Toxicity and metabolism of malathion and its impurities in isolated rat hepatocytes: Role of glutathione

The role of glutathione (GSH) in the detoxification of malathion and in the potentiating action of impurities on the toxicity of malathion was investigated in freshly isolated rat hepatocytes. Malathion and four of its major impurities at concentrations of 0.01 to 1 mm caused a marked depletion of the hepatocellular GSH content within 60 min. The potency of the compounds to deplete the cellular GSH level declined in the following order: isomalathion = O,S,S-trimethyl phosphorodithioate > malathion=O,O,S-trimethyl phosphorodithioate >O,O,S-trimethyl phosphorothioate. Preexposure of hepatocytes to 0.03 mm of isomalathion or O,S,S-trimethyl phosphorodithioate enhanced the GSH-dependent detoxification of malathion up to threefold. When carboxylesterase activity was inhibited, the resulting depletion of the GSH level by more than 70% greatly potentiated the toxicity of malathion as measured by the inhibition of cholinesterase activity. These experiments indicate that the simultaneous blockage of the carboxylesterase- and GSH-dependent routes of malathion detoxification is a possible mechanism for the potentiating action of impurities on the malathion toxicity in mammals.