The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver

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.

Potential for cardiac toxicity with methylimidazolium ionic liquids

“…As water-soluble chemicals, they are also problematic to identify and quantify through traditional approaches. Finally, it has recently be determined that a low use MIL – M8OI – is detectable, albeit at low levels, in serum from humans ( Leitch et al, 2021 ). No examination of the small chain/high use MILs has been undertaken.…”

“…It was determined that the hepatic carboxylic acid metabolite of M8OI was capable of being incorporated into the autoantigen associated with the auto-immune liver disease primary biliary cholangitis (PBC) and therefore we proposed that M8OI and other MILs are potential hazard triggers for the disease. More recently, M8OI has been shown to be detectable in human sera ( Leitch et al, 2021 ). Whilst these observations do not establish a cause and effect with regard to PBC, it does indicate that both the environment and human population are being exposed to M8OI, and presumably other MILs (particularly smaller alkyl chain variants, which have higher use levels in the EU ( Leitch et al, 2020a ).…”

Mechanisms of Biological Effects of Ionic Liquids: From Single Cells to Multicellular Organisms

“…The metabolic transformation was shown to depend on cytochrome P450 monooxygenation followed by alcohol and acetaldehyde dehydrogenase oxidation. 411 The presence of C 8 MIm Cl in the environment has been tentatively correlated with the occurrence of primary biliary cholangitis (PBC), which is an autoimmune liver disease presumably triggered by an unknown environmental pollutant. 412 The toxic potential of C 8 MIm Cl was also studied in mice.…”

“…Evidence of metabolic transformations of ILs was obtained only for C 8 MIm Cl, which was shown to be partially metabolized by hepatocytes to (HOOC)C 7 MIm; the process presumably involved cytochrome P450-dependent monooxygenation followed by oxidation by alcohol dehydrogenase and acetaldehyde dehydrogenase. 411,413 In addition, AMMOENG 130 was shown to undergo dealkylation in zebrafish. 443 In contrast, no evidence of metabolic transformation was found for C 4 MIm Cl and C 4 C 1 Pyr Cl tested in rats.…”

“…In addition, according to an experiment with perfused human livers, C 8 MIm Cl was partially metabolized to 1-(7-carboxyheptyl)-3-methylimidazolium ((HOOC)­C 7 MIm) by hepatocytes, and both parent and product substances were subsequently excreted with the bile. The metabolic transformation was shown to depend on cytochrome P450 monooxygenation followed by alcohol and acetaldehyde dehydrogenase oxidation . The presence of C 8 MIm Cl in the environment has been tentatively correlated with the occurrence of primary biliary cholangitis (PBC), which is an autoimmune liver disease presumably triggered by an unknown environmental pollutant …”