780963

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. The pharmacogenomics journal 405 20386561
2003 The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nature medicine 372 12514743
2002 Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Molecular pharmacology 366 12065767
2001 Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. The Journal of pharmacology and experimental therapeutics 273 11714865
2003 The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors. Biochimica et biophysica acta 267 12573484
2009 MicroRNAs regulate CYP3A4 expression via direct and indirect targeting. Drug metabolism and disposition: the biological fate of chemicals 214 19581388
2014 Functional gene variants of CYP3A4. Clinical pharmacology and therapeutics 203 24926778
2001 Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics 191 11470997
2002 Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor. Molecular pharmacology 188 12130689
2003 Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug metabolism and disposition: the biological fate of chemicals 183 12695340
2006 MDR- and CYP3A4-mediated drug-herbal interactions. Life sciences 177 16442130
2013 CYP3A4*22: promising newly identified CYP3A4 variant allele for personalizing pharmacotherapy. Pharmacogenomics 173 23252948
2015 Interactions between CYP3A4 and Dietary Polyphenols. Oxidative medicine and cellular longevity 135 26180597
1997 Expression and localization of CYP3A4 and CYP3A5 in human lung. American journal of respiratory cell and molecular biology 133 9070608
2006 MDR- and CYP3A4-mediated drug-drug interactions. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 132 18040809
2004 CYP3A4 induction by xenobiotics: biochemistry, experimental methods and impact on drug discovery and development. Current drug metabolism 127 15578943
2007 Transcriptional regulation and expression of CYP3A4 in hepatocytes. Current drug metabolism 122 17305497
2016 Effects of triazole fungicides on androgenic disruption and CYP3A4 enzyme activity. Environmental pollution (Barking, Essex : 1987) 120 28012672
2004 CYP3A4, CYP3A5, and CYP3A43 genotypes and haplotypes in the etiology and severity of prostate cancer. Cancer research 111 15548719
2002 CYP3A4 variant alleles in white individuals with low CYP3A4 enzyme activity. Clinical pharmacology and therapeutics 107 11907494
2006 Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity. Clinical pharmacology and therapeutics 96 16580902
2012 Interplay between vitamin D and the drug metabolizing enzyme CYP3A4. The Journal of steroid biochemistry and molecular biology 94 22985909
2003 CYP3A4 and CYP3A5 genotypes, haplotypes, and risk of prostate cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 94 14504207
2016 CYP3A4 intronic SNP rs35599367 (CYP3A4*22) alters RNA splicing. Pharmacogenetics and genomics 88 26488616
2018 CYP3A4 mutation causes vitamin D-dependent rickets type 3. The Journal of clinical investigation 85 29461981
1996 Expression of CYP3A4, CYP3A5 and CYP3A7 in human duodenal tissue. British journal of clinical pharmacology 84 8877031
2007 Gut instincts: CYP3A4 and intestinal drug metabolism. The Journal of clinical investigation 81 17975661
2011 Metformin suppresses pregnane X receptor (PXR)-regulated transactivation of CYP3A4 gene. Biochemical pharmacology 79 21920351
2007 Molecular basis for rhythmic expression of CYP3A4 in serum-shocked HepG2 cells. Pharmacogenetics and genomics 73 18004209
2014 The role of CYP3A4 in the biotransformation of bile acids and therapeutic implication for cholestasis. Annals of translational medicine 72 25332983
2005 Modelling atypical CYP3A4 kinetics: principles and pragmatism. Archives of biochemistry and biophysics 69 15581591
2008 PXR-mediated transcriptional activation of CYP3A4 by cryptotanshinone and tanshinone IIA. Chemico-biological interactions 67 18805405
2017 Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery. Current drug metabolism 66 28558634
2000 Regulation of the CYP3A4 gene by hydrocortisone and xenobiotics: role of the glucocorticoid and pregnane X receptors. Drug metabolism and disposition: the biological fate of chemicals 62 10772626
2005 Differential mechanism-based inhibition of CYP3A4 and CYP3A5 by verapamil. Drug metabolism and disposition: the biological fate of chemicals 61 15689501
