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

Probert, Philip M.; Leitch, Alistair C.; Dunn, Michael P.; Meyer, Stephanie K.; Palmer, Jeremy M.; Abdelghany, Tarek M.; Lakey, Anne F.; Cooke, Martin P.; Talbot, Helen; Wills, Corinne; McFarlane, William; Blake, Lynsay I.; Rosenmai, Anna K.; Oskarsson, Agneta; Figueiredo, Rodrigo; Wilson, Colin; Kass, George E.; Jones, David E.; Blain, Peter G.; Wright, Matthew C.

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Authors

Philip M. Probert

Alistair C. Leitch

Michael P. Dunn

Stephanie K. Meyer

Jeremy M. Palmer

Tarek M. Abdelghany

Anne F. Lakey

Martin P. Cooke

Helen Talbot

Corinne Wills

William McFarlane

Lynsay I. Blake

Anna K. Rosenmai

Agneta Oskarsson

Rodrigo Figueiredo

Colin Wilson

George E. Kass

David E. Jones

Peter G. Blain

Matthew C. Wright



Abstract

Background and Aims: Primary 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). Methods: Urban 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. Results: A 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. Conclusions: These 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. Lay summary: PBC is a liver disease in which most patients have antibodies to mitochondrial proteins containing lipoic acid binding site(s). This paper identified a man-made chemical present in soils around a waste site and shows that it is metabolised to a product having structural similarity to lipoic acid and is capable of replacing lipoic acid in mitochondrial proteins.

Citation

Probert, P. M., Leitch, A. C., Dunn, M. P., Meyer, S. K., Palmer, J. M., Abdelghany, T. M., …Wright, M. C. (2018). Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis. Journal of Hepatology, 69(5), 1123-1135. https://doi.org/10.1016/j.jhep.2018.06.027

Journal Article Type Article
Acceptance Date Jun 26, 2018
Online Publication Date Jul 11, 2018
Publication Date Nov 5, 2018
Deposit Date Aug 8, 2018
Publicly Available Date Oct 16, 2018
Journal Journal of Hepatology
Print ISSN 0168-8278
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 69
Issue 5
Pages 1123-1135
DOI https://doi.org/10.1016/j.jhep.2018.06.027
Related Public URLs https://eprint.ncl.ac.uk/249986

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