DEVELOPMENTAL PHARMACOGENETICS OF MICROSOMAL STEROID HYDROXYLASES

工作概述：细胞色素P450的代谢是一种抵御环境毒物和致癌物质的防御系统。因此，代谢能力影响人类对异种化学物质暴露的易感性。面对几乎无限数量的结构多样的异种化学物质，P450基因能够被诱导以应对暴露。因此，找到诱导机制对于我们预测对异种化学物质的敏感性至关重要。使用小鼠原代肝细胞，我们确定了在人类CYP2B基因中发现的51-bp DNA作为苯巴比妥反应增强子模块或PBREM。我们还发现核孤儿受体CAR是一种苯巴比妥反应转录因子，可激活PBREM并诱导CYP2B基因。CAR是非诱导肝脏中的细胞质受体，在苯巴比妥治疗后易位到细胞核。CAR核易位是苯巴比妥诱导CYP2B基因的初始调控步骤。CAR和PBREM在小鼠、大鼠和人体内均保守，不仅对苯巴比妥有反应，而且对多种苯巴比妥型诱导剂也有反应，表明其功能的多功能性。细胞色素P450，基因调控，核受体，药物代谢，诱导，苯巴比妥

Summary of Work: Metabolism by cytochromes P450 is a defense system against environmental toxicants and carcinogens. Consequently, the metabolic capability affects human susceptability to xenochemical exposure. To encounter virtually unlimited numbers of structurally diverse xenochemicals, P450 genes are capable of being induced in response to the exposures. Thus, finding the induction mechanism is critical for our ability to predict the susceptibility to xenochemicals. Using mouse primary hepatocytes, we have defined a 51-bp DNA found in the human CYP2B gene as the phenobarbital-responsive enhancer module or PBREM. We have also identified the nuclear orphan receptor CAR as a phenobarbital-responsive transcription factor that activates PBREM and induces the CYP2B gene. CAR is a cytosolic receptor in non-induced livers and translocates to nucleus following treatment by phenobarbital. The CAR nuclear translocation is an initial regulatory step in induction by phenobarbital of the CYP2B gene. CAR and PBREM are conserved in mouse, rat and human and can respond to not only phenobarbital but also numerous phenobarbital-type inducers, indicating their functional versatility. - Cytochrome P450, Gene regulation, Nuclear receptor, Drug metabolism, Induction, Phenobarbital