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，给艾滋病毒/艾滋病患者带来严重的健康并发症。这些并发症包括肝毒性，据报道约 10% 接受含利托那韦蛋白酶抑制剂治疗方案的患者出现肝毒性。含利托那韦的蛋白酶抑制剂方案引起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，在接受一线抗结核药物利福平预处理的受试者中，含利托那韦的蛋白酶抑制剂方案的肝毒性显着增强。利福平也被称为人孕烷 X 受体 (PXR) 的激活剂，可调节包括 CYP3A 在内的大量蛋白质的基因转录。我们在双转基因人 PXR 和 CYP3A4 小鼠中概括了与利福平预处理随后使用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 在与利福平预处理随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成分。此外，CYP3A 被确定为促进利托那韦生物活化的主要酶。我们还观察了用利福平和利托那韦预处理的双转基因人 PXR 和 CYP3A 小鼠肝脏中的内质网 (ER) 应激、未折叠蛋白反应和细胞凋亡。我们假设 PXR 激活会增加 ER 负荷并增强 CYP450 介导的利托那韦生物活化，从而协同 ER 应激并导致肝毒性。为了检验这一假设，提出了以下三个具体目标：（1）鉴定介导与利福平预处理然后利托那韦相关的肝毒性的代谢酶； (2) 阐明与利托那韦诱导的肝毒性相关的利托那韦代谢途径； (3) 确定 ER 应激在含利托那韦蛋白酶抑制剂方案的肝毒性中的作用。该项目的结果预计将提供对与含利托那韦蛋白酶抑制剂方案相关的肝损伤的机制了解，这将用于开发基于证据的方法，以改善 HIV 蛋白酶抑制剂的安全性。