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Lookup NU author(s): Dr Alistair Leitch, Dr Ibrahim Ibrahim, Dr Tarek Mamdouh AbdelghanyORCiD, Dr Alex Charlton, Clair Roper, Dr Daniel Vidler, Dr Jeremy Palmer, Colin Wilson, Professor David Jones, Professor Peter Blain, Professor Matt Wright
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2021 The Author(s)A methylimidizolium ionic liquid (M8OI) was recently found to be contaminating the environment and to be related to and/or potentially a component of an environmental trigger for the autoimmune liver disease primary biliary cholangitis (PBC). The aims of this study were to investigate human exposure to M8OI, hepatic metabolism and excretion. PBC patient and control sera were screened for the presence of M8OI. Human livers were perfused with 50μM M8OI in a closed circuit and its hepatic disposition examined. Metabolism was examined in cultured human hepatocytes and differentiated HepaRG cells by the addition of M8OI and metabolites in the range 10–100 μM. M8OI was detected in the sera from 5/20 PBC patients and 1/10 controls. In perfused livers, M8OI was cleared from the plasma with its appearance – primarily in the form of its hydroxylated (HO8IM) and carboxylated (COOH7IM) products – in the bile. Metabolism was reflected in cultured hepatocytes with HO8IM production inhibited by the cytochrome P450 inhibitor ketoconazole. Further oxidation of HO8IM to COOH7IM was sequentially inhibited by the alcohol and acetaldehyde dehydrogenase inhibitors 4-methyl pyrazole and disulfiram respectively. Hepatocytes from 1 donor failed to metabolise M8OI to COOH7IM over a 24 h period. These results demonstrate exposure to M8OI in the human population, monooxygenation by cytochromes P450 followed by alcohol and acetaldehyde dehydrogenase oxidation to a carboxylic acid that are excreted, in part, via the bile in human liver.
Author(s): Leitch AC, Ibrahim I, Abdelghany TM, Charlton A, Roper C, Vidler D, Palmer JM, Wilson C, Jones DE, Blain PG, Wright MC
Publication type: Article
Publication status: Published
Journal: Toxicology
Year: 2021
Volume: 459
Print publication date: 01/07/2021
Online publication date: 13/07/2021
Acceptance date: 07/07/2021
Date deposited: 03/08/2021
ISSN (print): 0300-483X
ISSN (electronic): 1879-3185
Publisher: Elsevier Ireland Ltd
URL: https://doi.org/10.1016/j.tox.2021.152854
DOI: 10.1016/j.tox.2021.152854
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