Studies on the activation mechanism of xenobiotic-responsive nuclear receptor CAR and establishment of in vitro evaluation system for its ligands

包括人类在内的动物对药物和环境污染物等外来物质的毒性有一种防御机制。结构性雄烷受体(CAR)通过转录激活编码代谢酶、转运蛋白等靶基因，在这种防御机制中发挥重要作用。本研究阐明了微管网络和Importin/RAN系统在激活剂介导的原代肝细胞CAR核转位中起重要作用。然而，在永生细胞中，没有配体的CAR自发地移位到核室，在那里它反式激活目标基因。利用配体依赖的CAR突变体，建立了不牺牲动物的CAR配体筛选体系。所有这些发现不仅将有助于我们理解和理解

Animals including human beings have a defense mechanism against the toxicity of xenobiotics such as medicinal compounds and environmental pollutants. The constitutive androstane receptor (CAR) plays an important role in this defense mechanism by transcriptionally activating target genes coding for the metabolic enzymes, transporters and so on. In this study, it was elucidated that the microtubule network and importin/Ran system played important roles in the activator mediated nuclear translocation of CAR in primary hepatocytes. In immortal cells, however, the ligand-free CAR is spontaneously translocated into the nuclear compartment where it transactivates target genes. Using the ligand-dependent CAR mutant, the novel screening system for CAR ligand was established without sacrificing animals. All these findings will be beneficial in not only understanding of the d