Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo
Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo
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DOI：
10.1016/j.clpt.2004.11.112
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发表时间：
2005-05-01
影响因子：
6.7
通讯作者：
von Moltke, LL
中科院分区：
文献类型：
--
作者：
He, P;Court, MH;von Moltke, LL
在遗传水平上研究了细胞色素P450 (CYP) 3A代谢活性的广泛个体间差异的分子基础。对26名健康受试者口服单剂量咪达唑仑。咪达唑仑口服清除率的变异性为11倍。未观察到咪达唑仑口服清除率与性别或种族相关的差异。对CYP3A4和CYP3A5基因进行选择性测序，发现18个单核苷酸多态性（snp），其中8个为CYP3A4新snp。还鉴定出13个CYP3A4新单倍型、2个CYP3A5新单倍型和1个主要的多基因单倍型（CYP3A4*VI-CYP3A5*3A）。即使考虑种族，也没有发现任何snp或单倍型的基因型-表型或单倍型-表型关联，包括CYP3A4*1B， CYP3A5*3和CYP3A5*6。唯一的例外是单倍型CYP3A4*VI和多基因单倍型CYP3A4*VI- cyp3a5 *3A。单倍型CYP3A4*VI携带者对咪达唑仑的清除率比其他人群高1.8倍（方差分析，P = 0.028），多基因单倍型CYP3A4*VI- cyp3a5 *3A携带者对咪达唑仑的清除率比其他人群高1.7倍（方差分析，P = 0.012）。综上所述，这些结果表明，目前在CYP3A4和CYP3A5基因中发现的遗传变异对cyp3a介导的体内药物代谢的影响有限。
The molecular basis for the wide interindividual variability of cytochrome P450 (CYP) 3A metabolic activity was studied in vivo at a genetic level. A single oral dose of midazolam was administered to 26 healthy subjects. The variability in midazolam oral clearance was 11-fold. No differences in midazolam oral clearance related to gender or ethnicity were observed. Selective sequencing of CYP3A4 and CYP3A5 genes revealed 18 single nucleotide polymorphisms (SNPs), including 8 novel CYP3A4 SNPs. Thirteen novel CYP3A4 haplotypes, 2 novel CYP3A5 haplotypes, and 1 major novel multigene haplotype (CYP3A4*VI-CYP3A5*3A) were also identified. No significant genotype-phenotype or haplotype-phenotype associations were found for any of the SNPs or haplotypes studied, including CYP3A4*1B, CYP3A5*3, and CYP3A5*6, even when ethnicity was considered. The only exceptions were the haplotype CYP3A4*VI and the multigene haplotype CYP3A4*VI-CYP3A5*3A. The carriers of the haplotype CYP3A4*VI had a 1.8-fold higher clearance of midazolam in black subjects (ANOVA on ranks, P = .028) compared with other individuals, and the carriers of the multigene haplotype CYP3A4*VI-CYP3A5*3A had a 1.7-fold higher clearance in the entire population (ANOVA on ranks, P = .012). In conclusion, these results indicate that the genetic variants identified so far in the CYP3A4 and CYP3A5 genes have only a limited impact on CYP3A-mediated drug metabolism in vivo.