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Published on: November 27, 2016
The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused
Alistair C Leitch1, Ibrahim Ibrahim2, Tarek M Abdelghany3
1Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom.
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.
Insights
Methylimidizolium ionic liquid (M8OI) exposure is present in humans, including primary biliary cholangitis (PBC) patients. The liver metabolizes M8OI via P450 enzymes and dehydrogenases, excreting it in bile.
Area of Science:
- Environmental Science
- Hepatology
- Toxicology
Background:
- Methylimidizolium ionic liquid (M8OI) is an environmental contaminant potentially linked to primary biliary cholangitis (PBC).
- Understanding human exposure and the liver's role in M8OI processing is crucial for assessing its health impacts.
Purpose of the Study:
- To investigate human exposure to M8OI.
- To elucidate the metabolic pathways and excretion routes of M8OI in the human liver.
Main Methods:
- Serum screening for M8OI in PBC patients and controls.
- In vitro perfusion of human livers with M8OI.
- Metabolism studies using cultured human hepatocytes and HepaRG cells.
- Inhibition studies using specific enzyme inhibitors (ketoconazole, 4-methyl pyrazole, disulfiram).
Main Results:
- M8OI detected in sera of PBC patients and controls, indicating human exposure.
- Perfused livers cleared M8OI, with hydroxylated (HO8IM) and carboxylated (COOH7IM) metabolites appearing in bile.
- Hepatocytes metabolized M8OI to HO8IM via cytochrome P450, further oxidized to COOH7IM by dehydrogenases.
- Metabolic pathways were confirmed through inhibition studies, though one donor showed impaired COOH7IM formation.
Conclusions:
- Demonstrates human population exposure to M8OI.
- Identifies hepatic metabolism involving P450 monooxygenation and subsequent dehydrogenase oxidation.
- Reveals biliary excretion of M8OI metabolites as a key elimination route in the human liver.
