Role of metabolic activation, covalent binding, and glutathione depletion in pulmonary toxicity produced by an impurity of malathion

O,O,S-Trimethyl phosphorothioate (OOS-TMP) is an impurity present in widely used organophosphorus insecticides such as malathion. Oral treatment of rats with the compound produces prominent bronchiolar epithelial necrosis. Following the administration of [3H]OOS-TMP to rats, substantial amounts of radiolabeled material were covalently bound to lung with a concomitant depletion of glutathione (GSH). Other organs showing significant covalently bound radioactivity were liver, kidneys, and ileum. The maximal accumulation occurred in the tissues within 6 hr, and reached a plateau between 6 and 12 hr. Pretreatment of rats with either phenobarbital or piperonyl butoxide decreased the level of radiolabeled material bound in lung, GSH depletion, and the toxicity of OOS-TMP. These results suggest that the covalent binding is due to a metabolite(s) of OOS-TMP and that the metabolite(s) is involved in the mechanism of toxicity of OOS-TMP. Pulmonary GSH may play a protective role against OOS-TMP induced lung toxicity.