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

Graphical abstract
Highlights • Soil samples around landfill waste sites were screened for their ability to activate xenobiotic receptors and toxicity. • Xenoestrogens were present at higher levels in soils around a landfill site. • An ionic liquid was found to be present at high levels in two soil sampling sites near landfill. • The ionic liquid inhibited cellular oxidative phosphorylation, was toxic to a liver progenitor cell line and induced apoptosis. • The ionic liquid was metabolised by human hepatocytes to a carboxylic acid that bore structural similarity to lipoic acid.
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.