title: Establishment of a Drug-Induced, Bile Acid-Dependent Hepatotoxicity Model Using HepaRG Cells.
abstract: Bile acid (BA) retention within hepatocytes is an underlying mechanism of cholestatic drug-induced liver injury (DILI). We previously developed an assay using sandwich-cultured human hepatocytes (SCHHs) to evaluate drug-induced hepatocyte toxicity accompanying intracellular BA accumulation. However, due to shortcomings commonly associated with the use of primary human hepatocytes (e.g., limited availability, lot-to-lot variability, and high cost), we examined if the human hepatic stem cell line, HepaRG, might also be applicable to our assay system. Consequently, mRNA expression levels of human BA efflux and uptake transporters were lower in HepaRG cells than in SCHHs but higher than in HepG2 human hepatoma cells. Nevertheless, HepaRG cells and SCHHs showed similar toxicity responses to 22 selected drugs, including cyclosporine A (CsA). CsA (10 μM) was cytotoxic toward HepaRG cells in the presence of BAs and also reduced the biliary efflux rate of [(3)H]taurocholic acid from 38.5% to 19.2%. Therefore, HepaRG cells are useful for the evaluation of BA-dependent drug toxicity caused by biliary BA efflux inhibition. Regardless, the prediction accuracy for cholestatic DILI risk was poor for HepaRG cells versus SCHHs, suggesting that our DILI model system requires further improvements to increase the utility of HepaRG cells as a preclinical screening tool.
authors.affiliation: Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Susukida
authors.affiliation: Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sekine
authors.affiliation: Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Mayuka
authors.initials: M
authors.lastname: Nozaki
authors.affiliation: Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Tokizono
authors.affiliation: Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Oizumi
authors.affiliation: Biopharmaceutics and Molecular Toxicology Unit, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Horie
authors.affiliation: Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. Electronic address: itokousei@chiba-u.jp.
authors.forename: Kousei
authors.initials: K
authors.lastname: Ito
mesh_terms: D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D001647:Bile Acids and Salts; D002352:Carrier Proteins; D012333:RNA, Messenger
keywords: bile acid transporters; biliary excretion; cell lines; hepatocytes; in vitro models; toxicology