Genetic polymorphism in drug oxidation: in vitro studies of human debrisoquine 4-hydroxylase and bufuralol 1'-hydroxylase activities

Abstract

A sensitive, specific assay utilizing fluorescence-HPLC has been developed for determining the 1'-hydroxylation of bufuralol by human liver. The 1'-hydroxylation of the isomers of bufuralol varied threefold, both the Vmax and the Km for the (+) isomer being greater than the corresponding values for the (-) isomer. Debrisoquine was a competitive inhibitor of the 1'-hydroxylation of both isomers and of the racemate of bufuralol. Both isomers and the racemate of bufuralol were competitive inhibitors of debrisoquine 4-hydroxylase activity. The competitive inhibition of debrisoquine and bufuralol of each other's metabolism, together with the similarity in the values for Km and Ki, support the conclusion that the same form of cytochrome P-450 catalyses these two reactions.