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Undifferentiated HepaRG cells show reduced sensitivity to the toxic effects of M8OI through a combination of CYP3A7-mediated oxidation and a reduced reliance on mitochondrial function

Lookup NU author(s): Shireen Hedya, Adam Charlton, Fahad Aljehani, Khalid Alanazi, Professor Matthew Wright

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2024 The AuthorsThe methylimidazolium ionic liquid M8OI (1-octyl-3-methylimidazolium chloride, also known as [C8mim]Cl) has been detected in the environment and may represent a hazard trigger for the autoimmune liver disease primary biliary cholangitis, based in part on studies using a rat liver progenitor cell. The effect of M8OI on an equivalent human liver progenitor (undifferentiated HepaRG cells; u-HepaRG) was therefore examined. u-HepaRG cells were less sensitive (>20-fold) to the toxic effects of M8OI. The relative insensitivity of u-HepaRG cells to M8OI was in part, associated with a detoxification by monooxygenation via CYP3A7 followed by further oxidation to a carboxylic acid. Expression of CYP3A7 - in contrast to the related adult hepatic CYP3A4 and CYP3A5 forms - was confirmed in u-HepaRG cells. However, blocking M8OI metabolism with ketoconazole only partly sensitized u-HepaRG cells. Despite similar proliferation rates, u-HepaRG cells consumed around 75% less oxygen than B-13 cells, reflective of reduced dependence on mitochondrial activity (Crabtree effect). Replacing glucose with galactose, resulted in an increase in u-HepaRG cell sensitivity to M8OI, near similar to that seen in B-13 cells. u-HepaRG cells therefore show reduced sensitivity to the toxic effects of M8OI through a combination of metabolic detoxification and their reduced reliance on mitochondrial function.

Publication metadata

Author(s): Abdelghany TM, Hedya SA, Charlton A, Aljehani FA, Alanazi K, Budastour AA, Marin L, Wright MC

Publication type: Article

Publication status: Published

Journal: Food and Chemical Toxicology

Year: 2024

Volume: 188

Print publication date: 01/06/2024

Online publication date: 25/04/2024

Acceptance date: 21/04/2024

Date deposited: 08/05/2024

ISSN (print): 0278-6915

ISSN (electronic): 1873-6351

Publisher: Elsevier Ltd

URL: https://doi.org/10.1016/j.fct.2024.114681

DOI: 10.1016/j.fct.2024.114681

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