Wang Yue-Ming, Chai Sergio C, Brewer Christopher T, Chen Taosheng
St. Jude Children's Research Hospital, Department of Chemical Biology and Therapeutics , 262 Danny Thomas Place, Memphis, TN 38105 , USA.
Expert Opin Drug Metab Toxicol. 2014 Nov;10(11):1521-32. doi: 10.1517/17425255.2014.963555. Epub 2014 Sep 25.
The liver plays a central role in transforming and clearing foreign substances. The continuous exposure of the liver to xenobiotics sometimes leads to impaired liver function, referred to as drug-induced liver injury (DILI). The pregnane X receptor (PXR) tightly regulates the expression of genes in the hepatic drug-clearance system and its undesired activation plays a role in DILI.
This review focuses on the recent progress in understanding PXR-mediated DILI and highlights the efforts made to assess and manage PXR-mediated DILI during drug development.
Future efforts are needed to further elucidate the mechanisms of PXR-mediated liver injury, including the epigenetic regulation and polymorphisms of PXR. Novel in vitro models containing functional PXR could improve our ability to predict and assess DILI during drug development. PXR inhibitors may provide chemical tools to validate the potential of PXR as a therapeutic target and to develop drugs to be used in the clinic to manage PXR-mediated DILI.
肝脏在对外源物质的转化和清除过程中起着核心作用。肝脏持续接触外源性物质有时会导致肝功能受损，即药物性肝损伤（DILI）。孕烷X受体（PXR）严格调控肝脏药物清除系统中基因的表达，其异常激活在DILI中起作用。
本综述聚焦于理解PXR介导的DILI方面的最新进展，并着重介绍在药物研发过程中评估和管理PXR介导的DILI所做的努力。
未来需要进一步阐明PXR介导肝损伤的机制，包括PXR的表观遗传调控和多态性。含有功能性PXR的新型体外模型可以提高我们在药物研发过程中预测和评估DILI的能力。PXR抑制剂可能提供化学工具，以验证PXR作为治疗靶点的潜力，并开发用于临床治疗PXR介导的DILI的药物。
