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FLASH GENE

Symbol

CYP3A4

contributors: mct - updated : 05-04-2021

HGNC name	cytochrome P450, family 3, subfamily A, polypeptide 4
HGNC id	2637

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_017460 13 - 2768 NP_059488 57.3 503 - 1986 3460094 NM_001202855 13 - 2789 NP_001189784 58 502 - 1986 3460094 also called CYP3A3 variant

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive liver       predominantly Homo sapiens Adult   liver       predominantly Homo sapiens Fetal Reproductive male system prostate

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

N-terminal 33-AAs domain embedded in the ER membrane with the bulk of its structure in the cytosol

conjugated

HemoP

mono polymer

monomer

HOMOLOGY

interspecies

homolog to C.elegans t10b9.10

Homologene

FAMILY	cytochrome P450 family
	subfamily IIIA
	multigenic cytochrome P450 superfamily of mixed-function monooxygenases

CATEGORY

enzyme , transport

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria,inner
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,cytosolic,microsome

basic FUNCTION	heme-thiolate monooxygenases, involved in an NADPH-dependent electron transport pathway
	vitamin D 25-hydroxylase for vitamin D2 in hepatic microsomes and hydroxylates both 1alpha(OH)D2 and 1alpha(OH)D3
	involved in the metabolism of more than 50 p100 of drugs and other xenobiotics
	its induction represents an important detoxification mechanism
	endoplasmic reticulum (ER)-anchored hemoprotein engaged in the oxidative biotransformation of various endo- and xenobiotics
	encoding the major drug metabolizing enzyme, exhibits a high interindividual variation in hepatic expression that can lead to interindividual differences in drug metabolism and associated adverse drug effects
	is a novel tumor suppressor gene related to a poor prognosis in Hepatocellular Carcinoma

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

electron transport

PATHWAY

metabolism

drug , lipid/lipoprotein

signaling

	drug including acetaminophen, codeine, cyclosporin A, diazepam, erythromycin
	an FGF21-NR1I2 signaling pathway may be involved in decreased hepatic CYP3A4 metabolic activity in Nonalcoholic fatty liver disease (NAFLD)

a component

INTERACTION

DNA

RNA

small molecule	cofactor, nucleotide,
	NADPH, heme

protein	flavoprotein P450 oxidoreductase (POR)
	transcriptional target of SMARCA4
	NR1I2 promoter methylation is involved in the regulation of intestinal NR1I2 and CYP3A4 mRNA expression and might be associated with the inter-individual variability of the drug responses of colon cancer cells
	PPARA is a direct transcriptional regulator of hepatic CYP3A4
	RXRA mediates the sex-dependent influence of GH on CYP3A expression as an important signalling molecule
	CYP3A4 activates, rather than inactivates, 20(OH)D3
	steroid hormones are likely able to regulate CYP3A4 mRNA expression, although the circulating levels of these hormones can only regulate control endometrium and not endometriosis tissues
	cross-talk between NR1I2 and AHR plays a role in the regulation of CYP3A4 gene expression
	NR1I2 plays a central role in cortisol-mediated induction of CYP3A4 activity during pregnancy

cell & other

REGULATION

induced by	induced to high levels in liver and other tissues by various foreign compounds, including drugs,
		pesticides, and carcinogens.
		glucocorticoids and some pharmacological agents
		VDR, transactivating CYP3A4 in the intestine by secondary bile acids
		NR1I2

inhibited by	by cholesterol
	Ketamine (Ketamine may inhibit CYP3A4 expression possibly through reducing calcium mobilization and mitochondrial ATP synthesis and consequently disturbing cytoskeleton remodeling)

repressed by

binding of nuclear receptors (NR2F1, NR2F2, THRA, THRB) competing for response element in the promoter

Other

phosphorylation of CYP3A4 Ser478, Thr264, and Ser420 AAs by cytosolic kinases is important both for its ubiquitination and proteasomal degradation

ASSOCIATED DISORDERS

corresponding disease(s)

related resource

Human Cytochrome P450 (CYP) Allele Nomenclature Committee

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   in lung cancer constitutional       loss of function marked reduction of CYP3A4 activity among individuals with Crohn disease

Susceptibility

to prostate cancer to treatment-related leukemia

Variant & Polymorphism other	polymorphism CYP3A4V potentially increased susceptibility to prostate cancer
	CYP3A4-W genotype may be at increased risk for treatment-related leukemia
	CYP3A4-W genotype may increase production of potentially DNA-damaging reactive intermediates and may decrease production of the epipodophyllotoxin catechol metabolite, which is the precursor of the potentially DNA-damaging quinone
	CYP3A4 and CYP3A5 polymorphisms were significantly associated with an increased risk of prostate cancer

Candidate gene
Marker	combination of CYP3A4 and CYP3A5 may serve as a novel prognostic biomarker in lung adenocarcinoma, which contribute to the precision of predicting the survival in lung adenocarcinoma
Therapy target

ANIMAL & CELL MODELS