DEVELOPMENTAL PHARMACOGENETICS OF MICROSOMAL STEROID HYDROXYLASES

工作概述：细胞色素P450代谢是抵御环境毒物和致癌物的防御系统。因此，代谢能力会影响人类对外来化学物质暴露的敏感性。面对几乎无限数量的结构不同的外来化学物质，P450基因能够被诱导对暴露做出反应。因此，找到诱导机制对于我们预测外来化学物质的易感性至关重要。利用小鼠原代肝细胞，我们已经定义了在人类CYP2B基因中发现的51bpDNA为苯巴比妥反应增强模块或PBREM。我们还鉴定了核孤儿受体CAR是一种苯巴比妥反应性转录因子，激活PBREM并诱导CYP2B基因。CAR是非诱导性肝细胞胞浆受体，经苯巴比妥处理后移位至胞核。CAR核转位是苯巴比妥诱导CYP2B基因表达的最初调控步骤。CAR和PBREM在小鼠、大鼠和人中都是保守的，不仅对苯巴比妥有反应，而且对多种苯巴比妥类诱导剂都有反应，这表明它们的功能是多功能性的。-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