학술논문
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.
Document Type
Academic Journal
Author
Abdelghany TM; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt; Institute of Education in Healthcare and Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresthill, Aberdeen, AB25 2ZD, United Kingdom.; Hedya SA; Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt.; Charlton A; School of Natural and Environmental Sciences, Bedson Building, Newcastle University, NE1 8QB, United Kingdom.; Aljehani FA; Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.; Alanazi K; Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom.; Budastour AA; Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom.; Marin L; Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom.; Wright MC; Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom. Electronic address: m.c.wright@ncl.ac.uk.
Source
Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 8207483 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-6351 (Electronic) Linking ISSN: 02786915 NLM ISO Abbreviation: Food Chem Toxicol Subsets: MEDLINE
Subject
Language
English
Abstract
The 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shireen Hedya reports financial support was provided by Newton-Mosharafa Fund. Fahad Aljehani reports financial support was provided by Royal Government of Saudi Arabia. The authors declare that funding has been received in the past (2019) to investigate the metabolism of 3 compounds for Lubrizol (Wright). None of the compounds were ionic liquids and this work is considered by the authors to be unrelated to the study described herein. Wright has served as an Expert Member of the scientific panel on Food Additives and Nutrient Sources (ANS) of the European Food Safety Authority (2011–2018); is currently an expert Member of the scientific panel on Food Additives and Flavourings (FAF) of the of the European Food Safety Authority (2020 – present); is currently a member of the UK Committee on Toxicity (2017-present) and is currently a member of the UK Expert Committee for Pesticides (2022- present). The authors certify that their freedom to design, conduct, interpret, and publish research was - and is not - compromised by any controlling sponsor. The other authors declare they have no actual or potential competing financial interests. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shireen Hedya reports financial support was provided by Newton-Mosharafa Fund. Fahad Aljehani reports financial support was provided by Royal Government of Saudi Arabia. The authors declare that funding has been received in the past (2019) to investigate the metabolism of 3 compounds for Lubrizol (Wright). None of the compounds were ionic liquids and this work is considered by the authors to be unrelated to the study described herein. Wright has served as an Expert Member of the scientific panel on Food Additives and Nutrient Sources (ANS) of the European Food Safety Authority (2011–2018); is currently an expert Member of the scientific panel on Food Additives and Flavourings (FAF) of the of the European Food Safety Authority (2020 – present); is currently a member of the UK Committee on Toxicity (2017-present) and is currently a member of the UK Expert Committee for Pesticides (2022- present). The authors certify that their freedom to design, conduct, interpret, and publish research was - and is not - compromised by any controlling sponsor. The other authors declare they have no actual or potential competing financial interests. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)