CYP3A5 Gene: Function, Polymorphisms, and Clinical Significance

CYP3A5 encodes a member of the cytochrome P450 superfamily of enzymes, which are heme-thiolate monooxygenases involved in the metabolism of endogenous compounds and xenobiotics. CYP3A5 is primarily expressed in the liver, kidney, intestine, and prostate, and it metabolizes a wide range of drugs, including tacrolimus, midazolam, and statins. The gene exhibits significant interindividual variability due to common polymorphisms, most notably CYP3A5*3 (rs776746), which creates a cryptic splice site leading to a truncated, non-functional protein. This polymorphism is a major determinant of CYP3A5 expression and activity, with important implications for drug dosing and disease susceptibility.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Drug metabolism - cytochrome P450 (KEGG: hsa00982)

• Metabolism of xenobiotics by cytochrome P450 (KEGG: hsa00980)

• Chemical carcinogenesis (KEGG: hsa05204)

• Retinol metabolism (KEGG: hsa00830)

• Linoleic acid metabolism (KEGG: hsa00591)

CYP3A5 is a 502-amino acid microsomal heme-thiolate monooxygenase (UniProt P20815) that catalyzes the oxidative metabolism of a broad spectrum of drugs, steroids, and carcinogens. The protein is anchored to the endoplasmic reticulum membrane via an N-terminal transmembrane domain. Its active site contains a heme iron coordinated by a conserved cysteine residue. CYP3A5 shares 84% sequence identity with CYP3A4 but exhibits distinct substrate specificity and tissue expression. The enzyme is highly polymorphic, with the CYP3A5*3 allele being the most common cause of reduced activity in non-African populations.