Bufuralol 1'-hydroxylase activity of the rat: Strain differences and the effects of inhibitors

Abstract

The kinetics of bufuralol 1'-hydroxylase activity of hepatic microsomal fractions have been determined in female DA and Fischer 344 rats, strains between which there is a large difference in debrisoquine 4-hydroxylase activity. Two components of bufuralol 1'-hydroxylase activity could be observed in both strains. Although there were differences between the strains in V max and K m of both components of activity, these were much less marked than the differences previously reported for debrisoquine 4-hydroxylase (Kahn et al., Drug Metab. Dispos. 13, 510 (1985)). The kinetics of bufuralol 1'-hydroxylase activity were such that the difference in activity between the strains varied with the concentration of bufuralol, 4–5-fold at 2.5 μM, no difference at 100 μM. Competitive inhibitors of debrisoquine 4-hydroxylase activity in man were competitive inhibitors of bufuralol 1'-hydroxylase activity in the Fischer 344 rat, but not in the DA rat. The K i for inhibition of bufuralol 1'-hydroxylase activity by debrisoquine in the Fischer 344 rat was 184 μM, compared with a K m for the 4-hydroxylation of this compound of 10.5 μM. It is concluded that the major isozyme of cytochrome P-450 catalysing the 1'-hydroxylation of bufuralol in the rat is different from that catalysing debrisoquine 4-hydroxylation (P-450 ut-h).