Effect of piperonyl butoxide on the metabolism of dimethyl and diethyl phosphorothionate insecticides

Abstract

Pretreatment with piperonyl butoxide (400 mg/kg) 1 hr prior to challenge antagonizes the toxicity of the dimethyl phosphorothionate insecticides, methyl parathion and Guthion, but potentiates the toxicity of the diethyl phosphorothionates, parathion and Ethyl Guthion. The effect of piperonyl butoxide on the metabolism of phosphorothionates and their oxygen analogs was studied in livers from male mice in an attempt to correlate metabolism with toxicity. Oxidative desulfuration (activation) and oxidative cleavage of both dimethyl and diethyl phosphorothionates by liver homogenates in vitro was inhibited by piperonyl butoxide to approximately the same extent. Enzymatic hydrolysis of paraoxon and methyl paraoxon was unaffected by piperonyl butoxide. No appreciable metabolism of parathion, Ethyl Guthion, or their oxygen analogs by glutathione-requiring enzyme systems was observed. Glutathione-dependent detoxification of methyl parathion in mouse liver in vitro occurred irrespective of microsomal oxidase activity. In contrast degradation of Guthion by glutathione-requiring enzyme systems only occurred during inhibition of oxidative metabolism. Furthermore, methyl paraoxon was rapidly metabolized by glutathione-dependent enzyme systems in vitro, whereas gutoxon did not appear to be detoxified by these enzymes. In vivo metabolism experiments suggested that methyl paraoxon was more rapidly detoxified than methyl parathion by glutathione-dependent enzymes. These results are consistent with the observation of a 40-fold antagonism of methyl parathion toxicity by piperonyl butoxide compared to the only three-fold antagonism of Guthion toxicity.