Segawa Masahiro, Sekine Shuichi, Sato Tomoyuki, Ito Kousei
Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University.
Department of Investigative Toxicology, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd.
J Toxicol Sci. 2018;43(5):339-351. doi: 10.2131/jts.43.339.
Troglitazone, a member of the thiazolidinedione class of antidiabetic drugs, was withdrawn from the market because it causes severe liver injury. One of the mechanisms for this adverse effect is thought to be mitochondrial toxicity. To investigate the characteristics of troglitazone-induced liver toxicity in more depth, the toxicological effects of troglitazone on hepatocytes and liver mitochondria were investigated using a rat model of type 2 diabetes mellitus (T2DM). Troglitazone was found to increase mitochondrial permeability transition (MPT) in the liver mitochondria of diabetic rats to a greater extent than in control rats, whereas mitochondrial membrane potential and oxidative phosphorylation were not affected. To identify the factors associated with this increase in susceptibility to MPT in diabetic rats, we assessed the oxidative status of the liver mitochondria and found a decrease in mitochondrial glutathione content and an increase in phospholipid peroxidation. Moreover, incorporation of oxidized cardiolipin, a mitochondrion-specific phospholipid, was involved in the troglitazone-induced alteration in susceptibility to MPT. In conclusion, liver mitochondria display disease-associated mitochondrial lipid peroxidation in T2DM, which facilitates the higher susceptibility to troglitazone-induced MPT. Thus, greater susceptibility of liver mitochondria may be a host factor leading to troglitazone-induced hepatotoxicity in T2DM.
曲格列酮是噻唑烷二酮类抗糖尿病药物的一种，因其会导致严重肝损伤而被撤出市场。这种不良反应的机制之一被认为是线粒体毒性。为了更深入地研究曲格列酮诱导的肝毒性特征，利用2型糖尿病（T2DM）大鼠模型研究了曲格列酮对肝细胞和肝线粒体的毒理学作用。结果发现，曲格列酮使糖尿病大鼠肝线粒体的线粒体通透性转换（MPT）增加的程度大于对照大鼠，而线粒体膜电位和氧化磷酸化未受影响。为了确定与糖尿病大鼠对MPT敏感性增加相关的因素，我们评估了肝线粒体的氧化状态，发现线粒体谷胱甘肽含量降低，磷脂过氧化增加。此外，线粒体特异性磷脂氧化型心磷脂的掺入参与了曲格列酮诱导的对MPT敏感性的改变。总之，在T2DM中，肝线粒体表现出与疾病相关的线粒体脂质过氧化，这促进了对曲格列酮诱导的MPT的更高敏感性。因此，肝线粒体更高的敏感性可能是导致T2DM中曲格列酮诱导肝毒性的宿主因素。
