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

Autor: Tarek M. Abdelghany, Ibrahim Ibrahim, Matthew C. Wright, Alex Charlton, Clair Roper, Colin H Wilson, Jeremy M. Palmer, Dan Vidler, Alistair C. Leitch, David Jones, Peter G. Blain
Rok vydání: 2021
Předmět:
Male
FMO
flavin-containing monooxygenases
Aldehyde dehydrogenase
C8mim
Toxicology
Bile
Cytochrome P-450 Enzyme Inhibitors
COOH7IM
1-(7-carboxyheptyl)-3-methyl-1H-imidazol-3-ium
Enzyme Inhibitors
M8OI+
1-octyl 3-methylimidazolium cation
Cells
Cultured
education.field_of_study
biology
Chemistry
MI+
methylimidazolium cation
Imidazoles
Middle Aged
Aldehyde Oxidoreductases
PFOA
perfluorooctanoic acid
Ionic liquids
Hepatobiliary Elimination
Ketoconazole
PDC
pyruvate dehydrogenase complex
CYP
cytochrome P450
Female
Cytochromes P450
medicine.drug
DCD
donation after circulatory death
Adult
DBD
donation after brain death
Primary Cell Culture
Population
In Vitro Techniques
Hydroxylation
digestive system
Article
Excretion
Young Adult
PBS
phosphate buffered saline
ALT
alanine aminotransferase
medicine
Humans
education
Aged
Alcohol dehydrogenase
Acetaldehyde dehydrogenase
ALP
alkaline phosphatase
M8OI
1-octyl 3-methylimidazolium chloride salt
PFOS
perfluorooctanesulfonic acid
Cytochrome P450
Molecular biology
AMA
anti-mitochondrial antibody
Disulfiram
Hepatocytes
biology.protein
HO8IM
1-(8-hydroxyoctyl)-3-methyl-imidazolium
PBC
primary biliary cholangitis
Acetaldehyde Dehydrogenase Inhibitors
Drug metabolism
Zdroj: Toxicology
ISSN: 0300-483X
DOI: 10.1016/j.tox.2021.152854
Popis: 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.
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.
Databáze: OpenAIRE
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