The methylimidazolium ionic liquid M8OI is a substrate for OCT1 and p-glycoprotein-1 in rat. (April 2023)

• Record Type: Journal Article
• Authors: Hedya, Shireen; Charlton, Alex; Leitch, Alistair C.; Aljehani, Fahad A.; Pinker, Benjamin; Wright, Matthew C.; Abdelghany, Tarek M.
• Is Part Of: Toxicology in vitro. Volume 88(2023)
• Publication Date: 2023-04
• Subjects: C8[mim] -- AR42J-B13 -- Liver -- Transporter -- Ionic solvents -- Apoptosis; BCRP breast cancer resistance protein -- B-13 historically known as the AR42J-B13 cell line -- B-13/H hepatocyte-like cell derived from B-13 cells -- COOH7IM 1-(7-carboxyheptyl)-3-methyl-1H-imidazol-3-ium -- CPSI carbamoyl phosphate synthetase -- CPZ chlorpromazine -- CYP2E1 cytochrome P450 2E1 -- HO8IM 1-(8-Hydroxyoctyl)-3-methyl-imidazolium -- JC-1 5, 5′, 6, 6′-Tetrachloro-1, 1′, 3, 3′-tetraethylbenzimidazolylcarbocyanine Iodide -- LDH lactate dehydrogenase -- MRM multiple reaction monitoring -- MTT Thiazolyl blue tetrazolium bromide -- M8OI 1-ocytl-3-methylimidazolium -- OCT organic cation transporter -- PBC primary biliary cholangitis (formerly known as primary biliary cirrhosis) -- PBS phosphate buffered saline -- PCNA proliferating cell nuclear antigen; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2022.105550
• Languages: English
• ISSNs: 0887-2333

Abstract

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. Highlights: B-13 cells are more sensitive than B-13/H cells to the toxic effects of M8OI. M8OI sensitivity is not associated with M8OI metabolism in the B-13:B-13/H model. M8OI toxicity is reduced by the Oct1 inhibitor clonidine in B-13 cells. M8OI toxicity is enhanced by p-glycoprotein-1 substrates and inhibitors in B-13 cells.