A phosphorothionate isomer protects against the pneumotoxicity caused by O,O,S-trimethyl phosphorothioate

O,O,S-Trimethyl phosphorothioate (OOS-TMP), an impurity in many organophosphorus insecticides, causes pneumotoxicity in rats at low doses (20 mg/kg) resulting in increases in bronchopulmonary lavage lactate dehydrogenase (LDH) activity and morphological alterations of bronchiolar epithelium. Coadministration of the nontoxic isomer, O,O,O-trimethyl phosphorothioate (OOO-TMP), at 1% of the toxicant dose, has been found to protect against the increase in LDH levels and morphological changes in bronchioles caused by OOS-TMP. Since OOO-TMP appears to require metabolic activation for pneumotoxicity, the effects of OOO-TMP on pulmonary and hepatic P-450 content and P-450-mediated monooxygenases were examined as a possible biochemical mechanism of antagonism. Oral treatment with OOO-TMP (0.5, 1.0, and 4.0 mg/kg) decreased pulmonary P-450 levels by 23 to 50% at 2 and 6 hr, while no changes were detected in hepatic P-450 levels. Lung microsomal 7-ethoxycoumarin O-deethylase (7-Ec) was inhibited by 71 to 100%, while liver 7-Ec was inhibited by 26 to 52%. p-Nitroanisole demethylase activity was decreased 22 to 47% following treatment with the two highest dose levels of OOO-TMP. These results further support the view that the lung is a target organ of delayed toxicity produced by OOS-TMP, and that the antagonistic effect of OOO-TMP is due to alterations in the metabolic activation processes of OOS-TMP in the lung and/or liver.