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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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Abstract

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.

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Abbreviations

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

APAP:

Acetaminophen

AST:

Aspartate aminotransferase

CCK-8:

Cell counting kit-8

CHE:

Cholinesterase

DILI:

Drug-induced liver injury

GLDH:

Glutamate dehydrogenase

γ-GT:

γ-Glutamyl transferase

HCS:

High-content screening

LDH:

Lactate dehydrogenase

MAO:

Monoamine oxidase

MDH:

Malate dehydrogenase

NAT:

N-acetyltransferase

5’-NT:

5’-nucleotidase

PSTC:

Predictive Safety Testing Consortium

TPL:

Triptolide

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Acknowledgments

The authors are grateful for Prof. Deng Hong-kui and his research team for supplying ample hiHeps cell line as well as excellent technical assistance in cell culture and liver function maintenance. This work was supported by the National Key Technology R&D Program of China (2012ZX09302001).

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Authors and Affiliations

  1. Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China

    Yu Wu & Bo Li

  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

    Yu Wu, Xing-chao Geng, Ju-feng Wang, Yu-fa Miao & Yan-li Lu

  3. National Institutes for Food and Drug Control, No. 2 Tiantan Xili, Dongcheng District, Beijing, 100050, China

    Bo Li

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  1. Yu Wu
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  2. Xing-chao Geng
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  5. Yan-li Lu
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Correspondence to Xing-chao Geng or Bo Li.

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Wu, Y., Geng, Xc., Wang, Jf. et al. The HepaRG cell line, a superior in vitro model to L-02, HepG2 and hiHeps cell lines for assessing drug-induced liver injury. Cell Biol Toxicol 32, 37–59 (2016). https://doi.org/10.1007/s10565-016-9316-2

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  • DOI: https://doi.org/10.1007/s10565-016-9316-2

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