Li Yan, Qi Xin-Ming, Xue Xiang, Wu Xiong-Fei, Wu Yuan-Feng, Chen Min, Xing Guo-Zhen, Luan Yang, Ren Jin
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
Toxicol Lett. 2009 Apr 25;186(2):111-4. doi: 10.1016/j.toxlet.2009.01.005. Epub 2009 Jan 16.
Many nonsteroidal anti-inflammatory drugs (NSAIDs) with diphenylamine structure induce severe hepatotoxicities. We evaluated the role of diphenylamine structure in liver injuries induced by these NSAIDs.
Effects of diphenylamine, diclofenac and tolfenamic acid on mitochondrial permeability transition (MPT) and efflux of calcium in isolated liver mitochondria as well as on cellular ATP content and mitochondrial membrane depolarization in rat primary hepatocyte cultures were examined.
Diclofenac and tolfenamic acid induced cyclosporine A (CsA)-sensitive mitochondrial swelling and membrane depolarization in isolated liver mitochondria. Only diclofenac caused the release of calcium in isolated liver mitochondria. Diphenylamine had no effects on isolated liver mitochondria. All three compounds decreased ATP content and induced mitochondrial membrane depolarization. CsA attenuated these effects, suggesting MPT might be involved in the hepatotoxicities caused by diphenylamine, diclofenac and tolfenamic acid. SKF-525A, a general inhibitor of CYP450, markedly inhibited the injury induced by diphenylamine, but not diclofenac or tolfenamic acid.
The hepatotoxicities caused by diclofenac and tolfenamic acid may be attributed to the mitochondrial dysfunction induced by these drugs instead of the diphenylamine structure per se.
许多具有二苯胺结构的非甾体抗炎药（NSAIDs）会引发严重的肝毒性。我们评估了二苯胺结构在这些NSAIDs所致肝损伤中的作用。
检测了二苯胺、双氯芬酸和托芬那酸对离体肝线粒体的线粒体通透性转换（MPT）和钙外流的影响，以及对大鼠原代肝细胞培养物中细胞ATP含量和线粒体膜去极化的影响。
双氯芬酸和托芬那酸在离体肝线粒体中诱导了环孢素A（CsA）敏感的线粒体肿胀和膜去极化。仅双氯芬酸导致离体肝线粒体中钙的释放。二苯胺对离体肝线粒体无影响。这三种化合物均降低了ATP含量并诱导了线粒体膜去极化。CsA减弱了这些作用，提示MPT可能参与了二苯胺、双氯芬酸和托芬那酸所致的肝毒性。CYP450的通用抑制剂SKF-525A显著抑制了二苯胺诱导的损伤，但对双氯芬酸或托芬那酸无抑制作用。
双氯芬酸和托芬那酸所致的肝毒性可能归因于这些药物诱导的线粒体功能障碍，而非二苯胺结构本身。
