Xenobiotic and endobiotic inhibitors of cytochrome P-450dbl function, the target of the debrisoquine/sparteine type polymorphism

Abstract

Five to 10% of Caucasians are poor metabolizers (PM) of debrisoquine, sparteine, bufuralol and numerous other drugs. A deficiency in cytochrome P-450dbl (P-450dbl) function is the cause of this polymorphism of drug oxidation with autosomal recessive inheritance. In the present study, inhibition of bufuralol-1'-hydroxylase in human liver microsomes by drugs and chemicals was performed in a search for potential new substrates for this polymorphic enzyme. Among the 80 alkaloids and drugs tested, 25 were competitive inhibitors. In vitro competitive inhibition of bufuralol oxidation by a substance indicates that this compound is able to bind to the same enzymatic site as bufuralol. This may mean that the competing drug also is metabolized by P-450dbl and that its metabolism is subject to the same genetic variation as the oxidation of bufuralol. However, some of these competitive inhibitors are not oxidized by P-450dbl. In this case, however, they may interfere with the in vivo phenotyping procedure by inhibiting the formation of metabolites of test drugs such as debrisoquine, sparteine, metoprolol or dextrometorphan.