Journal
TOXICOLOGY IN VITRO
Volume 29, Issue 4, Pages 732-740Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2015.02.011
Keywords
Mitochondria; Drug-induced liver injury; HepG2; Toxicity; Dysfunction
Categories
Funding
- European Community under the Innovative Medicines Initiative (IMI) Programme [115336 (MIP-DILI)]
- Janssen Pharmaceutica N.V. [387882]
- Medical Research Council, United Kingdom [G0700654]
- Medical Research Council [MR/L006758/1, G0700654] Funding Source: researchfish
- MRC [MR/L006758/1, G0700654] Funding Source: UKRI
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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 flepG2 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. (C) 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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