The effects of the phosphorothioate insecticide fenitrothion on mammalian cytochrome P450-dependent metabolism of estradiol

Abstract

Phosphorothioate insecticides, such as fenitrothion, are suicide substrates of cytochromes P450 (P450). These compounds undergo oxidative desulfuration by P450 resulting in the release and subsequent binding of atomic sulfur to the enzyme. Consequently, the P450-dependent metabolism of certain endogenous substrates could be inhibited by exposure to these insecticides. Formation of 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), 16 alpha-hydroxyestrone (16 alpha-OHE1), and estriol in mammals occurs by P450-dependent hydroxylation of estradiol at various positions on the steroid nucleus. In the present study, pretreatment of male Swiss Webster mice with increasing doses of fenitrothion resulted in dose-dependent biphasic decreases in 2-OHE2 and 4-OHE2 production in mouse hepatic microsomes compared to control, with substantial decreases even at a dosage as low as 7 mg/kg. Fenitrothion pretreatment also resulted in dose-dependent biphasic increases in 16 alpha-OHE1 and estriol production, along with substantial increases in estrone formation, probably as a result of shunting from the inhibition of 2- and 4-hydroxylation. These data suggest that exposure to fenitrothion might alter estradiol metabolism by inhibition of certain P450 isozymes.