Mitochondrial permeability transition as a potential determinant of hepatotoxicity of antidiabetic thiazolidinediones
Mitochondrial permeability transition as a potential determinant of hepatotoxicity of antidiabetic thiazolidinediones
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DOI：
10.1016/j.tox.2006.02.017
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发表时间：
2006-05-15
期刊：
影响因子：
4.5
通讯作者：
Horie, Toshiharu
中科院分区：
文献类型：
--
作者：
Masubuchi, Yasuhiro;Kano, Satomi;Horie, Toshiharu
曲格列酮是一种噻唑烷二酮类抗糖尿病药物，可引起严重的特异质肝毒性。曲格列酮被代谢为与细胞大分子共价结合的活性代谢物，但共价加合物在肝毒性中的作用存在争议。由于已发现曲格列酮可导致肝细胞毒性沿着线粒体功能障碍，因此我们使用从雄性CD-1小鼠分离的肝线粒体组分研究了曲格列酮和其他噻唑烷二酮类药物对线粒体功能的影响。在Ca ~（2+）和曲格列酮存在下，琥珀酸与线粒体孵育可诱导线粒体肿胀，环孢素A可部分抑制线粒体肿胀。曲格列酮还诱导线粒体膜电位和线粒体Ca 2+蓄积降低。这些结果表明，曲格列酮诱导线粒体通透性转换（MPT）。环格列酮也得到了类似的结果，而罗格列酮和吡格列酮的肝毒性低于曲格列酮，对这些线粒体功能的影响很小。因此，可能是曲格列酮诱导的MPT孔开放，而不是由罗格列酮或吡格列酮诱导的，可能有助于曲格列酮特异性诱导的肝毒性。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
Troglitazone, a thiazolidinedione class of antidiabetic agent, causes serious idiosyncratic hepatotoxicity. Troglitazone is metabolized to a reactive metabolite that covalently binds to cellular macromolecules, but the role of the covalent adduct in the hepatotoxicity is controversial. Because troglitazone has been found to cause cytotoxicity to hepatocytes along with mitochondrial dysfunction, we investigated the effects of troglitazone and other thiazolidinediones on mitochondrial function by using liver mitochondria fraction isolated from male CD-1 mice. Incubation of energized mitochondria with succinate in the presence of Ca2+ and troglitazone induced mitochondrial swelling, and the swelling was partially inhibited by cyclosporin A. Troglitazone also induced decreases in mitochondrial membrane potential and mitochondrial Ca2+ accumulation. These results demonstrate that troglitazone induces mitochondrial permeability transition (MPT). Similar results were obtained for ciglitazone, whereas rosiglitazone and pioglitazone, which are less hepatotoxic than troglitazone, had little effect on these mitochondria functions. It is therefore possible that the troglitazone-induced opening of MPT pore, which is not induced by rosiglitazone or pioglitazone, may contribute to the hepatotoxicity induced specifically by troglitazone. (c) 2006 Elsevier Ireland Ltd. All rights reserved.