Genomic organization of the human CYP3Alocus identification of a new, inducible CYP3Agene

Proteins encoded by the human CYP3Agenes metabolize every second drug currently in use. The activity of CYP3Agene 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 CYP3Aexpression and to provide a basis for a screen of genetic polymorphisms, we determined and analysed the sequence of the human CYP3Alocus. The 231 kb locus sequence contains the three CYP3Agenes described previously (CYP3A4, CYP3A5and CYP3A7), three pseudogenes as well as a novel CYP3Agene 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 CYP3A43mRNA is observed in the prostate, an organ with extensive steroid metabolism. CYP3A43is also expressed in several other tissues including liver, where it can be induced by rifampicin. CYP3A43transcripts undergo extensive splicing. The identification of a new member of the CYP3Afamily and the characterization of the full CYP3Alocus 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.