The utility of HepaRG cells for bioenergetic investigation and detection of drug-induced mitochondrial toxicity

Kamalian, Laleh, Douglas, Oisin, Jolly, Carol E, Snoeys, Jan, Simic, Damir, Monshouwer, Mario, Williams, Dominic P ORCID: 0000-0002-0758-3152, Park, B Kevin ORCID: 0000-0001-8384-824X and Chadwick, Amy E ORCID: 0000-0002-7399-8655 (2018) The utility of HepaRG cells for bioenergetic investigation and detection of drug-induced mitochondrial toxicity. TOXICOLOGY IN VITRO, 53. pp. 136-147.

Access the full-text of this item by clicking on the Open Access link.

Text Resubmission_HepaRG_Final.docx - Author Accepted Manuscript Download (883kB)

Abstract

The importance of mitochondrial toxicity in drug-induced liver injury is well established. The bioenergetic phenotype of the HepaRG cell line was defined in order to assess their suitability as a model of mitochondrial hepatotoxicity. Bioenergetic phenotyping categorised the HepaRG cells as less metabolically active when measured beside the more energetic HepG2 cells. However, inhibition of mitochondrial ATP synthase induced an increase in glycolytic activity of both HepaRG and HepG2 cells suggesting an active Crabtree Effect in both cell lines. The suitability of HepaRG cells for the acute metabolic modification assay as a screen for mitotoxicity was confirmed using a panel of compounds, including both positive and negative mitotoxic compounds. Seahorse respirometry studies demonstrated that a statistically significant decrease in spare respiratory capacity is the first indication of mitochondrial dysfunction. Furthermore, based upon comparing changes in respiratory parameters to those of the positive controls, rotenone and carbonyl cyanide m-chlorophenyl hydrazone, compounds were categorised into two mechanistic groups; inhibitors or uncouplers of the electron transport chain. Overall, the findings from this study have demonstrated that HepaRG cells, despite having different resting bioenergetic phenotype to HepG2 cells are a suitable model to detect drug-induced mitochondrial toxicity with similar detection rates to HepG2 cells.

Item Type:	Article
Uncontrolled Keywords:	Mitochondria, Drug-induced liver injury, HepaRG, Seahorse, Glucose/galactose, Bioenergetic phenotype
Depositing User:	Symplectic Admin
Date Deposited:	14 Nov 2018 11:30
Last Modified:	19 Jan 2023 01:24
DOI:	10.1016/j.tiv.2018.08.001
Open Access URL:	https://doi.org/10.1016/j.tiv.2018.08.001
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3025983