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Lookup NU author(s): Dr Phillip Probert, Dr Alistair Leitch, Dr Michael Dunn, Dr Stephanie Meyer, Dr Jeremy Palmer, Dr Tarek Mamdouh AbdelghanyORCiD, Anne Lakey, Dr Martin Cooke, Dr Helen Talbot, Dr Corinne Wills, Emeritus Professor William McFarlane, Dr Lynsay Blake, Rodrigo Figueiredo, Professor Colin Wilson, Professor George Kass, Professor David Jones, Professor Peter Blain, Professor Matthew Wright
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Background and AimsPrimary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors - such as exposure to xenobiotics - leading to a loss of tolerance to the lipoic acid conjugated regions of the mitochondrial branched-chain α-ketoacid dehydrogenase complex, typically to the E2 component (PDC-E2).MethodsUrban landfill and control soil samples from a region with high PBC incidence were screened for xenobiotic activities using analytical, cell-based xenobiotic receptor activation assays and toxicity screens.ResultsA variety of potential xenobiotic classes were ubiquitously present, as identified by their interaction with xenobiotic receptors - aryl hydrocarbon (AhR), androgen (AR) and peroxisome proliferator activated receptor alpha (PPARα) receptors - in cell-based screens. In contrast, xenoestrogen – estrogen receptor (ERα) - interacting chemicals were present at higher levels in soil extracts from around an urban landfill. Furthermore, two landfill sampling sites contained a chemical(s) that inhibited mitochondrial oxidative phosphorylation and induced the apoptosis of an hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from 3 separate donors. The chemical was identified as the ionic liquid [3-methyl-1-octyl-1H-imidazol-3-ium]+ (M8OI) and the toxic effects were recapitulated using authentic pure chemical. A carboxylate-containing human hepatocyte metabolite of M8OI - bearing structural similarity to lipoic acid - was also enzymatically incorporated into the E2 component of pyruvate dehydrogenase via the exogenous lipoylation pathway in vitro.ConclusionsThese results identify for the first time, a xenobiotic in the environment that may be related to and/or potentially be a component of an environmental trigger for PBC.
Author(s): Probert PM, Leitch AC, Dunn MP, Meyer SK, Palmer JM, Abdelghany TM, Lakey AF, Cooke MP, Talbot H, Wills C, McFarlane W, Blake LI, Rosenmai AK, Oskarsson A, Figueiredo R, Wilson C, Kass GE, Jones DE, Blain PG, Wright MC
Publication type: Article
Publication status: Published
Journal: Journal of Hepatology
Year: 2018
Volume: 69
Issue: 5
Pages: 1123-1135
Print publication date: 01/11/2018
Online publication date: 11/07/2018
Acceptance date: 26/06/2018
Date deposited: 20/07/2018
ISSN (print): 0168-8278
ISSN (electronic): 1600-0641
Publisher: Elsevier BV
URL: https://doi.org/10.1016/j.jhep.2018.06.027
DOI: 10.1016/j.jhep.2018.06.027
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