The HepaRG cell line, a superior in vitro model to L-02, HepG2 and hiHeps cell lines for assessing drug-induced liver injury

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• 作者：Yu Wu ; Xing-chao Geng ; Ju-feng Wang ; Yu-fa Miao ; Yan-li Lu…
• 关键词：Drug ; induced liver injury ; HepaRG cell line ; CCK ; 8 assay ; High ; content screening ; Malate dehydrogenase
• 刊名：Cell Biology and Toxicology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：32
• 期：1
• 页码：37-59
• 全文大小：2,088 KB
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• 作者单位：Yu Wu (1) (2)
  Xing-chao Geng (2)
  Ju-feng Wang (2)
  Yu-fa Miao (2)
  Yan-li Lu (2)
  Bo Li (1) (3)
  
  1. Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
  2. National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Key Laboratory of Beijing for Nonclinical Safety Evaluation of Drugs, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing, 100176, China
  3. National Institutes for Food and Drug Control, No. 2 Tiantan Xili, Dongcheng District, Beijing, 100050, China
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Cell Biology
  Pharmacology and Toxicology
  Biochemistry
  
• 出版者：Springer Netherlands
• ISSN：1573-6822

文摘

Drug-induced liver injury (DILI) is a leading cause of discontinuation of new drug approval or withdrawal of marketed medicine based on safety due to organ vulnerability. The aim of this research is to investigate the potential abilities of four different in vitro cell models (L-02, HepG2, HepaRG, and hiHeps cell lines) in assessing marketed drugs labeled with apparently different types of liver injury. A total of 17 drugs with versatile pharmacological profiles were chosen, of which, 14 drugs are recognized as DILI agents and 3 drugs are DILI irrelevant. Preliminary cellular screening assays indicated that the HepaRG cell line had an advantage over other cell lines in predicting drugs associated with DILI in vitro as it had the highest Youden’s index (71.4 %). A multi-parametric screening assay showed that oxidative stress, mitochondrial damage, and disorders of neutral lipid metabolism were changed notably in the HepaRG cell line after DILI-related drugs exposure, accounting for its high sensitivity in comparison with other three cell lines. In addition, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and malate dehydrogenase (MDH) all correlated with the cytotoxic effects of diclofenac sodium (p < 0.05), buspirone hydrochloride (p < 0.01), and danazol (p < 0.01) in the HepaRG cell line. We conclude that the HepaRG cell line is a superior in vitro cell model to other three cell lines for evaluating drugs with DILI potential.