The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver. (July 2021)

• Record Type: Journal Article
• Authors: Leitch, Alistair C.; Ibrahim, Ibrahim; Abdelghany, Tarek M.; Charlton, Alex; Roper, Clair; Vidler, Dan; Palmer, Jeremy M.; Wilson, Colin; Jones, David E.; Blain, Peter G.; Wright, Matthew C.
• Is Part Of: Toxicology. Volume 459(2021)
• Publication Date: 2021-07
• Subjects: ALP alkaline phosphatase -- ALT alanine aminotransferase -- AMA anti-mitochondrial antibody -- COOH7IM 1-(7-carboxyheptyl)-3-methyl-1H-imidazol-3-ium -- CYP cytochrome P450 -- DBD donation after brain death -- DCD donation after circulatory death -- FMO flavin-containing monooxygenases -- HO8IM 1-(8-hydroxyoctyl)-3-methyl-imidazolium -- M8OI 1-octyl 3-methylimidazolium chloride salt -- M8OI+ 1-octyl 3-methylimidazolium cation -- MI+ methylimidazolium cation -- PBC primary biliary cholangitis -- PBS phosphate buffered saline -- PDC pyruvate dehydrogenase complex -- PFOA perfluorooctanoic acid -- PFOS perfluorooctanesulfonic acid; Cytochromes P450 -- Alcohol dehydrogenase -- Acetaldehyde dehydrogenase -- Ionic liquids -- Bile -- C8mim; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2021.152854
• Languages: English
• ISSNs: 0300-483X

Abstract

Highlights: M8OI was recently found to be contaminating the environment. M8OI was detected in the sera from 5/20 PBC patients and 1/10 controls. M8OI is taken up by human liver hepatocytes. M8OI is sequentially metabolised by CYPs followed by oxidation by dehydrogenases. The final carboxylic acid metabolite COOH7IM is, in part, excreted into human bile. Abstract: A methylimidizolium ionic liquid (M8OI) was recently found to be contaminating the environment and to be related to and/or potentially a component of an environmental trigger for the autoimmune liver disease primary biliary cholangitis (PBC). The aims of this study were to investigate human exposure to M8OI, hepatic metabolism and excretion. PBC patient and control sera were screened for the presence of M8OI. Human livers were perfused with 50μM M8OI in a closed circuit and its hepatic disposition examined. Metabolism was examined in cultured human hepatocytes and differentiated HepaRG cells by the addition of M8OI and metabolites in the range 10–100 μM. M8OI was detected in the sera from 5/20 PBC patients and 1/10 controls. In perfused livers, M8OI was cleared from the plasma with its appearance – primarily in the form of its hydroxylated (HO8IM) and carboxylated (COOH7IM) products – in the bile. Metabolism was reflected in cultured hepatocytes with HO8IM production inhibited by the cytochrome P450 inhibitor ketoconazole. Further oxidation of HO8IM to COOH7IM was sequentially inhibited by the alcohol and acetaldehyde dehydrogenase inhibitors 4-methyl pyrazole and disulfiram respectively. Hepatocytes from 1 donor failed to metabolise M8OI to COOH7IM over a 24 h period. These results demonstrate exposure to M8OI in the human population, monooxygenation by cytochromes P450 followed by alcohol and acetaldehyde dehydrogenase oxidation to a carboxylic acid that are excreted, in part, via the bile in human liver.