Cytochrome P450 isozymes involved in propranolol metabolism in human liver microsomes. The role of CYP2D6 as ring-hydroxylase and CYP1A2 as N-desisopropylase

• Published in: Drug metabolism and disposition Vol. 22; no. 6; p. 909
• Main Authors: Masubuchi, Y, Hosokawa, S, Horie, T, Suzuki, T, Ohmori, S, Kitada, M, Narimatsu, S
• Format: Journal Article
• Language: English
• Published: United States 01.11.1994
• Subjects: Benzoflavones - pharmacology; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - analysis; Cytochrome P-450 Enzyme System - physiology; Humans; Hydroxylation; Isoenzymes - physiology; Male; Microsomes, Liver - metabolism; Mixed Function Oxygenases - analysis; Mixed Function Oxygenases - physiology; Oxidoreductases - analysis; Oxidoreductases - physiology; Propranolol - metabolism; Quinidine - pharmacology
• ISSN: 0090-9556

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.