THE ROLE OF HUMAN PXR IN ANTI-TUBERCULOSIS DRUG-INDUCED LIVER INJURY

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 药物性肝损伤是抗结核化疗的主要安全性问题。 本项目的目的是研究利福平和异烟肼联合治疗相关的肝损伤机制，并开发新的策略来管理利福平和异烟肼诱导的肝损伤。 通过使用人源化的PXR小鼠，我们的初步研究确定了人PXR在利福平和异烟肼诱导的肝损伤中是必需的。 我们的中心假设是，利福平介导的人PXR激活干扰异烟肼和胆汁酸的代谢，这些代谢紊乱导致利福平和异烟肼联合治疗引起的肝损伤。 为了验证我们的假设，我们将利用基因工程小鼠模型（PXR-无效，PXR-人源化和Cyp 3a-无效小鼠）和基于LC-MS的代谢组学方法来追求以下特定目标：（1）。确定Cyp 3a在利福平和异烟肼诱导的肝损伤中的重要性。 （二）、确定利福平介导的PXR激活对异烟肼代谢和处置的影响，并确定利福平增强异烟肼毒性的机制。 （三）、确定利福平和异烟肼联合治疗对胆汁酸代谢的影响，并确定其在利福平和异烟肼诱导的胆汁淤积性损伤中的作用。 这项工作是创新的，因为人PXR被确定为利福平和异烟肼诱导的肝损伤的重要介质。 本项目的成功完成将极大地提高我们对利福平和异烟肼引起的肝损伤的认识，这将应用于预测、预防和治疗利福平和异烟肼联合治疗引起的肝损伤。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Drug-induced liver injury is a major safety issue in anti-tuberculosis chemotherapy. The objective of this project is to investigate the mechanisms of liver injury associated with rifampicin and isoniazid co-therapy and to develop novel strategies to manage rifampicin and isoniazid induced liver injury. By using pregnane X receptor (PXR)-humanized mice, our preliminary studies identified that human PXR is essential in rifampicin and isoniazid induced liver injury. Our central hypothesis is that rifampicin-mediated human PXR activation disturbs the metabolism of isoniazid and bile acids, and these metabolic disorders result in the liver injury caused by rifampicin and isoniazid co-therapy. In order to test our hypothesis, we will utilize the genetically engineered mouse models (Pxr-null, PXR-humanized, and Cyp3a-null mice) and the LC-MS-based metabolomic approach to pursue the following specific aims: (1). Determine the importance of Cyp3a in rifampicin and isoniazid induced liver injury. (2). Define the effects of rifampicin-mediated PXR activation on isoniazid metabolism and disposition, and determine the mechanism of rifampicin-boosted isoniazid toxicity. (3). Define the effect of rifampicin and isoniazid co-treatment on bile acid metabolism, and determine its contribution in rifampicin and isoniazid induced cholestatic injury. This work is innovative in that human PXR is identified as an essential mediator of rifampicin and isoniazid induced liver injury. Successful completion of this project will greatly enhance our knowledge on rifampicin and isoniazid induced liver injury which will be applied towards predicting, preventing, and treating the liver injury caused by rifampicin and isoniazid co-therapy.