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

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