Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis.
| Title: | Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis. |
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| Authors: | Probert PM; Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom.; Leitch AC; Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom.; Dunn MP; Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom.; Meyer SK; Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom.; Palmer JM; Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom.; Abdelghany TM; Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt.; Lakey AF; Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom.; Cooke MP; School of Civil Engineering and Geosciences, Drummond Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom.; Talbot H; School of Civil Engineering and Geosciences, Drummond Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom.; Wills C; School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom.; McFarlane W; School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom.; Blake LI; Institute for Sustainability, The Key Building, Newcastle University, Newcastle upon Tyne NE4 5TQ, United Kingdom.; Rosenmai AK; Swedish University of Agricultural Sciences, Uppsala, Sweden.; Oskarsson A; Swedish University of Agricultural Sciences, Uppsala, Sweden.; Figueiredo R; Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom; Freeman Hospital, Newcastle upon Tyne, Tyne and Wear NE7 7DN, United Kingdom.; Wilson C; Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom; Freeman Hospital, Newcastle upon Tyne, Tyne and Wear NE7 7DN, United Kingdom.; Kass GE; European Food Safety Authority, Via Carlo Magno 1A, 43126 Parma, Italy.; Jones DE; Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom.; Blain PG; Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom.; Wright MC; Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom. Electronic address: m.c.wright@ncl.ac.uk. |
| Source: | Journal of hepatology [J Hepatol] 2018 Nov; Vol. 69 (5), pp. 1123-1135. Date of Electronic Publication: 2018 Jul 11. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8503886 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0641 (Electronic) Linking ISSN: 01688278 NLM ISO Abbreviation: J Hepatol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2001- : Amsterdam : Elsevier; Original Publication: Copehnagen : Munksgaard International Publishers, [c1984- |
| MeSH Terms: | Cholangitis/*chemically induced ; Imidazoles/*toxicity ; Soil Pollutants/*toxicity ; Xenobiotics/*toxicity; Adenosine Triphosphate/metabolism ; Estrogen Receptor alpha/drug effects ; Imidazoles/isolation & purification ; Liver/drug effects ; Mitochondria, Liver/drug effects ; Pesticides/toxicity ; Polycyclic Aromatic Hydrocarbons/toxicity ; Soil Pollutants/analysis ; Xenobiotics/isolation & purification ; Animals ; Cells, Cultured ; Hep G2 Cells ; Humans ; Mice ; Rats |
| 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.; Lay Summary: Primary biliary cholangitis 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. It was then shown that this chemical was metabolized into a product with structural similarity to lipoic acid, which was capable of replacing lipoic acid in mitochondrial proteins.; (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.) |
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| Grant Information: | NC/K500471/1 United Kingdom NC3RS_ National Centre for the Replacement, Refinement and Reduction of Animals in Research; United Kingdom DH_ Department of Health; United Kingdom MRC_ Medical Research Council |
| Contributed Indexing: | Keywords: AHR*; AR42J-B13*; B-13*; Biliary disease*; C8mim*; Cholangiocyte*; ERα*; Ionic solvent*; Liver progenitor*; Mitochondria*; PPARα* |
| Substance Nomenclature: | 0 (Estrogen Receptor alpha); 0 (Imidazoles); 0 (M8OI compound); 0 (Pesticides); 0 (Polycyclic Aromatic Hydrocarbons); 0 (Soil Pollutants); 0 (Xenobiotics); 8L70Q75FXE (Adenosine Triphosphate) |
| Entry Date(s): | Date Created: 20180715 Date Completed: 20191028 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC6192827 |
| DOI: | 10.1016/j.jhep.2018.06.027 |
| PMID: | 30006067 |
| Database: | MEDLINE |
Journal Article