Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice
Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice
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DOI：
10.1016/j.jhep.2004.09.015
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发表时间：
2005-01-01
影响因子：
25.7
通讯作者：
Horie, T
中科院分区：
文献类型：
--
作者：
Masubuchi, Y;Suda, C;Horie, T
背景/目标：虽然线粒体已被证明是对乙酰氨基酚肝毒性的主要靶点，但线粒体介导的毒性机制尚未确定。方法：雄性CD-1小鼠腹腔注射醋氨酚（350 mg/kg），同时给予MPT特异性抑制剂环孢菌素A（50 mg/kg）。血清丙氨酸氨基转移酶（ALT），肝损伤的标志物，和其他生化参数进行了determined.Results：醋氨酚诱导的ALT渗漏的共同管理的环孢素A衰减。环孢菌素A不影响对乙酰氨基酚诱导的肝脏还原型谷胱甘肽（GSH）含量的早期降低，表明对代谢活化缺乏影响。对乙酰氨基酚诱导的线粒体GSH和ATP含量的下降，和细胞色素c的胞浆泄漏衰减环孢素A，表明线粒体氧化应激和ATP耗竭导致的MPT参与对乙酰氨基酚诱导的肝损伤的主要机制。在从对乙酰氨基酚处理的小鼠中分离的线粒体中，钙引起的线粒体肿胀加剧。体外完整线粒体暴露于含钙的N-乙酰基对苯醌亚胺（NAPQI）引起线粒体肿胀。结论：目前的数据表明MPT是对乙酰氨基酚诱导的肝损伤的主要机制，NAPQI是打开过渡孔的候选者。(C)2004年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: Although mitochondria have been demonstrated as primary targets in acetaminophen hepatotoxicity, the mechanism for mitochondria-mediated toxicity has not been defined. We examined the role of mitochondrial permeability transition (MPT) in the acetaminophen-induced liver injury.Methods: Male CD-1 mice were given intraperitoneally acetaminophen (350 mg/kg) without or with cyclosporin A (50 mg/kg), a specific inhibitor of MPT. Serum alanine aminotransferase (ALT), a marker of liver injury, and other biochemical parameters were determined.Results: Acetaminophen-induced ALT leakage was attenuated by co-administration of cyclosporin A. Cyclosporin A did not affect acetaminophen-induced early decrease in hepatic reduced glutathione (GSH) contents, indicating lack of the effect on the metabolic activation. Acetaminophen-induced decrease in mitochondrial GSH and ATP contents, and cytosolic leakage of cytochrome c were attenuated by cyclosporin A, suggesting that mitochondrial oxidative stress and ATP depletion resulting from MPT are principle mechanisms involved in acetaminophen-induced liver injury. Mitochondrial swelling by calcium was exacerbated in the mitochondria isolated from the acetaminophen-treated mice. In vitro exposure of intact mitochondria to N-acetyl-p-benzoquinone imine (NAPQI) with calcium caused mitochondrial swelling.Conclusions: The present data indicate that the MPT is the principal mechanism in the acetaminophen-induced liver injury and NAPQI is a candidate to open the transition pore. (C) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.