Cytochrome P450 (CYP) represents a large superfamily of enzymes catalyzing oxidation of organic substances. CYP enzymes are integral in metabolizing both endogenous and exogenous substances, which include intermediates of lipids and steroidal hormones, drugs and toxic chemicals.
CYP3A, a subfamily of CYP450, consists of 4 genes CYP3A4, CYP3A5, CYP3A7, and CYP3A43. The substrates of the CYP3A subfamily constitute half of the drugs that are metabolized oxidatively by the CYP superfamily. Together, they help facilitate the elimination of 37% of the 200 most frequently prescribed drugs in the U.S. In adults, CYP3A4 and CYP3A5 are metabolically active and constitute approximately 30% of CYP activity. CYP3A5 expression is highly polymorphic. To date, there are 25 allelic variants of CYP3A5 (alleles numbered *1–*9).
Alleles CYP3A5*1 and CYP3A5*3 are distributed widely across various geographical and ethnic groups. CYP3A5*1 represents a functional CYP3A5 while CYP3A5*3 represents the most common non-functional variant which results in an enzyme with no activity. The CYP3A5*3B and *6 are also null alleles resulting also in no enzyme activity. The CYP3A5 alleles *2, 8 and 9 result in an enzyme that is partially active. Individuals with CYP3A5*1/*1 and *1/*3 genotypes express CYP3A5 and hence metabolize the substrates more rapidly than CYP3A5 3/*3* genotype and other non-expressers. Clinically important substrates include tacrolimus (immunosuppressive drug used in organ transplantation), midazolam, saquinavir (anti-retroviral drug), vincristine (mitotic inhibitor) and the statin group of drugs. The CYP3A5 enzyme activity influences the therapeutic dosing and dose-dependent adverse reactions of these substrates.
CYP3A5 variations have been associated with certain disease states including malignancies such as acute lymphoid leukemia and chronic myeloid leukemia.