The 1'-hydroxylation of rac-bufuralol, which is catalyzed by polymorphic CYP2D6 in humans, was studied in brain microsomes from male and female Wistar rats and from the female Dark Agouti rat, a model of the CYP2D6 poor metabolizer phenotype. The kinetics of the 1'-hydroxylation of bufuralol (1-1500 microM) by brain microsomes were biphasic. The activity of the high-affinity site of metabolism was consistent with Michaelis-Menten kinetics (apparent K(m1) = 0. 61-1.42 microM, V(max1) = 4.3-4.8 fmol/min/mg of protein), whereas the low-affinity activity was better described by a Hill function (K(50%(2)) = 253-258 microM, V(max2) = 817-843 fmol/min/mg of protein, n = 1.2-1.3). Values for kinetic constants were similar in all rat strains. Quinine was only a weak inhibitor of both the high- (apparent K(i) = 90 microM) and low-affinity (210 microM) sites of metabolism. In contrast, the kinetics of 1'-hydroxylation of bufuralol by rat liver microsomes were best described by a two-site Michaelis-Menten function. V(max) values were 3 to 5 orders of magnitude greater compared with those for brain microsomes (male and female Wistar), and liver microsomes from female Dark Agouti rats were significantly less active than those from Wistar rats. These data, together with the known potent inhibitory effect of quinine on bufuralol 1'-hydroxylation by rat liver microsomes, indicate tissue-specific differences in the enzymology of this reaction. The role of brain CYP2D enzymes remains to be clarified.