Add time:07/13/2019         Source:sciencedirect.com

The cytotoxic effects of 2,6-di-tert-butyl-4-methylphenyl N-methylcarbamate (terbutol) and its major metabolites were investigated in freshly isolated rat hepatocytes. Terbutol and its metabolite, especially 2,6-di-tert-butyl-4-methylphenyl carbamate (N-demethylterbutol), at a concentration of 1.0 mM resulted in a time dependent cell killing accompanied by losses of intracellular ATP, protein thiols, and glutathione (GSH) and the accumulation of oxidized GSH. Supplementation of the hepatocyte suspension with 5 mM N-acetylcysteine, a precursor of intracellular GSH, inhibited the cytotoxicity of N-demethylterbutol. In mitochondria isolated from rat liver, terbutol and its metabolites impaired respiration related to oxidative phosphorylation and the potency of their toxicity is associated with impairment of mitochondrial respiration. These results indicate that N-demethylterbutol is the most cytotoxic followed by terbutol and other metabolites, and that both the mitochondrial respiratory system and protein thiols are important targets for these compounds.

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