Masubuchi, Y; Hosokawa, S; Horie, T; Suzuki, T; Ohmori, S; Kitada, M; Narimatsu, S
Oxidative metabolic pathways of propranolol consist of
naphthalene ring-hydroxylations (at the 4-, 5-, and 7-positions) and side-chain N-
desisopropylation in mammals. We characterized cytochrome P450 isozymes responsible for
propranolol metabolism, especially N-desisopropylation and 5-hydroxylation, in human liver
microsomes. 4-Hydroxy, 5-hydroxy-, and N-desisopropylpropranolol were detected as primary
metabolites, whereas 7-hydroxypropranolol was in trace amounts. Good correlations were obtained
for activities of propranolol 4- and 5-hydroxylases with immunochemically determined CYP2D6
content, whereas correlations of these activities with CYP1A2, CYP2C, or CYP3A4 content were
relatively low. The activities also correlated highly with debrisoquine 4-hydroxylase, compared
with other metabolic activities such as phenacetin O-deethylase, hexobarbital 3'-hydroxylase,
and testosterone 6 beta-hydroxylase, which are typical reactions for CYP1A2, CYP2C, and CYP3A4,
respectively. Propranolol N-desisopropylase activity in the samples highly correlated with CYP1A2
content and phenacetin O-deethylase activity, but not with the other P450 isozyme contents or
metabolic activities. Quinidine, a specific inhibitor of CYP2D6, inhibited propranolol 4- and 5-
hydroxylase activities selectively and in a concentration-dependent manner. alpha-Naphthoflavone,
a potent inhibitor of CYP1A2, inhibited all of the propranolol oxidation activities, and the IC50
value for N-desisopropylase activity was much smaller than the values for ring-hydroxylase
activities. Antibody directed to CYP2D inhibited propranolol 4- and 5-hydroxylase activities by
70% at an antibody/microsomal protein ratio of 1.0. Anti-CYP2C9 antibody did not inhibit any
activity determined. These results indicate that propranolol 5-hydroxylation, as well as 4-
hydroxylation, is mainly catalyzed by CYP2D6 in human liver microsomes. Furthermore, CYP1A2,
rather than S-mephenytoin 4-hydroxylase, seems to be responsible for propranolol N-
desisopropylation.