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The methylimidazolium ionic liquid M8OI is a substrate for OCT1 and p-glycoprotein-1 in rat
Shireen Hedya1, Alex Charlton2, Alistair C Leitch3
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt; Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom.
Abstract:
The methylimidazolium ionic liquid M8OI was recently found to be present in both the environment and man. In this study, M8OI disposition and toxicity were examined in an established rat progenitor-hepatocyte model. The progenitor B-13 cell was approx. 13 fold more sensitive to the toxic effects of M8OI than the hepatocyte B-13/H cell. However, this difference in sensitivity was not associated with a difference in metabolic capacities. M8OI toxicity was significantly decreased in a dose-dependent manner by co-addition of the OCT1 (SLC22A1) inhibitor clonidine, but not by OCT2 or OCT3 inhibitors in B-13 cells. M8OI toxicity was also dose-dependently increased by the co-addition of p-glycoprotein-1 (ABCB1B, multi drug resistant protein 1 (MDR1)) substrates/inhibitors. Excretion of B-13-loaded fluorophore Hoechst 33342 was also inhibited by the p-glycoproteins substrate cyclosporin A and by M8OI in a dose-dependent manner. Comparing levels of OCT and p-glycoprotein transcripts and proteins in B-13 and B-13/H cells suggest that the lower sensitivity to M8OI in B-13/H cells is predominantly associated with their higher expression of p-glycoprotein-1. These data together therefore suggest that a determinant in M8OI toxicity in rats is the expression and activity of the p-glycoprotein-1 transporter.
Insights
Methylimidazolium ionic liquid M8OI shows toxicity in rats. Its toxicity is linked to p-glycoprotein-1 (P-gp) transporter expression, with higher P-gp levels reducing M8OI
Area of Science:
- Environmental toxicology
- Pharmacokinetics
- Cell biology
Background:
- Methylimidazolium ionic liquid (M8OI) has been detected in the environment and humans.
- Understanding M8OI's toxicological impact and disposition is crucial.
Purpose of the Study:
- To investigate the disposition and toxicity of M8OI in a rat progenitor-hepatocyte model.
- To identify the cellular mechanisms underlying M8OI's toxicity.
Main Methods:
- Utilized a rat progenitor-hepatocyte model (B-13 and B-13/H cells).
- Assessed M8OI toxicity with and without inhibitors/substrates of organic cation transporters (OCTs) and p-glycoprotein-1 (P-gp).
- Quantified transporter expression at transcript and protein levels.
Main Results:
- Progenitor B-13 cells were significantly more sensitive to M8OI than hepatocyte B-13/H cells.
- M8OI toxicity in B-13 cells was reduced by an OCT1 inhibitor but unaffected by OCT2/3 inhibitors.
- M8OI toxicity was increased by P-gp substrates/inhibitors, and M8OI inhibited P-gp substrate excretion.
- Higher P-gp-1 expression in B-13/H cells correlated with lower M8OI sensitivity.
Conclusions:
- M8OI toxicity in rats is significantly influenced by the expression and activity of the p-glycoprotein-1 transporter.
- P-gp-1 plays a key role in mediating M8OI disposition and mitigating its toxic effects.
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