Relative contributions of the cytochrome P450 and flavin-containing monooxygenases to the microsomal oxidation of phorate following treatment of mice with phenobarbital, hydrocortisone, acetone, and piperonyl butoxide

Abstract

The relative contributions of the cytochrome P450-dependent monooxygenase system (P450) and the flavin-containing monooxygenase (FMO) in the microsomal oxidation of phorate, O,O-diethyl S-[(ethylthio)methyl]phosphorodithioate, were investigated in mice following treatment with phenobarbital (PB), piperonyl butoxide (PBO), acetone, or hydrocortisone. PBO treatment produced a distinct biphasic effect (initial inhibition and subsequent induction) on several hepatic enzyme activities, including phorate sulfoxidation. The relative contribution by P450 to phorate sulfoxidation decreased from 76% in control to 58% at 2 hr after treatment and increased to 89% at 12 hr. Hydrocortisone treatment caused an increase in FMO activity in liver microsomes, but not in lung microsomes. Administration of acetone caused an increase in benzphetamine N-demethylation and p-nitrophenol hydroxylation in the liver, but no change in phorate sulfoxidase activity was observed, nor was the relative contributions due to P450 and FMO altered. Treatment with phenobarbital produced a large increase in both benzphetamine N-demethylase and phorate sulfoxidase activity in liver microsomes, with the percentage of phorate sulfoxidase activity due to P450 being increased from 76% in the control livers to 85% in the treated livers.