In vitro metabolic characteristics of cytochrome P-450 2A6 in Chinese liver microsomes  

中国人肝微粒体细胞色素P450 2A6的体外代谢特征(英文)

作　　者：夏雪雁[1] 彭仁琇[1] 于皆平[2] 汪晖[1] 王君[1] 

机构地区：[1]武汉大学医学院药理教研室,武汉430071 [2]武汉大学人民医院消化内科,武汉中国430060

出　　处：《Acta Pharmacologica Sinica》2002年第5期471-476,共6页中国药理学报（英文版）

摘　　要：AIM: To investigate the metabolic characteristics of cytochrome P-450 CYP2A6 in human liver microsomes. METHODS: Cytochrome P-450 enzyme activities were measured by biochemical assays. Xenobiotics were employed to observe their effects on CYP2A6 in vitro. The kinetics of coumarin 7-hydroxylase was determined, and the correlation between CYP2A6 and UDP-glucuro-nosyltransferase (UGT) was analyzed. RESULTS: CYP2A6 activities of human liver microsomes were from 0.47 to 4.14 μmol ·min-1 · g-1, with a 8.8-fold variation. The Km and Vmax of CYP2A6 ranged from 0.25 to 1.56 μmol·L-1 and 1.41 to 8.70 μmol·min-1. g-1, respectively. CYP2A6 activity was markedly inhibited ( > 50 % ) by pilocarpine, diethyldithio car-bamic (DDC), and rifampicin, the IC50 was 5.31 μmol· L-1, 156.35 μmol·L-1, and 38.81 μmol·L-1, respectively. α-Naphthoflavone, sulfaphenazole, troleando-mycin (TAO), ketoconazole, phenobarbital, predniso-lone, and azithromycin had little or no effects on coumarin 7-hydroxylation. A significant correlation was observed between CYP2A6 and UGT2 ( r = 0.9453, P < 0.05). CONCLUSION: CYP2A6 activity and kinetics exhibited a considerable variation in human liver microsomes in vitro, and a significant correlation was existed between CYP2A6 and phase Ⅱ enzyme UGT2. Not only pilocarpine, CYP2A6 specific inhibitor, but also rifampicin and DDC inhibited CYP2A6 activity selectively.目的:观察人肝微粒体CYP2A6动力学特征.方法:采用生化分析法,体外研究化学异物对CYP2A6酶活性的影响.测定香豆素7-羟化酶的动力学参数.同时分析CYP2A6与Ⅱ相酶UGT之间的相关性.结果:CYP2A6活性差异8.8倍,K_m和V_(max)分别为0.25-1.56μmol·L^(-1)、1.41-8.70μmol·min^(-1)·g^(-1).匹鲁卡品、二乙基二硫代氨基甲酸盐、利福平明显抑制CYP2A6活性,IC_(50)值分别为 5.31μmol·L^(-1)、156.35μmol·L^(-1)和38.81μmol·L^(-1).α-萘黄酮、磺胺苯吡唑、醋竹桃霉素、酮康唑、泼尼松龙和阿奇霉素对香豆素7-羟化反应几乎无影响.CYP2A6与UGT_2之间存在显著相关性(r=0.9453,P<0.05).结论:中国人细胞色素P4502A6酶活性及动力学参数存在个体差异,CYP2A6与UGT_2之间有显著相关.除匹鲁卡品有CYP2A6选择性抑制作用外,利福平和二乙基二硫代氨基甲酸盐也明显抑制CYP2A6活性.

关 键 词：cytochrome P-450 CYP2A6 couma- rins GLUCURONOSYLTRANSFERASE liver microsomes rifampi- cin 

分 类 号：R96[医药卫生—药理学]