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Drug-induced liver injury associated with anti-retroviral therapy

与抗逆转录病毒治疗相关的药物性肝损伤

基本信息

批准号：
8774772
负责人：
Xiaochao Ma
金额：
$ 18.33万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8774772
关键词：
Drug induced liver injury associated

项目摘要

DESCRIPTION (provided by applicant): Adverse drug reactions associated with anti-retroviral therapy have emerged that pose significant health complications to HIV/AIDS patients. These complications include hepatotoxicity, which has been reported in ~10% of patients who receive ritonavir-containing protease inhibitor regimens. The mechanism of ritonavir-containing protease inhibitor regimen-induced liver injury is currently unknown. The long-term goal of our research is to improve the safety of anti-retroviral therapy. The objective of this application is to understan the mechanism of hepatotoxicity caused by ritonavir-containing protease inhibitor regimens. In a recent series of clinical trials, the hepatotoxicity of ritonavir-containing protease inhibitor regimens was significantly enhanced in subjects who were pretreated with rifampicin, a first-line anti-tuberculosis drug. Rifampicin is also known as an activator of human pregnane X receptor (PXR) that regulates the gene transcription of a large number of proteins including CYP3A. We recapitulated the hepatotoxicity associated with rifampicin pretreatment followed by ritonavir-containing protease inhibitor regimens in double transgenic human PXR and CYP3A4 mice. We found: (1) Human PXR is critical in the hepatotoxicity associated with rifampicin pretreatment followed by ritonavir-containing protease inhibitor regimens, and (2) Ritonavir is the key component that causes the hepatotoxicity of ritonavir-containing protease inhibitor regimens. In addition, CYP3A was determined as the primary enzyme contributing to ritonavir bioactivation. We also observed endoplasmic reticulum (ER) stress, unfolded protein response, and apoptosis in livers of double transgenic human PXR and CYP3A mice pretreated with rifampicin followed by ritonavir. We hypothesize that PXR activation increases ER load and potentiates CYP450-mediated ritonavir bioactivation, which synergizes ER stress and results in hepatotoxicity. To test this hypothesis, the following three specific aims are proposed: (1) Identify the metabolic enzyme(s) mediating the hepatotoxicity associated with rifampicin pretreatment followed by ritonavir; (2) Elucidate the metabolic pathway(s) of ritonavir that are associated with ritonavir-induced hepatotoxicity; and (3) Determine the role of ER stress in the hepatotoxicity of ritonavir-containing protease inhibitor regimens. The results from this project are expected to provide a mechanistic understanding of liver injury associated with ritonavir-containing protease inhibitor regimens, which will be applied toward the development of an evidence-based approach to improve the safety profile of HIV protease inhibitors.

描述（由申请人提供）：与抗逆转录病毒治疗相关的药物不良反应已经出现，对HIV/AIDS患者造成严重的健康并发症。这些并发症包括肝毒性，约10%接受含利托那韦蛋白酶抑制剂方案的患者报告了肝毒性。利托那韦蛋白酶抑制剂方案诱导肝损伤的机制目前尚不清楚。我们研究的长期目标是提高抗逆转录病毒治疗的安全性。本申请的目的是了解含利托那韦的蛋白酶抑制剂方案引起肝毒性的机制。在最近的一系列临床试验中，在接受利福平（一线抗结核药物）预治疗的受试者中，含利托那韦的蛋白酶抑制剂方案的肝毒性显著增强。利福平也被认为是人β-内酰胺X受体（PXR）的激活剂，可调节包括CYP 3A在内的大量蛋白质的基因转录。我们在双转基因人PXR和CYP 3A 4小鼠中概述了利福平预处理后含利托那韦的蛋白酶抑制剂方案相关的肝毒性。我们发现：（1）人PXR在利福平预处理后含利托那韦蛋白酶抑制剂方案相关的肝毒性中至关重要，（2）利托那韦是导致含利托那韦蛋白酶抑制剂方案肝毒性的关键组分。此外，CYP 3A被确定为利托那韦生物活化的主要酶。我们还观察到内质网（ER）的压力，未折叠蛋白质的反应，和细胞凋亡的双转基因人PXR和CYP 3A小鼠用利福平，然后利托那韦预处理的肝脏。我们假设PXR激活增加了ER负荷并增强了CYP 450介导的利托那韦生物激活，从而协同ER应激并导致肝毒性。为了验证这一假设，提出了以下三个具体目标：（1）确定介导利福平预处理后利托那韦肝毒性相关的代谢酶;（2）阐明利托那韦与利托那韦诱导的肝毒性相关的代谢途径;（3）确定ER应激在含利托那韦蛋白酶抑制剂方案肝毒性中的作用。该项目的结果预计将提供与利托那韦蛋白酶抑制剂方案相关的肝损伤的机制理解，这将应用于开发基于证据的方法来改善HIV蛋白酶抑制剂的安全性。