Differential toxic effects of bile acid mixtures in isolated mitochondria and physiologically relevant HepaRG cells

Penman, Sophie L ORCID: 0000-0001-5326-1675, Sharma, Parveen, Aerts, Helene, Park, B Kevin ORCID: 0000-0001-8384-824X, Weaver, Richard J and Chadwick, Amy E ORCID: 0000-0002-7399-8655 (2019) Differential toxic effects of bile acid mixtures in isolated mitochondria and physiologically relevant HepaRG cells. TOXICOLOGY IN VITRO, 61. 104595-.

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Abstract

Bile acids (BAs) are recognised as the causative agents of toxicity in drug-induced cholestasis (DIC). Research inisolated mitochondria and HepG2 cells have demonstrated BA-mediated mitochondrial dysfunction as a keymechanism of toxicity in DIC. However, HepG2 cells are of limited suitability for DIC studies as they do notexpress the necessary physiological characteristics. In this study, the mitotoxic potentials of BA mixtures wereassessed in isolated mitochondria and a better-suited hepatic model, HepaRG cells. BAs induced structural al-terations and a loss of mitochondrial membrane potential (MMP) in isolated mitochondria however, this toxicitydid not translate to HepaRG cells. There were no changes in oxygen consumption rate, MMP or ATP levels inglucose and galactose media, indicating that there was no direct mitochondrial toxicity mediated via electrontransport chain dysfunction in HepaRG cells. Assessment of key biliary transporters revealed that there was atime-dependent reduction in the expression and activity of multi-drug resistance protein 2 (MRP2), which wasconsistent with the induction of cytotoxicity in HepaRG cells. Overall, the findings from this study have de-monstrated that mitochondrial dysfunction is not a mechanism of BA-induced toxicity in HepaRG cells.

Item Type:	Article
Uncontrolled Keywords:	Bile acids, Drug-induced cholestasis, Mitochondria, HepaRG, Biliary transporters
Depositing User:	Symplectic Admin
Date Deposited:	15 Jul 2019 07:54
Last Modified:	19 Jan 2023 00:37
DOI:	10.1016/j.tiv.2019.104595
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3049919