CYP3A4

Cytochrome P450, family 3, subfamily A, polypeptide 4
Structure of CYP3A4 (from PDB 1W0E). Heme group visible at center.
Available structures
1tqn, 1w0e, 1w0f, 1w0g, 2j0c, 2j0d
Identifiers
Symbols	CYP3A4; CYP3A; CP33; CP34; CYP3A3; HLP; MGC126680; NF-25; P450C3; P450PCN1
External IDs	OMIM: 124010 HomoloGene: 111391
EC number	1.14.13.97
Gene ontology Molecular function • monooxygenase activity • iron ion binding • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen • oxygen binding • heme binding • metal ion binding • unspecific monooxygenase activity • quinine 3-monooxygenase activity • testosterone 6-beta-hydroxylase activity Cellular component • membrane fraction • endoplasmic reticulum • microsome • cell surface • membrane • integral to membrane Biological process • electron transport • lipid metabolic process • xenobiotic metabolic process
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1576	n/a
Ensembl	ENSG00000160868	n/a
UniProt	P05184	n/a
RefSeq	NM_017460 (mRNA)	n/a (mRNA)
	NP_059488 (protein) n/a (protein)
Location	Chr 7: 99.08 - 99.22 Mb	n/a
PubMed search	[1]	n/a

Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1.14.13.97), a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. CYP3A4 is also, correspondingly, present in the largest quantity of all the CYPs in the liver.

Fetuses do not express CYP3A4 in their liver/tissues; but rather CYP3A7, which acts on a similar range of substrates. CYP3A7 is gradually replaced by CYP3A4 in the developing neonate.

Distribution

Although CYP3A4 is predominantly found in the liver, it is also present in other organs and tissues of the body where it may play an important role in metabolism. CYP3A4 in the intestine plays an important role in the metabolism of certain drugs. Often this allows prodrugs to be activated and absorbed - as in the case of the histamine H₁-receptor antagonist terfenadine.

Recently CYP3A4 has also been identified in the brain, however its role in the central nervous system is still unknown.^[1]

Variability

While over 28 single nucleotide polymorphisms (SNPs) have been identified in the CYP3A4 gene, it has been found that this does not translate into significant interindividual variability in vivo. It can be supposed that this may be due to the induction of CYP3A4 on exposure to substrates.

Variability in CYP3A4 function can be determined noninvasively by the erythromycin breath test (ERMBT). The ERMBT estimates in vivo CYP3A4 activity by measuring the radiolabelled carbon dioxide exhaled after an intravenous dose of (¹⁴C-N-methyl)-erythromycin.^[2]

Induction

CYP3A4 is induced by a wide variety of ligands. These ligands bind to the Pregnane X Receptor (PXR). The activated PXR complex forms a heterodimer with the Retinoid X Receptor (RXR) which binds to the XREM region of the CYP3A4 gene. XREM is a regulatory region of the CYP3A4 gene, and binding causes a cooperative interaction with proximal promoter regions of the gene, resulting in increased transcription and expression of CYP3A4.

CYP3A4 ligands

References

External links

• PharmGKB: Annotated PGx Gene Information for CYP3A4

v • d • e PDB Gallery 1tqn: Crystal Structure of Human Microsomal P450 3A4   1w0e: CRYSTAL STRUCTURE OF HUMAN CYTOCHROME P450 3A4   1w0f: CRYSTAL STRUCTURE OF HUMAN CYTOCHROME P450 3A4   1w0g: CRYSTAL STRUCTURE OF HUMAN CYTOCHROME P450 3A4   2j0d: CRYSTAL STRUCTURE OF HUMAN P450 3A4 IN COMPLEX WITH ERYTHROMYCIN