2012 DNA methylation dynamics in the hepatic CYP3A4 gene promoter. Biochimie 60 22906825
2021 CYP3A4 Genotyping in Clinical Practice: Ready for Implementation? Frontiers in genetics 58 34306041
2006 Hyperforin and its analogues inhibit CYP3A4 enzyme activity. Phytochemistry 55 17083953
2003 Transgenic mouse models of human CYP3A4 gene regulation. Molecular pharmacology 55 12815159
2008 Metabolism of quetiapine by CYP3A4 and CYP3A5 in presence or absence of cytochrome B5. Drug metabolism and disposition: the biological fate of chemicals 54 19022943
2012 Chemotherapeutic agents induce the expression and activity of their clearing enzyme CYP3A4 by activating p53. Carcinogenesis 52 23054612
1999 Simultaneous assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and caffeine. Pharmacogenetics 52 10634135
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
2009 Genetic variants of CYP3A4 and CYP3A5 in cynomolgus and rhesus macaques. Drug metabolism and disposition: the biological fate of chemicals 51 19910514
2013 Effect of Chinese herbs on CYP3A4 activity and expression in vitro. Journal of ethnopharmacology 49 23876595
2011 Genetic epidemiology of induced CYP3A4 activity. Pharmacogenetics and genomics 49 21750469
2017 MicroRNA regulation of CYP 1A2, CYP3A4 and CYP2E1 expression in acetaminophen toxicity. Scientific reports 48 28951593
2012 Intestinal CYP3A4 and midazolam disposition in vivo associate with VDR polymorphisms and show seasonal variation. Biochemical pharmacology 44 22484315
2015 Anion-Dependent Stimulation of CYP3A4 Monooxygenase. Biochemistry 43 26066995
2017 PXR mediated induction of CYP3A4, CYP1A2, and P-gp by Mitragyna speciosa and its alkaloids. Phytotherapy research : PTR 42 29071751
2011 Pregnane X receptor- and CYP3A4-humanized mouse models and their applications. British journal of pharmacology 42 21091656
2023 Activation/Inactivation of Anticancer Drugs by CYP3A4: Influencing Factors for Personalized Cancer Therapy. Drug metabolism and disposition: the biological fate of chemicals 41 36732076
2017 Effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism. European journal of clinical pharmacology 41 28849250
2009 Statin regulation of CYP3A4 and CYP3A5 expression. Pharmacogenomics 41 19530969
2004 Allelic expression imbalance of the human CYP3A4 gene and individual phenotypic status. Human molecular genetics 41 15459178
2010 CYP3A4*16 and CYP3A4*18 alleles found in East Asians exhibit differential catalytic activities for seven CYP3A4 substrate drugs. Drug metabolism and disposition: the biological fate of chemicals 40 20847137
2010 Endosulfan induces CYP2B6 and CYP3A4 by activating the pregnane X receptor. Toxicology and applied pharmacology 39 20361990
2006 Hypericum perforatum: which constituents may induce intestinal MDR1 and CYP3A4 mRNA expression? Planta medica 39 16755466
1996 Selective expression of CYP3A5 and not CYP3A4 in human blood. Pharmacogenetics 37 8946469
2011 Polycyclic aromatic hydrocarbons activate CYP3A4 gene transcription through human pregnane X receptor. Drug metabolism and pharmacokinetics 35 22076448
2003 Expression of CYP3A4 in human breast tumour and non-tumour tissues. Cancer letters 34 14643022
2012 CYP2C8 but not CYP3A4 is important in the pharmacokinetics of montelukast. British journal of clinical pharmacology 31 21838784
2007 CYP3A4 and pregnane X receptor humanized mice. Journal of biochemical and molecular toxicology 31 17936928
2021 Roles of CYP3A4, CYP3A5 and CYP2C8 drug-metabolizing enzymes in cellular cytostatic resistance. Chemico-biological interactions 30 33775687
2020 A comparison of hepato-cellular in vitro platforms to study CYP3A4 induction. PloS one 30 32106230
2015 Expression of CYP3A4 and CYP3A7 in Human Foetal Tissues and its Correlation with Nuclear Receptors. Basic & clinical pharmacology & toxicology 30 25689036
2014 Resveratrol suppresses the inducible expression of CYP3A4 through the pregnane X receptor. Journal of pharmacological sciences 30 25341566
2017 Functional Characterization of 22 CYP3A4 Protein Variants to Metabolize Ibrutinib In Vitro. Basic & clinical pharmacology & toxicology 28 29117640
2024 Flavonoids as CYP3A4 Inhibitors In Vitro. Biomedicines 27 38540257
2021 Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids. Molecules (Basel, Switzerland) 27 34069400
