Masubuchi Y, Hosokawa S, Horie T, Suzuki T, Ohmori S, Kitada M, Narimatsu S
Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba University Japan.
Drug Metab Dispos. 1994 Nov-Dec;22(6):909-15.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
在哺乳动物体内，普萘洛尔的氧化代谢途径包括萘环羟基化（在4、5和7位）以及侧链N - 去异丙基化。我们对人肝微粒体中负责普萘洛尔代谢的细胞色素P450同工酶进行了表征，尤其关注N - 去异丙基化和5 - 羟基化。检测到4 - 羟基、5 - 羟基和N - 去异丙基普萘洛尔为主要代谢产物，而7 - 羟基普萘洛尔含量极少。普萘洛尔4 - 羟化酶和5 - 羟化酶的活性与免疫化学测定的CYP2D6含量具有良好的相关性，而这些活性与CYP1A2、CYP2C或CYP3A4含量的相关性相对较低。与其他代谢活性（如分别为CYP1A2、CYP2C和CYP3A4典型反应的非那西丁O - 脱乙基酶、己巴比妥3'-羟化酶和睾酮6β - 羟化酶）相比，这些活性与去甲丙咪嗪4 - 羟化酶也高度相关。样品中的普萘洛尔N - 去异丙基酶活性与CYP1A2含量和非那西丁O - 脱乙基酶活性高度相关，但与其他P450同工酶含量或代谢活性无关。CYP2D6的特异性抑制剂奎尼丁以浓度依赖性方式选择性抑制普萘洛尔4 - 和5 - 羟化酶活性。CYP1A2的强效抑制剂α - 萘黄酮抑制所有普萘洛尔氧化活性，且N - 去异丙基酶活性的IC50值远小于环羟化酶活性的值。针对CYP2D的抗体在抗体/微粒体蛋白比为1.0时，抑制普萘洛尔4 - 和5 - 羟化酶活性达70%。抗CYP2C9抗体未抑制任何测定的活性。这些结果表明，在人肝微粒体中，普萘洛尔的5 - 羟基化以及4 - 羟基化主要由CYP2D6催化。（摘要截短至250字）
