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

Abstract

1. A sensitive, specific assay utilizing fluorescence-HPLC has been developed for determining the 1′-hydroxylation of bufuralol by human liver. 2. The 1′-hydroxylation of the isomers of bufuralol varied threefold, both the V max and the K m for the (+) isomer being greater than the corresponding values for the (−) isomer. 3. Debrisoquine was a competitive inhibitor of the 1′-hydroxylation of both isomers and of the racemate of bufuralol. 4. Both isomers and the racemate of bufuralol were competitive inhibitors of debrisoquine 4- hydroxylase activity. 5. The competitive inhibition of debrisoquine and bufuralol of each other's metabolism, together with the similarity in the values for K m and K i support the conclusion that the same form of cytochrome P-450 catalyses these two reactions.