Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene

Abstract

Proteins encoded by the human CYP3A genes metabolize every second drug currently in use. The activity of CYP3A gene products in the general population is highly variable and may affect the efficacy and safety of drugs metabolized by these enzymes. The mechanisms underlying this variability are poorly understood, but they include gene induction, protein inhibition and unknown genetic polymorphisms. To better understand the regulation of CYP3A expression and to provide a basis for a screen of genetic polymorphisms, we determined and analysed the sequence of the human CYP3A locus. The 231 kb locus sequence contains the three CYP3A genes described previously (CYP3A4, CYP3A5 and CYP3A7), three pseudogenes as well as a novel CYP3A gene termed CYP3A43. The gene encodes a putative protein with between 71.5% and 75.8% identity to the other CYP3A proteins. The highest expression level of CYP3A43 mRNA is observed in the prostate, an organ with extensive steroid metabolism. CYP3A43 is also expressed in several other tissues including liver, where it can be induced by rifampicin. CYP3A43 transcripts undergo extensive splicing. The identification of a new member of the CYP3A family and the characterization of the full CYP3A locus will aid efforts to identify the genetic variants underlying its variable expression. This, in turn, will lead to a better optimization of therapies involving the numerous substrates of CYP3A proteins.

Association of the CYP3A5 polymorphism (6986G>A) with blood pressure and hypertension

“…The CYP3A5 gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. 8 Cytochrome P450 proteins are monooxygenases that have an important role in the metabolism of both endogenous substances (for example, hormones) and exogenous substances (for example, drugs). 9,10 Cytochrome P450 proteins are expressed in an organ-specific manner, with CYP3A5 predominantly expressed in the kidney.…”

CYP3A5 polymorphism and sensitivity of blood pressure to dietary salt in Japanese men

“…1 CYP3A consists of four genes, CYP3A4, CYP3A43, CYP3A5 and CYP3A7, located on 7q21-7q22.1. 2 The CYP3A5 gene is the major class representing about 50% of the hepatic CYP3A content, and is also highly expressed in the kidney. 3,4 An extreme interindividual and interethnic variability for the expression of CYP3A5 has been reported.…”

The frameshift polymorphism CYP3A43_74_delA is associated with poor differentiation of breast tumors

“…This interpretation is plausible, because it has been shown that CYP3A43 is expressed in tissues related to steroid hormone synthesis and metabolism, and moreover in hormone related cancers, including carcinoma of the breast. [17][18][19] Thus, our finding of an association between the CYP3A43_74_delA polymorphism and poorly differentiated breast tumors adds a new candidate to the list of modulators of hormone-driven tumors. This should draw attention to CYP3A43 as a potential candidate marker for breast cancer prognosis.…”