DEALKYLATION OF ORGANOPHOSPHORUS ESTERS BY MOUSE LIVER ENZYMES IN VITRO AND IN VIVO

The mechanism and relative importance of O-dealkylation in detoxication of insecticidal organophosphate esters were investigated in white mice. The products of O-dealkylation of methyl paraoxon in liver supernatants were identified as demethyl methyl paraoxon and S-methylglutathione. Dimethyl esters were degraded by this enzyme much more readily than diethyl or diisopropyl esters. Liver microsomes with NADPH produced dimethyl phosphate. Little if any oxidative O-dealkylation occurred. Methyl paraoxon administered orally to mice gave dimethyl phosphate as the main urinary metabolite with lesser amounts of the demethyl derivative. No S-methylglutathione appeared in the urine because of further metabolism to volatile respirable compounds. The depletion of glutathione in the livers of Sumithion-treated mice and synergism of toxicity by methyl iodide suggest that, as in vitro, the major route of O-dealkylation in vivo is by alkylation of glutathione. © 1969, American Chemical Society. All rights reserved.