慢性肝病中CYP2C19和CYP3A的体内代谢活性与CYP2C19基因多态性的关系

In vivo metabolic activity of CYP2C19 and CYP3A in relation to CYP2C19 genetic polymorphism in chronic liver disease.

作者信息

Ohnishi Akihiro, Murakami Shigeto, Akizuki Setsuko, Mochizuki Junko, Echizen Hirotoshi, Takagi Ichiro

机构信息

Department of Laboratory Medicine, Daisan Hospital, Jikei University School of Medicine, 4-11-1 Izumihonchyo, Komae, Tokyo 201-8601, Japan.

出版信息

J Clin Pharmacol. 2005 Nov;45(11):1221-9. doi: 10.1177/0091270005280787.

DOI:10.1177/0091270005280787

PMID:16239354

Abstract

To study whether chronic liver disease (CLD) and genetic polymorphism affect the hepatic activity of cytochrome P450 (CYP) isoforms, we compared in vivo CYP2C19 and CYP3A activities using 3-hour omeprazole hydroxylation index (plasma concentration ratio of omeprazole to its 5-hydroxylated metabolite; a higher index indicates lower CYP2C19 activity) and partial formation clearance of cortisol to 6beta-hydroxycortisol (CL(cortisol-->6beta-HC)) in 31 CLD patients (9 with chronic hepatitis; 22 with cirrhosis comprising 20 Child-Pugh type A, 1 type B, and 1 type C) and 30 healthy subjects with different CYP2C19 genotypes. The mean (+/-SEM) omeprazole hydroxylation index in CLD patients with homozygous extensive metabolizer (EM) genotype (*1/*1, n = 8), heterozyous EM (*1/*2, n = 11; *1/*3, n = 6) genotypes and poor metabolizer (PM) genotypes (*2/*2, n = 3; *3/*3, n = 3) were 17.15 +/- 2.12, 20.02 +/- 2.63, and 26.04 +/- 3.15, respectively, which were significantly higher compared with control subjects with the corresponding CYP2C19 genotypes (0.81 +/- 0.09, 1.55 +/- 0.20, and 15.5 +/- 1.52). CLD patients with PM genotype had significantly (P < .05) higher omeprazole hydroxylation indexes than did those with homozygous EM genotype, and those with heterozygous EM genotypes had intermediate values. The mean CL(cortisol-->6beta-HC) decreased significantly (P < .001) in CLD patients compared with control subjects (1.19 +/- 0.12 versus 2.26 +/- 0.24 mL/min). Multiple regression analysis showed that CLD, serum albumin level, and CYP2C19 genotype correlated significantly (P < .05) with the omeprazole hydroxylation index, whereas no significant correlation was observed between CL(cortisol-->6beta-HC) and other variables, except CLD. Because CLD and genetic polymorphism of CYP2C19 act additively to reduce CYP2C19 activity, genotyping these patients may be of value in averting adverse reactions of drugs that depend on CYP2C19 for elimination.

摘要

为研究慢性肝病（CLD）和基因多态性是否影响细胞色素P450（CYP）同工酶的肝脏活性，我们使用3小时奥美拉唑羟化指数（奥美拉唑与其5-羟基代谢产物的血浆浓度比；指数越高表明CYP2C19活性越低）和皮质醇向6β-羟基皮质醇的部分生成清除率（CL(皮质醇→6β-HC)），比较了31例CLD患者（9例慢性肝炎患者；22例肝硬化患者，包括20例Child-Pugh A级、1例B级和1例C级）和30例具有不同CYP2C19基因型的健康受试者体内的CYP2C19和CYP3A活性。纯合子广泛代谢型（EM）基因型（*1/*1，n = 8）、杂合子EM（*1/*2，n = 11；*1/*3，n = 6）基因型和慢代谢型（PM）基因型（*2/*2，n = 3；*3/*3，n = 3）的CLD患者的平均（±SEM）奥美拉唑羟化指数分别为17.15±2.12、20.02±2.63和26.04±3.15，与具有相应CYP2C19基因型的对照受试者（0.81±0.09、1.55±0.20和15.5±1.52）相比显著更高。PM基因型的CLD患者的奥美拉唑羟化指数显著高于（P <.05）纯合子EM基因型的患者，杂合子EM基因型的患者指数处于中间值。与对照受试者相比，CLD患者的平均CL(皮质醇→6β-HC)显著降低（P <.001）（1.19±0.12对2.26±0.24 mL/min）。多元回归分析显示，CLD、血清白蛋白水平和CYP2C19基因型与奥美拉唑羟化指数显著相关（P <.05），而除CLD外，未观察到CL(皮质醇→6β-HC)与其他变量之间存在显著相关性。由于CLD和CYP2C19基因多态性共同作用降低CYP2C19活性，对这些患者进行基因分型可能有助于避免依赖CYP2C19进行消除的药物的不良反应。