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Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis

Lookup NU author(s): Dr Phillip Probert, Dr Alistair Leitch, Dr Michael Dunn, Dr Stephanie Meyer, Dr Jeremy Palmer, Tarek Abdelghany, Anne Lakey, Dr Martin Cooke, Dr Helen Talbot, Dr Corinne Wills, Emeritus Professor William McFarlane, Dr Lynsay Blake, Rodrigo Figueiredo, Colin Wilson, Professor George Kass, Professor David Jones, Professor Peter Blain CBE, 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

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.


Publication metadata

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

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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