Negishi Masahiko
Pharmacogenetics, Reproductive and Developmental Biology, National Institutes of Health National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
Drug Metab Dispos. 2017 May;45(5):532-539. doi: 10.1124/dmd.116.074872. Epub 2017 Mar 29.
Phenobarbital was the first therapeutic drug to be characterized for its induction of hepatic drug metabolism. Essentially at the same time, cytochrome P450, an enzyme that metabolizes drugs, was discovered. After nearly 50 years of investigation, the molecular target of phenobarbital induction has now been delineated to phosphorylation at threonine 38 of the constitutive androstane receptor (NR1I3), a member of the nuclear receptor superfamily. Determining this mechanism has provided us with the molecular basis to understand drug induction of drug metabolism and disposition. Threonine 38 is conserved as a phosphorylation motif in the majority of both mouse and human nuclear receptors, providing us with an opportunity to integrate diverse functions of nuclear receptors. Here, I review the works and accomplishments of my laboratory at the National Institutes of Health National Institute of Environmental Health Sciences and the future research directions of where our study of the constitutive androstane receptor might take us.
苯巴比妥是第一种因其诱导肝脏药物代谢而被表征的治疗药物。基本上在同一时间，发现了一种代谢药物的细胞色素P450酶。经过近50年的研究，苯巴比妥诱导的分子靶点现已确定为组成型雄甾烷受体（NR1I3）第38位苏氨酸的磷酸化，该受体是核受体超家族的成员。确定这一机制为我们理解药物诱导的药物代谢和处置提供了分子基础。苏氨酸38在大多数小鼠和人类核受体中作为磷酸化基序保守存在，为我们整合核受体的多种功能提供了机会。在这里，我回顾了我在美国国立卫生研究院国家环境健康科学研究所实验室的工作和成就，以及我们对组成型雄甾烷受体的研究可能引领我们走向的未来研究方向。
