Regioselective contribution of the cytochrome P-450 2D subfamily to propranolol metabolism in rat liver microsomes.
The metabolism of propranolol was examined by using microsomes from Dark Agouti rats known as a poor-metabolizer animal model for debrisoquine 4-hydroxylation and Wistar rats. Propranolol 4- and 5-hydroxylations followed biphasic Michaelis-Menten kinetics, and 7-hydroxylation and N-desisopropylation were monophasic in both strains. The kinetic studies showed that the Vmax for propranolol 7-hydroxylase activity and the Vmax of high-affinity phases for propranolol 4- and 5-hydroxylase activities were markedly low in Dark Agouti rats compared with those in Wistar rats. The antibody against a cytochrome P-450 isozyme, P-450BTL (Suzuki, T., et al., Drug Metab. Dispos. 20, 367-373, 1992), belonging to the CYP2D subfamily, inhibited by 90% propranolol 4-, 5-, and 7-hydroxylase activities in liver microsomes from male Wistar rats at a low propranolol concentration (5 microM). However, less inhibitory effects of the antibody on propranolol 4- and 5-hydroxylase activities were observed at a high propranolol concentration (1 mM), whereas a similar inhibitory effect of the antibody on propranolol 7-hydroxylase activity was shown. The antibody inhibited propranolol N-desisopropylase activity, but less extent of the inhibition on this activity than those on ring-hydroxylase activities was observed at the low and high propranolol concentrations. These results indicate that a polymorphic cytochrome P-450 isozyme(s) belonging to the CYP2D subfamily is involved predominantly in propranolol 4-, 5-, and 7-hydroxylations at low substrate concentrations in the rat.
Masubuchi
Y
Y
Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Kagimoto
N
N
Narimatsu
S
S
Fujita
S
S
Suzuki
T
T
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D003647:Debrisoquin / Q000378:metabolism; D005260:Female; D006900:Hydroxylation; D007074:Immunoglobulin G / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008954:Models, Biological; D011433:Propranolol / Q000031:analogs & derivatives / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D013237:Stereoisomerism
D000906:Antibodies; D065607:Cytochrome P-450 Enzyme Inhibitors; D007074:Immunoglobulin G; D007527:Isoenzymes; C012878:N-desisopropylpropranolol; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; D003647:Debrisoquin