Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675, Japan.
Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675, Japan.
Toxicol Appl Pharmacol. 2021 Sep 15;427:115659. doi: 10.1016/j.taap.2021.115659. Epub 2021 Jul 29.
Mitochondrial injury contributes to severe drug-induced liver injury. Particularly, mitochondrial permeability transition (MPT) is thought to be relevant to cytolytic hepatitis. However, the mechanism of drug-induced MPT is unclear and prediction of MPT is not adequately evaluated in the preclinical stage. In a previous study, we found that troglitazone, a drug withdrawn due to liver injury, induced MPT via mild depolarization probably resulting from uncoupling. Herein, we investigated whether other drugs that induce MPT share similar properties as troglitazone, using isolated mitochondria from rat liver. Of the 22 test drugs examined, six drugs, including troglitazone, induced MPT and showed an uncoupling effect. Additionally, receiver operating characteristic analysis was conducted to predict the MPT potential from the respiratory control ratio, an indicator of uncoupling intensity. Results showed that 2.5 was the best threshold that exhibited high sensitivity (1.00) and high specificity (0.81), indicating that uncoupling was correlated with MPT potential. Activation of calcium-independent phospholipase A2 appeared to be involved in uncoupling-induced MPT. Furthermore, a strong relationship between MPT intensity and the uncoupling effect among similar compounds was confirmed. These results may help in predicting MPT potential using cultured cells and modifying the chemical structures of the drugs to reduce MPT risk.
线粒体损伤导致严重的药物性肝损伤。特别是线粒体通透性转换（MPT）被认为与细胞溶解性肝炎有关。然而，药物诱导的 MPT 的机制尚不清楚，在临床前阶段也没有充分评估 MPT 的预测。在之前的一项研究中，我们发现由于肝损伤而被撤回的药物曲格列酮通过轻微去极化诱导 MPT，可能是由于解偶联作用。在此，我们使用大鼠肝线粒体研究了其他诱导 MPT 的药物是否具有与曲格列酮相似的特性。在检查的 22 种测试药物中，包括曲格列酮在内的 6 种药物诱导 MPT 并显示解偶联作用。此外，还进行了受试者工作特征分析，以便根据呼吸控制比（解偶联强度的指标）预测 MPT 潜力。结果表明，2.5 是表现出高灵敏度（1.00）和高特异性（0.81）的最佳阈值，表明解偶联与 MPT 潜力相关。钙非依赖性磷脂酶 A2 的激活似乎参与了解偶联诱导的 MPT。此外，还证实了类似化合物之间 MPT 强度与解偶联效应之间的强相关性。这些结果可能有助于使用培养细胞预测 MPT 潜力，并对药物的化学结构进行修饰以降低 MPT 风险。
