药物性肝损伤（DILI）已成为困扰临床安全用药不容忽视的重要问题。2013年1月FDA发布了关于托伐普坦引发DILI的风险警告，另有文献报道多种血管加压素II型受体拮抗剂也存在肝毒性。但此类药物导致DILI的机制尚不清楚。本项目以托伐普坦为研究对象，采用细胞转染技术研究药物转运体NTCP与BSEP在胆汁酸摄取与分泌中的作用；选用"三明治"培养大鼠肝细胞模型与整体动物模型探讨Ntcp与Bsep介导的胆汁酸肝胆转运改变与托伐普坦引起肝毒性的相关性，寻找与肝毒性相关的生物标志物；并从细胞与整体动物两个层面深入研究托伐普坦对FXR介导的NTCP/Ntcp与BSEP/Bsep功能与表达分子调控机制，阐明托伐普坦产生DILI的作用机理。研究结果将为托伐普坦所致DILI提供实验依据，并为揭示此类药物肝毒性机制提供理论依据，具有重要的临床用药指导意义。

Drug-induced liver injury (DILI) has become a serious issue in the practice of clinical medicine and DILI is responsible for the post-marketing withdrawal of many drugs. In January 2013, FDA issued a drug warning for tolvaptan with potential risk of liver injury. Vasopressin II receptor antagonist-related hepatic impairment was also reported in several previous studies. However, the mechanisms underlying vasopressin II receptor antagonist-associated DILI are poorly understood. In the present project, cell transfection technique will be adopted to investigate the effect of tolvaptan on sodium taurocholate cotransporting peptide (NTCP/Ntcp) and bile salt export pump (BSEP/Bsep) mediated cellular uptake and excretion of bile acids, such as taurocholate and chenodeoxycholate. In vitro sandwich-cultured rat hepatocyte and in vivo animal models will be also employed to determine the correlation between tolvaptan induced liver injury and changes of Ntcp- and Bsep-mediated bile acid hepatobilliary transport. Subsequently, bile acid homostasis as well as toxicity associated biomarkers will be analyzed in mice following oral dosing of 180 mg/kg/day of tolvaptan for 30 days. Finally, FXR/Fxr- and SHP/Shp-mediated molecular regulation of NTCP/Ntcp and BSEP/Bsep will be studied and discussed in both cell and mouse models, which helps to clarify the mechanism of tolvaptan induced liver injury. In summary, the research results will not only provide a practical interpretation for tolvaptan induced liver injury, but also offer a theoretical understanding of vasopressin II receptor antagonist-related hepatic impairment.