Mechanisms of adverse effects of anti-tuberculosis drugs

抗结核药物不良反应的机制

• 批准号: 8738245
• 负责人: Xiaochao Ma
• 金额: $ 14.68万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-20 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8738245
• 关键词: Adverse effects; Aminolevulinic Acid; Antitubercular Agents; Cessation of life; Chemicals; Data; Drug Resistant Tuberculosis; Enzymes; Etiology; Event; Excretory function; Genes; Genetic; Goals; Hepatotoxicity; Human; Ligands; Liver; Liver Failure; Mediating; Mediator of activation protein; Metabolism; Mus; Pathway interactions; Pharmaceutical Preparations; Porphyrins; Rattus; Receptor Activation; Regimen; Relapse; Reporting; Research; Rifampin; Rodent; Safety; Testing; Tuberculosis; Up-Regulation; Work; Xenobiotic Metabolism; base; chemotherapy; improved; isoniazid; liver injury; loss of function; metabolomics; mouse model; novel; novel strategies; pregnane X receptor; prevent; protoporphyrin IX; species difference; transcription factor; tuberculosis drugs

DESCRIPTION (provided by applicant): Drug-induced liver injury is a major safety issue in anti-tuberculosis (TB) chemotherapy. The long- term goal of our research is to improve the safety profile of medication with anti-TB drugs. The objective of this application is to determine the mechanism of liver injury associated with rifampicin and isoniazid co-therapy. Extensive studies have been conducted previously to investigate the liver injury caused by rifampicin and isoniazid in mice or rats; however, none of these studies mimicked the hepatotoxicity in humans. Species differences between rodents and humans in responding to rifampicin and/or isoniazid are expected. Pregnane X receptor (PXR) is a transcription factor regulating a gene network involved in the metabolism of xenobiotics and endobiotics. The ability of chemicals to activate PXR is species- dependent. Rifampicin is a human specific PXR activator, which strongly activates human PXR, but has a very weak effect on mouse PXR. To overcome the species differences in ligand-dependent PXR activation, we generated a PXR-humanized mouse model. By using these PXR-humanized mice, we noted that rifampicin and isoniazid-induced liver injury is human PXR-dependent. However, rifampicin- mediated PXR activation does not alter isoniazid metabolism. By using a metabolomic approach, we found that rifampicin and isoniazid co-treatment caused protoporphyrin IX (PP-IX) accumulation, specifically in liver, and this is human PXR-dependent. PP-IX is an intermediate in porphyrin synthesis, and has been shown to be hepatotoxic in previous studies. Based upon our preliminary data and previous reports, we hypothesize that rifampicin and isoniazid co-treatment disturbs porphyrin synthesis, and the accumulation of PP-IX in liver mediates the hepatotoxicity. To test our hypothesis, we will pursue the following two specific aims: (1) identify the toxic mediator(s) in the liver injury caused by rifampicin and isoniazid co-therapy. Our working hypothesis is that the accumulation of PP-IX in liver is the key mediator of the hepatotoxicity caused by rifampicin and isoniazid co-therapy; and (2) determine the human PXR-dependent pathway(s) responsible for the hepatotoxicity in rifampicin and isoniazid co- therapy. Our working hypothesis is that human PXR-mediated up-regulation of aminolevulinic acid synthase 1, the rate-limiting enzyme in porphyrin synthesis in liver, is critical in the hepatotoxicity caused by rifampicin and isoniazid co-therapy. The results from these studies are expected to provide a new paradigm for the mechanistic understanding of rifampicin and isoniazid-induced hepatotoxicity. Novel strategies, based upon human PXR, aminolevulinic acid synthase 1, and PP-IX, can be developed to predict, prevent, and treat the liver injury caused by rifampicin and isoniazid co-therapy.

描述（由申请方提供）：药物性肝损伤是抗结核（TB）化疗的主要安全性问题。我们研究的长期目标是提高抗结核药物的安全性。本申请的目的是确定与利福平和异烟肼联合治疗相关的肝损伤机制。之前已进行了广泛的研究，以研究利福平和异烟肼在小鼠或大鼠中引起的肝损伤;然而，这些研究均未模拟人类的肝毒性。预计啮齿动物和人类对利福平和/或异烟肼的反应存在物种差异。孕烷X受体（PXR）是一种转录因子，调节参与外源性物质和内生生物代谢的基因网络。化学物质激活PXR的能力取决于物种。利福平是一种人特异性PXR激活剂，它强烈激活人PXR，但对小鼠PXR的作用很弱。为了克服配体依赖性PXR激活的物种差异，我们产生了PXR人源化小鼠模型。通过使用这些PXR人源化小鼠，我们注意到利福平和异烟肼诱导的肝损伤是人类PXR依赖性的。然而，利福平介导的PXR激活并不改变异烟肼的代谢。通过使用代谢组学方法，我们发现利福平和异烟肼联合治疗引起原卟啉IX（PP-IX）蓄积，特别是在肝脏中，这是人类PXR依赖性的。PP-IX是卟啉合成中的中间体，并且在先前的研究中已经显示出肝毒性。根据我们的初步数据和以前的报告，我们假设利福平和异烟肼共同治疗干扰卟啉合成，和PP-IX在肝脏中的积累介导的肝毒性。为了验证我们的假设，我们将追求以下两个具体目标：（1）确定利福平和异烟肼联合治疗引起的肝损伤中的毒性介质。我们的工作假设是PP-IX在肝脏中的积累是由利福平和异烟肼共同治疗引起的肝毒性的关键介体;和（2）确定引起利福平和异烟肼共同治疗中的肝毒性的人PXR依赖性途径。我们的工作假设是，人类PXR介导的上调氨基乙酰丙酸合成酶1，在肝脏卟啉合成的限速酶，是至关重要的利福平和异烟肼联合治疗引起的肝毒性。这些研究结果有望为利福平和异烟肼诱导的肝毒性机制的理解提供新的范式。基于人PXR、氨基乙酰丙酸合成酶1和PP-IX的新策略可以被开发用于预测、预防和治疗由利福平和异烟肼联合治疗引起的肝损伤。