線粒体损伤和二苯胺结构在非甾体类抗炎药引起的肝细胞损伤中的作用.docVIP

Role of Mitochondrial Dysfunction and Diphenylamine Structure in NSAIDs-induced Hepatocytes Injury Li yan, Ren jin (Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Scien Abstract OBJECTIVE: Evaluate the role of mitochondrial function and structure of NSAIDs in NSAIDs-induced liver injury. METHODS: The isolated liver mitochondria and primary rat hepatocytes were prepared to perform all the experiments. Diphenylamine was used as a control drug, which had the shared structure of the NSAIDs used in our studies. RESULTS: Diclofenac and tolfenamic acid could induce cyclosporine A (CsA)-sensitive mitochondrial swelling, membrane depolarization and calcium release in isolated mitochondria. However, Diphenylamine had no effects on isolated mitochondria. Dpa, Dcf and Tol all induced mitochondrial dysfunction in hepatocytes, including the decrease of ATP content and mitochondrial membrane depolarization. CsA could attenuate these effects. Meanwhile, we found that SKF-525A, a nonspecific inhibitor of CYP450, could markedly inhibit the injury induced by Dpa, but not Dcf or Tol. CONCLUSION: Dpa itself could not induce mitochondria injury, the hepatotoxicity induced by Dpa may be related to its metabolism. And the hepatotoxicity caused by diclofenac and tolfenamic acid could attribute to the mitochondrial dysfunction induced by these drugs instead of the effect of the shared diphenylamine structure of these drugs. Key words: Mitochondria, liver injury, NSAIDs 线粒体损伤和二苯胺结构在非甾体类抗炎药引起的肝细胞损伤中的作用 李妍，任进 （药物安全评价研究中心，上海药物研究所，中国科学院，201203） 摘要：目的：研究线粒体功能及骨架结构在非甾体抗炎药引起的肝损伤中的作用。方法：采用离体分离得到的线粒体及原代分离的大鼠肝细胞，采用多种分子生物学的方法进行研究。结果：双氯酚酸钠和托灭酸可以导致分离线粒体肿胀，膜电位下降和内钙释放，环孢菌素A可以明显的抑制这一过程。二苯胺对分离线粒体则没有作用。在原代肝脏细胞上，三者均可以引起肝细胞线粒体功能损伤，表现为细胞ATP含量和线粒体膜电位下降，环孢菌素A可以改善这一过程。细胞色素P450非特异性抑制剂可以明显的抑制二苯胺导致的肝细胞损伤，而对双氯酚酸钠和托灭酸的肝细胞损伤作用并不明显。结论：二苯胺本身并不能引起线粒体损伤，它导致的肝细胞损伤可能与其代谢有关，而非甾体类抗炎药双氯芬酸钠和托灭酸引起的肝损伤与线粒体功能异常密切相关，而与其骨架结构二苯胺关系不大。 关键词：线粒体、肝损伤、非甾体类抗炎药 非甾体类抗炎药（Nonsteroidal anti-