The utility of HepG2 cells to identify direct mitochondrial dysfunction in the absence of cell death.



Kamalian, Laleh, Chadwick, Amy ORCID: 0000-0002-7399-8655, Bayliss, Mark, French, Neil ORCID: 0000-0002-9376-3482, Monshouwer, Mario, Snoeys, Jan and Park, B Kevin ORCID: 0000-0001-8384-824X
(2015) The utility of HepG2 cells to identify direct mitochondrial dysfunction in the absence of cell death. Toxicology in Vitro, 29 (4). 732 - 740.

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Abstract

Drug-induced mitochondrial dysfunction has been hypothesized to be an important determining factor in the onset of drug-induced liver injury. It is essential to develop robust screens with which to identify drug-induced mitochondrial toxicity and to dissect its role in hepatotoxicity. In this study we have characterised a mechanistically refined HepG2 model, using a panel of selected hepatotoxicants and non-hepatotoxicants. We have demonstrated that acute metabolic modification, via glucose-deprivation over a 4 h period immediately prior to compound addition, is sufficient to allow the identification of drugs which induce mitochondrial dysfunction, in the absence of cell death over a short exposure (2 – 8 h) using a plate-based screen to measure cellular ATP content and cytotoxicity. These effects were verified by measuring changes in cellular respiration, via oxygen consumption and extracellular acidification rates. Overall, these studies demonstrate the utility of HepG2 cells for the identification of mitochondrial toxins which act directly on the electron transport chain and that the dual assessment of ATP content alongside cytotoxicity provides an enhanced mechanistic understanding of the causes of toxicity.

Item Type: Article
Uncontrolled Keywords: Mitochondria, Drug-induced liver injury, HepG2, Toxicity, Dysfunction
Subjects: R Medicine > RM Therapeutics. Pharmacology
Depositing User: Symplectic Admin
Date Deposited: 23 Mar 2015 10:51
Last Modified: 09 May 2020 07:10
DOI: 10.1016/j.tiv.2015.02.011
Related URLs:
URI: http://livrepository.liverpool.ac.uk/id/eprint/2007867