Interaction of drugs and retinol

In liver microsomes of ethanol-fed rats, retinol competitively inhibited the hydroxylation of aniline, the demethylation of dimethylnitrosamine, and the oxidation of ethanol to acetaldehyde, whereas the inhibition of benzphetamine demethylation was of the mixed type in microsomes of phenobarbital-treated, ethanol-treated or control rats. Conversely, benzphetamine exerted a striking inhibition of the 4-hydroxylation of retinol in microsomes of phenobarbital-treated rats. At the concentration used, ethanol (100 mM) and dimethylnitrosamine (10 mM) had no such effect. In vivo administration of phenobarbital resulted in a 9-fold increase in the Vmax of the microsomal retinol 4-hydroxylase activity, with a 3-fold increase of the Km, whereas ethanol feeding resulted in a doubling of the Vmax with no significant change in the Km. The induction of this microsomal retinol-metabolizing system may contribute to the hepatic vitamin A depletion that has been reported previously after either ethanol or drug administration. Conversely, the observed inhibition, by retinol, of microsomal drug metabolism, including the demethylation of dimethylnitrosamine, may be of significance with regards to the interaction of retinol with carcinogenesis.