Gellner K, Eiselt R, Hustert E, Arnold H, Koch I, Haberl M, Deglmann C J, Burk O, Buntefuss D, Escher S, Bishop C, Koebe H G, Brinkmann U, Klenk H P, Kleine K, Meyer U A, Wojnowski L
Epidauros Biotechnologie AG, Bernried, Germany.
Pharmacogenetics. 2001 Mar;11(2):111-21. doi: 10.1097/00008571-200103000-00002.
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.
人类CYP3A基因编码的蛋白质参与目前正在使用的每一种药物的代谢。普通人群中CYP3A基因产物的活性高度可变，可能会影响这些酶代谢的药物的疗效和安全性。这种变异性背后的机制尚不清楚，但包括基因诱导、蛋白质抑制和未知的基因多态性。为了更好地理解CYP3A表达的调控并为基因多态性筛选提供基础，我们测定并分析了人类CYP3A基因座的序列。这个231 kb的基因座序列包含之前描述的三个CYP3A基因（CYP3A4、CYP3A5和CYP3A7）、三个假基因以及一个新的CYP3A基因，称为CYP3A43。该基因编码一种推定的蛋白质，与其他CYP3A蛋白质的同一性在71.5%至75.8%之间。CYP3A43 mRNA的最高表达水平在前列腺中观察到，前列腺是一个具有广泛类固醇代谢的器官。CYP3A43也在包括肝脏在内的其他几种组织中表达，在肝脏中它可被利福平诱导。CYP3A43转录本经历广泛的剪接。CYP3A家族新成员的鉴定以及完整CYP3A基因座的表征将有助于识别其可变表达背后的基因变异。反过来，这将导致对涉及众多CYP3A蛋白质底物的治疗进行更好的优化。
