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

Proteins encoded by the human CYP3A genes metabolize every second drug curr ently in use. The activity of CYP3A gene products in the general population is highly variable and may affect the efficacy and safety of drugs metabol ized by these enzymes. The mechanisms underlying this variability are poorl y understood, but they include gene induction, protein inhibition and unkno wn genetic polymorphisms. To better understand the regulation of CYP3A expr ession and to provide a basis for a screen of genetic polymorphisms, we det ermined and analysed the sequence of the human CYP3A locus. The 231 kb locu s sequence contains the three CYP3A genes described previously (CYP3A4, CYP 3A5 and CYP3A7), three pseudogenes as well as a novel CYP3A gene termed CYP 3A43, The gene encodes a putative protein with between 71.5% and 75.8% iden tity to the other CYP3A proteins, The highest expression level of CYP3A43 m RNA 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 spl icing. The identification of a new member of the CYP3A family and the chara cterization of the full CYP3A locus will aid efforts to identify the geneti c variants underlying its variable expression. This, in turn, will lead to a better optimization of therapies involving the numerous substrates of CYP 3A proteins. Pharmacogenetics 11:111-121 (C) 2001 Lippincott Williams & Wil kins.