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.
journal_name
Cell Biol Toxicoljournal_title
Cell biology and toxicologyauthors
Wu Y,Geng XC,Wang JF,Miao YF,Lu YL,Li Bdoi
10.1007/s10565-016-9316-2subject
Has Abstractpub_date
2016-02-01 00:00:00pages
37-59issue
1eissn
0742-2091issn
1573-6822pii
10.1007/s10565-016-9316-2journal_volume
32pub_type
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