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Role of Mitochondria as Signal Sensors in Drug-Induced Liver Injury

线粒体作为信号传感器在药物性肝损伤中的作用

基本信息

批准号：
16590106
负责人：
MASUBUCHI Yasuhiro
金额：
$ 2.37万
依托单位：
CHIBA INSTITUTE OF SCIENCE (2005)Chiba University (2004)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Recent studies have suggested a pathogenetic role of mitochondrial permeability transition (MPT) in the mitochondria-mediated hepatocyte injury by chemical agents. MPT is characterized by a progressive permeabilization of the inner mitochondrial membrane dependent on the excessive amount of intramitochondrial Ca^<2+> and results in mitochondrial swelling, decrease in mitochondrial ΔΨ and release of accumulated Ca^<2+> Troglitazone, a thiazolidinedione class of antidiabetic agent, causes serious idiosyncratic hepatotoxicity. Troglitazone is metabolized to a reactive metabolite that covalently binds to cellular macromolecules, whereas its role 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 Ca^<2+> and troglitazone induced mitochondrial swelling, and the swelling was partially inhibited by cyclosporin A. Troglitazone also induced decreases in mitochondrial membrane potential and mitochondrial Ca^<2+> accumulation. These results demonstrate that troglitazone induces MPT. Similar results were obtained for ciglitazone, whereas rosiglitazone and pioglitazone, which are less hepatotoxic than troglitazone, had little effect on these mitochondria functions. In conclusion, the troglitazone-induced opening of MPT pore, which is not induced by rosiglitazone or pioglitazone, may contribute to the hepatotoxicity induced specifically by troglitazone.

近年来的研究表明，线粒体通透性转换（MPT）在化学物质介导的肝细胞损伤中起重要作用。MPT的特征在于依赖于线粒体内Ca^2+过量的线粒体内膜的进行性透化，并导致线粒体肿胀、线粒体Δ λ降低和累积的Ca^2+释放。曲格列酮（一种噻唑烷二酮类抗糖尿病药物）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，而其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+和曲格列酮存在的情况下，用琥珀酸孵育通电的线粒体可诱导线粒体肿胀，而这种肿胀可被环孢菌素A部分抑制。曲格列酮还可引起线粒体膜电位和线粒体Ca^2+积累的降低。这些结果表明曲格列酮诱导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。总之，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。