Potential for cardiac toxicity with methylimidazolium ionic liquids

by Selleckchem | Oct 21 2023

Methylimidazolium ionic liquids (MILs) are solvent chemicals used in industry. Recent work suggests that MILs are beginning to contaminate the environment and lead to exposure in the general population. In this study, the potential for MILs to cause cardiac toxicity has been examined. The effects of 5 chloride MIL salts possessing increasing alkyl chain lengths (2 C, EMI; 4 C, BMI; 6 C; HMI, 8 C, M8OI; 10 C, DMI) on rat neonatal cardiomyocyte beat rate, beat amplitude and cell survival were initially examined. Increasing alkyl chain length resulted in increasing adverse effects, with effects seen at 10-5 M at all endpoints with M8OI and DMI, the lowest concentration tested. A limited sub-acute toxicity study in rats identified potential cardiotoxic effects with longer chain MILs (HMI, M8OI and DMI) based on clinical chemistry. A 5 month oral/drinking water study with these MILs confirmed cardiotoxicity based on histopathology and clinical chemistry endpoints. Since previous studies in mice did not identify the heart as a target organ, the likely cause of the species difference was investigated. qRT-PCR and Western blotting identified a marked higher expression of p-glycoprotein-3 (also known as ABCB4 or MDR2) and the breast cancer related protein transporter BCRP (also known as ABCG2) in mouse, compared to rat heart. Addition of the BCRP inhibitor Ko143 - but not the p-glycoproteins inhibitor cyclosporin A - increased mouse cardiomyocyte HL-1 cell sensitivity to longer chain MILs to a limited extent. MILs therefore have a potential for cardiotoxicity in rats. Mice may be less sensitive to cardiotoxicity from MILs due in part, to increased excretion via higher levels of cardiac BCRP expression and/or function. MILs alone, therefore may represent a hazard in man in the future, particularly if use levels increase. The impact that MILs exposure has on sensitivity to cardiotoxic drugs, heart disease and other chronic diseases is unknown.

Comments:

The passage you provided describes a study that investigates the potential cardiac toxicity of Methylimidazolium ionic liquids (MILs), which are solvent chemicals used in various industries. The study examines the effects of different MIL salts with increasing alkyl chain lengths on rat neonatal cardiomyocytes.

The results of the study indicate that as the alkyl chain length of the MIL salts increases, so do the adverse effects on cardiomyocyte beat rate, beat amplitude, and cell survival. The adverse effects were observed even at low concentrations (10-5 M) with the longer chain MIL salts, specifically M8OI and DMI.

Further research was conducted using rats in a sub-acute toxicity study, which confirmed potential cardiotoxic effects with longer chain MILs (HMI, M8OI, and DMI) based on clinical chemistry. Additionally, a 5-month oral/drinking water study with these MILs demonstrated cardiotoxicity based on histopathology and clinical chemistry endpoints.

Interestingly, previous studies in mice did not identify the heart as a target organ for MIL toxicity. To investigate the potential species difference, the researchers examined the expression of certain transport proteins involved in MIL excretion. They found that mouse hearts had significantly higher expression levels of p-glycoprotein-3 (ABCB4 or MDR2) and the breast cancer-related protein transporter BCRP (ABCG2) compared to rat hearts. Inhibiting BCRP increased the sensitivity of mouse cardiomyocytes to longer chain MILs to some extent, suggesting that the higher expression and/or function of BCRP in mouse hearts may contribute to their lower sensitivity to MIL-induced cardiotoxicity.

The study concludes that MILs have the potential for cardiotoxicity in rats, and it suggests that mice may be less sensitive to MIL-induced cardiotoxicity due, in part, to increased excretion via higher levels of cardiac BCRP expression and/or function. The findings also raise concerns about the potential hazards of MIL exposure in humans, particularly if their use levels increase. However, the impact of MILs on sensitivity to cardiotoxic drugs, heart disease, and other chronic diseases in humans is currently unknown.