Phenacetin O-deethylase: an activity of a cytochrome P-450 showing genetic linkage with that catalysing the 4-hydroxylation of debrisoquine?

Abstract

Phenacetin O-deethylase activity was impaired, both in vivo and in vitro, in poor metabolisers of debrisoquine, consistent with the work of others. No impairment was observed in the oxidation of acetanilide, amylobarbitone or antipyrine in the PM phenotype. There was a good correlation (r = 0.804) between the high affinity component of phenacetin O-deethylase and debrisoquine 4-hydroxylase activities. No such correlation was observed with the low affinity component of phenacetin O-deethylase activity. Although debrisoquine was a competitive inhibitor of phenacetin O-deethylase activity, phenacetin was without effect on debrisoquine 4-hydroxylation. There was also marked differences in the effects of sparteine, guanoxan and alpha-naphthoflavone on the two activities. Cigarette smoking was associated with a significant, two-fold, increase in phenacetin O-deethylase activity whilst debrisoquine 4-hydroxylase activity was not affected. It is concluded that the high affinity component of phenacetin O-deethylase and debrisoquine 4-hydroxylase activities are catalysed by different isozymes of cytochrome P-450 but that these are most probably regulated by closely linked genes.