Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Toxicol Appl Pharmacol. 2010 Nov 1;248(3):242-8. doi: 10.1016/j.taap.2010.08.007. Epub 2010 Aug 12.
Troglitazone, a thiazolidinedione class antidiabetic drug, was withdrawn from the market because of its severe idiosyncratic hepatotoxicity. It causes a mitochondrial permeability transition (MPT), which may in part contribute to its hepatotoxicity. In the present study, the mechanism of troglitazone mitochondrial toxicity was investigated in isolated rat liver mitochondria. Mitochondrial swelling induced by 10 μM troglitazone was attenuated by bromoenol lactone (BEL), an inhibitor of Ca²+-independent phospholipase A₂ (iPLA₂). In contrast, that induced by 50 μM troglitazone was exacerbated by BEL. This exacerbation was diminished by addition of 2mM glutathione, an antioxidant. Oxygen consumption by state 3 respiration in isolated mitochondria was also decreased by troglitazone, but it was not affected by BEL. Mitochondrial swelling induced by 10 μM troglitazone was completely attenuated in the absence of Ca²+ while that induced by 50 μM troglitazone was not affected. Addition of 1 μM cyclosporin A (CsA), an inhibitor of MPT pores, completely attenuated swelling induced by 10 μM troglitazone while it only partly diminished that induced by 50 μM troglitazone. Thus, the MPT induced by 10 and 50 μM troglitazone are regulated by different mechanism; the MPT induced by 10 μM troglitazone is regulated by the activation of iPLA₂ and caused by the opening of CsA-regulating MPT pores followed by accumulation of Ca²+ in mitochondria, while that induced by 50 μM troglitazone is partly regulated by reactive oxygen species and mainly caused by the opening of CsA-insensitive MPT pores.
曲格列酮，噻唑烷二酮类抗糖尿病药物，由于其严重的特发性肝毒性而被撤出市场。它会引起线粒体通透性转变（MPT），这可能部分导致其肝毒性。在本研究中，我们研究了曲格列酮对离体大鼠肝线粒体的毒性机制。10μM 曲格列酮诱导的线粒体肿胀被钙非依赖性磷脂酶 A₂（iPLA₂）抑制剂溴烯内酯（BEL）减弱。相比之下，50μM 曲格列酮诱导的线粒体肿胀则被 BEL 加剧。加入抗氧化剂 2mM 谷胱甘肽后，这种加剧作用减弱。状态 3 呼吸时的耗氧量也被曲格列酮降低，但 BEL 不影响其耗氧量。在没有 Ca²+的情况下，10μM 曲格列酮诱导的线粒体肿胀完全被减弱，而 50μM 曲格列酮诱导的线粒体肿胀则不受影响。1μM 环孢菌素 A（CsA），一种 MPT 孔抑制剂，完全减弱了 10μM 曲格列酮诱导的肿胀，而只部分减弱了 50μM 曲格列酮诱导的肿胀。因此，10μM 和 50μM 曲格列酮诱导的 MPT 受不同机制调节；10μM 曲格列酮诱导的 MPT 受 iPLA₂的激活调节，由 CsA 调节的 MPT 孔的开放引起，随后线粒体中 Ca²+的积累，而 50μM 曲格列酮诱导的 MPT 部分受活性氧的调节，主要由 CsA 不敏感的 MPT 孔的开放引起。
