| Title: |
Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis |
| Authors: |
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 |
| Source: |
Journal of Hepatology |
| Publisher Information: |
Elsevier BV |
| Collection: |
Newcastle University Library ePrints Service |
| Description: |
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-1 H -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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://eprints.ncl.ac.uk/249986; https://eprints.ncl.ac.uk/fulltext.aspx?url=249986/4B98D798-8D3E-4E32-96CA-6A5A3B749514.pdf&pub_id=249986 |
| Availability: |
https://eprints.ncl.ac.uk/249986 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.FF99139D |
| Database: |
BASE |