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

Toxicology in Vitro : an International Journal Published in Association with BIBRA
Laleh KamalianB Kevin Park

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.

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Citations

Apr 17, 2016·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Julie EakinsPaul Walker
Jun 12, 2016·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Ana Marta SilvaTeresa Cunha-Oliveira
Jul 15, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·Amy L BallAmy E Chadwick
Oct 21, 2016·Expert Opinion on Drug Metabolism & Toxicology·Ajit DashBrian R Wamhoff
Jun 13, 2017·Expert Opinion on Drug Metabolism & Toxicology·Richard J WeaverB Kevin Park
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Jan 19, 2021·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Samantha W JonesAmy E Chadwick
Dec 29, 2020·Expert Opinion on Drug Safety·Haochen JiangPeihua Luo
May 21, 2017·Toxicology in Vitro : an International Journal Published in Association with BIBRA·David GrünigStephan Krähenbühl

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