Philip M. Probert
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.
Authors
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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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
Copyright Statement
© 2018 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Published Journal Article
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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
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