THE STEROID ANTAGONIST RU38486 IS METABOLIZED BY THE LIVER MICROSOMAL-P450 MONO-OXYGENASES

Microsomal preparations from adult male rat liver actively oxidized RU38486 into the 11β-monodemethylated, 11β-didemethylated and 17α-hydroxylated derivatives, metabolites which are known to be formed in vivo. These oxidative reactions were inhibited at different degrees by P450 chemical inhibitors. Pretreatment of the animals by P450 mono-oxygenase prototype inducers led to drastic changes in RU38486 metabolization. Methylcholanthrene treatment carried out a significant decrease while phenobarbital markedly increased the metabolic activity of the liver microsomes. Moreover, antibodies to methylcholantrene-inducible P450 forms did not affect the metabolic activity while a complete blockade of RU38486 oxidation was observed in the presence of antibodies to phenobarbital-inducible forms. The present results demonstrate that liver P450 mono-oxygenases are engaged in different oxidative steps of RU38486 metabolism and that phenobarbital-inducible but not methylcholanthrene-inducible P450 forms are active in RU38486 degradation. © 1990.