The effects of phenobarbital pretreatment on the metabolism and toxicity of paraoxon in the mouse.

Abstract

The effects of induction of various forms of cytochromes P450 by chemicals like phenobarbital on the hepatic oxidative desulfuration and acute toxicity of the phosphorothioate insecticide parathion have been well-characterized. However, the effects of these chemicals on the metabolism and acute toxicity of the active metabolite paraoxon are less understood. In the present study, daily pretreatment of mice with phenobarbital (intraperitoneally 75 mg/kg) for up to eight days resulted in a transient increase in hepatic microsomal A-esterase activity, with a corresponding transient decrease in serum A-esterase activity (A-esterase was defined as hydrolysis of paraoxon which could be inhibited by EDTA). These alterations could be accounted for by a temporary decrease in the rate of secretion of A-esterase from liver. However, the same pretreatment resulted in a sustained protective effect against the acute toxicity of paraoxon. These data suggest that alterations in A-esterase activity as a result of phenobarbital pretreatment cannot account for the observed antagonism of the acute toxicity of paraoxon. Furthermore, these data demonstrate that the protective effect of phenobarbital pretreatment on phosphorothioate insecticides like parathion cannot be attributed exclusively to alterations in oxidative desulfuration of these compounds.