Cargando…
The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver
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...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366605/ https://www.ncbi.nlm.nih.gov/pubmed/34271081 http://dx.doi.org/10.1016/j.tox.2021.152854 |
_version_ | 1783738912349356032 |
---|---|
author | 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. |
author_facet | 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. |
author_sort | Leitch, Alistair C. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8366605 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-83666052021-08-23 The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver 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. Toxicology Article 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. Elsevier 2021-07 /pmc/articles/PMC8366605/ /pubmed/34271081 http://dx.doi.org/10.1016/j.tox.2021.152854 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article 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. The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver |
title | The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver |
title_full | The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver |
title_fullStr | The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver |
title_full_unstemmed | The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver |
title_short | The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver |
title_sort | methylimidazolium ionic liquid m8oi is detectable in human sera and is subject to biliary excretion in perfused human liver |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366605/ https://www.ncbi.nlm.nih.gov/pubmed/34271081 http://dx.doi.org/10.1016/j.tox.2021.152854 |
work_keys_str_mv | AT leitchalistairc themethylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT ibrahimibrahim themethylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT abdelghanytarekm themethylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT charltonalex themethylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT roperclair themethylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT vidlerdan themethylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT palmerjeremym themethylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT wilsoncolin themethylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT jonesdavide themethylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT blainpeterg themethylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT wrightmatthewc themethylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT leitchalistairc methylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT ibrahimibrahim methylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT abdelghanytarekm methylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT charltonalex methylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT roperclair methylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT vidlerdan methylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT palmerjeremym methylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT wilsoncolin methylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT jonesdavide methylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT blainpeterg methylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver AT wrightmatthewc methylimidazoliumionicliquidm8oiisdetectableinhumanseraandissubjecttobiliaryexcretioninperfusedhumanliver |