In vitro studies on the interaction of the pyridoindole antioxidant stobadine with rat liver microsomal P450.

1. Stobadine, a pyridoindole antioxidant agent, elicited medium affinity, low capacity interaction with type I binding sites of the hepatic microsomal cytochromes P450 derived from control and acetone-pretreated rats. Reverse type I interaction of low affinity and low capacity was observed in microsomes from phenobarbital-treated rats. 2. Stobadine led to an increase of H2O2 production when added to liver microsomes derived from differently pretreated rats in an NADPH-dependent process with concomitantly increased oxygen consumption. 3. Stobadine, at concentrations stimulating H2O2 formation, was found to prevent NADPH-induced microsomal lipid peroxidation, assessed as thiobarbituric acid-reactive product accumulation. 4. Only a weak inhibitory effect of stobadine on either NADPH- or cumene hydroperoxide-dependent aminopyrine N-demethylation and aniline hydroxylation was observed in microsomes from control and phenobarbital-pretreated rats. An approximately 10 times higher inhibitory potency towards aminopyrine N-demethylase activity was observed in acetone-pretreated rats. 5. In spite of the direct interaction of stobadine with microsomal P450, the compound only marginally affected aminopyrine and aniline metabolism both by monooxygenase and peroxidase modes of action of the P450 enzyme system. The potent antioxidant activity of stobadine was not diminished by the ability of the drug to stimulate the oxidase function of P450.