Mechanisms of methimazole cytotoxicity in isolated rat hepatocytes

Abstract

Methimazole is an antithyroid drug widely used in the treatment of hyperthyroidism. Administration of this drug, often in a chronic manner, is associated with several adverse drug reactions in humans, including life-threatening hepatotoxicity. This study attempted to investigate the cytotoxic mechanism(s) of methimazole toward isolated rat hepatocytes. In addition, the role of proposed methimazole intermediary metabolites, such as N-methylthiourea and glyoxal, in the toxicity induced by this drug was evaluated. Isolated hepatocytes were prepared by the collagenase enzyme perfusion method. Cells were treated with methimazole, N-methylthiourea, and other chemicals and markers, such as cell viability, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) formation, lipid peroxidation (LPO), and cellular glutathione (GSH) content, were measured. Methimazole-induced cytotoxicity was accompanied by collapse in MMP, increase in ROS formation, and LPO. Further, methimazole caused reduction in GSH reservoirs, and the cytotoxic effect of the drug was much more severe in GSH-depleted cells. N-methylthiourea caused toxicity in lower concentrations than methimazole and reduced hepatocytes glutathione content. The specific flavin-containing monooxygenase inhibitor, N,N-dimethylaniline, attenuated toxicity induced by N-methylthiourea. Administration of glyoxal trapping agents, such as metformin, hydralazine, or N-acetyl cysteine, effectively prevented methimazole toxicity in intact or GSH-depleted rat hepatocytes. This study indicates that methimazole reactive metabolites are responsible for the cytotoxicity induced by this drug, but the role of glyoxal as a metabolite, which causes ROS formation, LPO, and mitochondrial injury, is predominant because the glyoxal-trapping agents diminished these adverse effects.

• Methimazole
• glyoxal
• N-methylthiourea
• hepatotoxicity
• glutathione
• mitochondria
• ROS formation

Acknowledgements

This article was a part of a PhD thesis for Reza Heidari and was supported by students’ research committee of Tabriz University of Medical Sciences (Tabriz, Iran). The authors thank the students’ research committee for the support.