CYP3A4 Gene

HGNC Family	Cytochrome P450s (CYP)
Name	cytochrome P450, family 3, subfamily A, polypeptide 4
Description	This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by glucocorticoids and some pharmacological agents. This enzyme is involved in the metabolism of approximately half the drugs in use today, including acetaminophen, codeine, cyclosporin A, diazepam, erythromycin, and chloroquine. The enzyme also metabolizes some steroids and carcinogens. This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. Previously another CYP3A gene, CYP3A3, was thought to exist; however, it is now thought that this sequence represents a transcript variant of CYP3A4. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2020]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Cytochrome P450 3A4 (CYP3A4) is the most abundant and functionally versatile drug‐metabolizing enzyme in the human liver. It is responsible for the oxidative biotransformation of approximately 50–60% of clinically used drugs and a wide range of xenobiotics, thereby playing a central role in determining drug clearance and mediating drug–drug interactions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " \n Its expression is inducible by a variety of structurally diverse compounds through activation of nuclear receptors—including the pregnane X receptor (PXR), the vitamin D receptor (VDR) and the constitutive androstane receptor (CAR)—which bind specific response elements in the CYP3A4 promoter. This regulation not only facilitates the detoxification of harmful endogenous substances such as lithocholic acid"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": ", but also provides a molecular basis for drug interactions."}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structural studies have revealed that CYP3A4’s active site, though relatively small in its unbound state, undergoes significant conformational changes upon ligand binding and can accommodate multiple substrates simultaneously. This structural flexibility underlies its atypical kinetics and the possibility of allosteric modulation by different inhibitors and substrates."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond transcriptional control, CYP3A4 expression and activity are further modulated post‐transcriptionally. For example, microRNA-mediated regulation of PXR has been shown to affect downstream CYP3A4 levels, while inflammatory signals via NF-κB can interfere with the PXR–RXRα complex and suppress CYP3A4 expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n Mature hepatocytes, which express high levels of CYP3A4 as part of their differentiated phenotype, underscore its importance in maintaining the balance between drug bioactivation and detoxification."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Functionally, CYP3A4 not only clears drugs such as tacrolimus, midazolam, and docetaxel—often used as probes for CYP3A activity—but it is also implicated in the bioactivation of compounds leading to toxicity. A notable example is the metabolism of acetaminophen, where CYP3A4 efficiently converts the drug into the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), a compound associated with hepatotoxicity at high doses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, CYP3A4 is a multifunctional enzyme central to drug metabolism and detoxification. Its broad substrate specificity, dynamic regulation by nuclear receptors and inflammatory mediators, as well as its flexible active site architecture, contribute to the considerable interindividual variability observed in drug responses. This variability has important implications for both therapeutic efficacy and the risk of adverse drug–drug interactions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "2"}, {"type": "fg_fs", "start_ref": "8", "end_ref": "10"}, {"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "12"}, {"type": "fg_f", "ref": "11"}, {"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "J M Lehmann, D D McKee, M A Watson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (1998)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI3703"}], "href": "https://doi.org/10.1172/JCI3703"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "9727070"}], "href": "https://pubmed.ncbi.nlm.nih.gov/9727070"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Pamela A Williams, Jose Cosme, Alison Ward, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crystal structure of human cytochrome P450 2C9 with bound warfarin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature01862"}], "href": "https://doi.org/10.1038/nature01862"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12861225"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12861225"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Pamela A Williams, Jose Cosme, Dijana Matak Vinkovic, et al. 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Synonyms	CP34, NF-25, CYP3A3, CYPIIIA3, P450PCN1, HLP, P450C3, CYP3A, CYPIIIA4, CP33
Proteins	CP3A4_HUMAN
NCBI Gene ID	1576
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

CYP3A4 has 9,820 functional associations with biological entities spanning 8 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 113 datasets.

Click the + buttons to view associations for CYP3A4 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

CYP3A4 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by CYP3A4 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CYP3A4 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of CYP3A4 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of CYP3A4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CYP3A4 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of CYP3A4 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CYP3A4 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of CYP3A4 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of CYP3A4 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of CYP3A4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with CYP3A4 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with CYP3A4 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CYP3A4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of CYP3A4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of CYP3A4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with CYP3A4 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of CYP3A4 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing CYP3A4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing CYP3A4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with CYP3A4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with CYP3A4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of CYP3A4 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with CYP3A4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with CYP3A4 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with CYP3A4 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by CYP3A4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with CYP3A4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with CYP3A4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with CYP3A4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with CYP3A4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	DrugBank Drug Targets	interacting drugs for CYP3A4 protein from the curated DrugBank Drug Targets dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at CYP3A4 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CYP3A4 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of CYP3A4 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	GAD Gene-Disease Associations	diseases associated with CYP3A4 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with CYP3A4 gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of CYP3A4 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with CYP3A4 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.
	GeneSigDB Published Gene Signatures	PubMedIDs of publications reporting gene signatures containing CYP3A4 from the GeneSigDB Published Gene Signatures dataset.
	GEO Signatures of Differentially Expressed Genes for Diseases	disease perturbations changing expression of CYP3A4 gene from the GEO Signatures of Differentially Expressed Genes for Diseases dataset.