HOW THE POTENCY OF THE STEROID RU486 IS RELATED TO P450 ACTIVITIES INDUCED BY DEXAMETHASONE AND PHENOBARBITAL IN RAT HEPATOMA-CELLS

In a previous work on rat liver microsomes, we demonstrated that cytochrome P450 isozymes (P450) are engaged in the metabolism of RU486. In order to study the underlying mechanism at the molecular level, our investigations were shifted to a simplified system of cultured hepatoma cells which present a dissociation in the expression of distinct P450 coding genes. Our results show that Fao cells represent a convenient model to study both: (i) the degradation of RU486. Forms IIB1,2 and IIC7, which are present in Fao cells, may contribute to the demethylation of the molecule. Form IIIA, which has not been detected in Fao cells, is probably responsible for its oxidation in the liver; (ii) the effect of RU486 on the expression of P450 enzymes. Unlike other steroids dexamethasone and pregnenolone 16-alpha-carbonitrile), RU486 does not induce P450 activity but inhibits the inducing activity of other agents such as dexamethasone and also phenobarbital. These findings may be important for the therapeutic use of RU486 since its inhibitory effect on P450 activity may be at the origin of drug interactions by modifying the endogenous hormonal status.