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.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D063086:Organothiophosphates / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity*; D009946:Organothiophosphorus Compounds / Q000494:pharmacology* / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D007507:Therapeutic Irrigation
D063086:Organothiophosphates; D009946:Organothiophosphorus Compounds; C023890:O,O,O-trimethyl phosphorothioate; C019123:O,O,S-trimethyl phosphorothioate; D003577:Cytochrome P-450 Enzyme System; D007770:L-Lactate Dehydrogenase; D001189:Aryl Hydrocarbon Hydroxylases