吡嗪酰胺是临床常用的一线抗结核药，但是其肝脏不良反应发生率高，而且毒副作用机制尚不明确。课题组已初步确定吡嗪酰胺大鼠肝脏毒性的主要终点和通路，并采用全基因组表达谱芯片、QPCR和WB等技术发现L-FABP、PPAR-α与吡嗪酰胺导致肝脏毒性具有密切作用，课题将继续考察L-FABP、PPAR-α的调控机制和下游效应蛋白和靶基因的变化对肝毒性的影响，阐明吡嗪酰胺的肝毒性机制，寻找其肝脏毒性的早期生物标志物，结合临床样本，考察L-FABP等是否适用于临床吡嗪酰胺肝损害的早期毒性敏感指标，并确定评价的标准。考察吡嗪酰胺与其主要代谢物吡嗪酸的肝脏毒性差异，探讨其毒性可能的物质基础，考察和利福平联合使用后的肝脏毒性加强的作用机理，建立病理状态动物模型模拟临床用药的实际情况评价吡嗪酰胺的肝脏毒性，为合理规避和治疗吡嗪酰胺所致肝损伤方案提供科学参考依据，项目研究对于提吡嗪酰胺的临床疗效具有重要的科学意义。

Pyrazinamide (PZA) is an important sterilizing prodrug that shortens the duration of tuberculosis therapy. However, hepatotoxicity has been reported during clinical trials investigating PZA. To determine the hepatotoxic effects of PZA in vivo, we performed a 28-day repeated dose oral toxicity study on PZA in Wistar rats of both sexes and investigated the influence of PZA on liver and serum biochemical parameters. To characterize more effectively the biological responses of mammals exposed to PZA, the hepatic gene expression profiles in PZA-treated rats were examined using oligonucleotide microarray analysis and confirmed by Real-time polymerase chain reaction. We also evaluate the role of liver fatty acid-binding protein (L-FABP) and peroxisome proliferator-activated receptor α (PPAR-α) in the hepatotoxic effects of PZA, investigate whether serum bile acid, L-FABP and PPAR-α can be used as biomarkers for early detection of liver damage induced by PZA, compare the hepatic toxicity of PZA and pyrazinoic acid, clarify the molecular mechanisms underlying combination of PZA and rifabutin induced liver damage, establish pathological state animal model to evaluate hepatotoxicity of PZA. These data provide a better understanding of the molecular mechanisms underlying PZA-induced liver damage, as well as useful information for predicting drug hepatotoxicity.