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Research article2018Peer reviewedOpen access

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

Probert, Philip M.; 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.; Leitch, Alistair C.; Wright, Matthew C.; Dunn, Michael P.; Meyer, Stephanie K.; Palmer, Jeremy M.; Abdelghany, Tarek M.; Lakey, Anne F.; Cooke, Martin P.; Talbot, Helen

Abstract

Background & Aims: Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors, such as exposure to xenobiotics, which leads to a loss of tolerance to the lipoic acid-conjugated regions of the mitochondrial pyruvate dehydrogenase complex, typically to the E2 component. We aimed to identify xenobiotics that might be involved in the environmental triggering of PBC.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 receptor, androgen receptor and peroxisome proliferator activated receptor alpha - in cell-based screens. In contrast, xenoestrogens 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 a hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from three 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 the pyruvate dehydrogenase complex 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 be a component of an environmental trigger for PBC. Therefore, further study in experimental animal models is warranted, to determine the risk of exposure to these ionic liquids. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V.

Keywords

Liver progenitor; Mitochondria; Cholangiocyte; Biliary disease; AHR; ER alpha; PPAR alpha; Ionic solvent; C8mim; B-13; AR42J-B13

Published in

Journal of Hepatology
2018, Volume: 69, number: 5, pages: 1123-1135

      SLU Authors

      • Sustainable Development Goals

      SDG11 Make cities and human settlements inclusive, safe, resilient and sustainable
      SDG3 Ensure healthy lives and promote well-being for all at all ages

      UKÄ Subject classification

      Pharmacology and Toxicology

      Publication identifier

      DOI: https://doi.org/10.1016/j.jhep.2018.06.027

      Permanent link to this page (URI)

      https://res.slu.se/id/publ/96786