2020 Pregnancy-Related Hormones Increase Nifedipine Metabolism in Human Hepatocytes by Inducing CYP3A4 Expression. Journal of pharmaceutical sciences 27 32931777
2018 Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro. British journal of clinical pharmacology 27 29105855
2015 Investigation of CYP3A4 and CYP2D6 Interactions of Withania somnifera and Centella asiatica in Human Liver Microsomes. Phytotherapy research : PTR 26 25684704
2007 Regulation of CYP3A4 and CYP2B6 expression by liver X receptor agonists. Biochemical pharmacology 26 17825266
2018 The Modulatory Role of CYP3A4 in Dictamnine-Induced Hepatotoxicity. Frontiers in pharmacology 25 30283337
2002 Pioglitazone: effect on CYP3A4 activity. Journal of clinical pharmacology 25 12463723
2010 Effects of commonly used excipients on the expression of CYP3A4 in colon and liver cells. Pharmaceutical research 24 20503067
2006 Tamoxifen activates CYP3A4 and MDR1 genes through steroid and xenobiotic receptor in breast cancer cells. Endocrine 24 17526937
2020 Functional Measurement of CYP2C9 and CYP3A4 Allelic Polymorphism on Sildenafil Metabolism. Drug design, development and therapy 23 33262574
2017 CYP3A4 inducer and inhibitor strongly affect the pharmacokinetics of triptolide and its derivative in rats. Acta pharmacologica Sinica 23 29283173
2020 Screening of Human CYP1A2 and CYP3A4 Inhibitors from Seaweed In Silico and In Vitro. Marine drugs 22 33260381
2013 The relative contributions of CYP3A4 and CYP3A5 to the metabolism of vinorelbine. Drug metabolism and disposition: the biological fate of chemicals 22 23780963
2014 Interactions of endosulfan and methoxychlor involving CYP3A4 and CYP2B6 in human HepaRG cells. Drug metabolism and disposition: the biological fate of chemicals 21 24832206
2010 CYP3A4-Mediated oxygenation versus dehydrogenation of raloxifene. Biochemistry 21 20405834
2010 Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2. The Annals of pharmacotherapy 21 20959500
2022 Panaxytriol upregulates CYP3A4 expression based on the interaction of PXR, CAR, HSP90α, and RXRα. Phytomedicine : international journal of phytotherapy and phytopharmacology 20 35417848
2020 Paclitaxel Nanoparticles Induce Apoptosis and Regulate TXR1, CYP3A4 and CYP2C8 in Breast Cancer and Hepatoma Cells. Anti-cancer agents in medicinal chemistry 20 32364081
2016 Metabolic-induced cytotoxicity of diosbulbin B in CYP3A4-expressing cells. Toxicology in vitro : an international journal published in association with BIBRA 20 27836570
2006 Metabolic activation of pradefovir by CYP3A4 and its potential as an inhibitor or inducer. Antimicrobial agents and chemotherapy 20 16940083
2020 Transcriptional regulation of CYP3A4 by nuclear receptors in human hepatocytes under hypoxia. Drug metabolism reviews 18 32270716
2016 Drug membrane transporters and CYP3A4 are affected by hypericin, hyperforin or aristoforin in colon adenocarcinoma cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 18 27261575
2018 CYP3A4 gene polymorphism is correlated with individual consumption of sufentanil. Acta anaesthesiologica Scandinavica 17 29926893
2016 Developmental regulation of CYP3A4 and CYP3A7 in Chinese Han population. Drug metabolism and pharmacokinetics 17 27727071
2015 Comparison of Paeoniflorin and Albiflorin on Human CYP3A4 and CYP2D6. Evidence-based complementary and alternative medicine : eCAM 17 26089940
2015 Fluoxetine reduces CES1, CES2, and CYP3A4 expression through decreasing PXR and increasing DEC1 in HepG2 cells. Xenobiotica; the fate of foreign compounds in biological systems 17 26340669
2018 Correlations between CYP3A4 polymorphism and susceptibility to breast cancer in Chinese Han population. International journal of clinical oncology 16 30218411
2022 Regulatory variants in a novel distal enhancer regulate the expression of CYP3A4 and CYP3A5. Clinical and translational science 15 36045613
2021 Cytochrome P450 3A4 (CYP3A4) protein quantification using capillary western blot technology and total protein normalization. Journal of pharmacological and toxicological methods 15 34474151
2019 Characterization of Genetic Variation in CYP3A4 on the Metabolism of Cabozantinib in Vitro. Chemical research in toxicology 15 31293154
2014 Characterization of CYP1A2, CYP2C19, CYP3A4 and CYP3A5 polymorphisms in South Brazilians. Molecular biology reports 15 24443221

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