{"title":"Use of Primary Rat Hepatocytes for Prediction of Drug-Induced Mitochondrial Dysfunction","authors":"Cong Liu, Shuichi Sekine, Binbin Song, Kousei Ito","doi":"10.1002/cptx.24","DOIUrl":null,"url":null,"abstract":"<p>Mitochondrial dysfunction plays a central role in drug-induced liver injury. To evaluate drug-induced mitochondrial impairment, several isolated mitochondria- or cell line-based assays have been reported. Among them, culturing HepG2 cells in galactose provides a remarkable method to assess mitochondrial toxicity by activating mitochondrial aerobic respiration. We applied this assay to primary rat hepatocytes by culturing cells in galactose and hyperoxia to enhance the evaluation of metabolism-related drug-induced mitochondrial toxicity. Conventional culture of primary hepatocytes under high-glucose and hypoxic conditions could force cells to switch energy generation to glycolysis. By contrast, cells cultured in galactose and hyperoxia could maintain energy generation from mitochondrial aerobic respiration, which is consistent with physiological conditions, and consequently improve the susceptibility of cells to mitochondrial toxicants. Measuring the toxicities of test compounds in primary rat hepatocytes cultured in modified conditions provides a useful model to identify mitochondrial dysfunction-mediated drug-induced hepatotoxicity. © 2017 by John Wiley & Sons, Inc.</p>","PeriodicalId":72743,"journal":{"name":"Current protocols in toxicology","volume":"72 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2017-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/cptx.24","citationCount":"4","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current protocols in toxicology","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cptx.24","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 4
Abstract
Mitochondrial dysfunction plays a central role in drug-induced liver injury. To evaluate drug-induced mitochondrial impairment, several isolated mitochondria- or cell line-based assays have been reported. Among them, culturing HepG2 cells in galactose provides a remarkable method to assess mitochondrial toxicity by activating mitochondrial aerobic respiration. We applied this assay to primary rat hepatocytes by culturing cells in galactose and hyperoxia to enhance the evaluation of metabolism-related drug-induced mitochondrial toxicity. Conventional culture of primary hepatocytes under high-glucose and hypoxic conditions could force cells to switch energy generation to glycolysis. By contrast, cells cultured in galactose and hyperoxia could maintain energy generation from mitochondrial aerobic respiration, which is consistent with physiological conditions, and consequently improve the susceptibility of cells to mitochondrial toxicants. Measuring the toxicities of test compounds in primary rat hepatocytes cultured in modified conditions provides a useful model to identify mitochondrial dysfunction-mediated drug-induced hepatotoxicity. © 2017 by John Wiley & Sons, Inc.
用原代大鼠肝细胞预测药物性线粒体功能障碍
线粒体功能障碍在药物性肝损伤中起核心作用。为了评估药物诱导的线粒体损伤,已经报道了几种基于分离线粒体或细胞系的检测。其中,在半乳糖中培养HepG2细胞提供了一种通过激活线粒体有氧呼吸来评估线粒体毒性的显著方法。我们将该方法应用于原代大鼠肝细胞,通过在半乳糖和高氧环境中培养细胞来增强代谢相关药物诱导的线粒体毒性的评估。原代肝细胞在高糖和缺氧条件下的常规培养可以迫使细胞将能量产生转换为糖酵解。相反,在半乳糖和高氧环境中培养的细胞可以维持线粒体有氧呼吸产生的能量,这与生理条件一致,从而提高细胞对线粒体毒物的易感性。在改良条件下培养的原代大鼠肝细胞中测量测试化合物的毒性,为鉴定线粒体功能障碍介导的药物引起的肝毒性提供了一个有用的模型。©2017 by John Wiley &儿子,Inc。
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