CYP3A5 Contributes significantly to CYP3A-mediated drug oxidations in liver microsomes from Japanese subjects.
CYP3A5 Contributes significantly to CYP3A-mediated drug oxidations in liver microsomes from Japanese subjects.
复制标题
DOI：
10.2133/dmpk.19.120
复制
发表时间：
2004-04-01
影响因子：
2.1
通讯作者：
Kamataki, Tetsuya
中科院分区：
文献类型：
--
作者：
Yamaori, Satoshi;Yamazaki, Hiroshi;Kamataki, Tetsuya
本研究的目的是评估多态性细胞色素 P450 (CYP) 3A5 对日本受试者肝微粒体氧化地尔硫卓、咪达唑仑和睾酮的贡献。 27份肝脏样本根据CYP3A5基因型分为三组； CYP3A5(*)1/(*)1 (n=3)、(*)1/(*)3 (n=12) 和 (*)3/(*)3 (n=12)。 CYP3A5蛋白的基因分型和免疫化学定量结果显示，肝微粒体中CYP3A5基因型和CYP3A5含量之间具有良好的一致性，但与CYP3A4含量之间没有一致性。在具有至少一种野生型等位基因的受试者中，肝脏CYP3A5蛋白的表达水平为CYP3A4和CYP3A5含量之和的20%至60%（(*)1）。在携带至少一个(*)1等位基因的受试者中，CYP3A5含量与地尔硫卓N-去甲基化、咪达唑仑1'-和4-羟基化以及睾酮6β-羟基化的肝微粒体活性密切相关。此外，CYP3A5含量与地尔硫卓N-去甲基化率、咪达唑仑1'-羟基化率和睾酮6β-羟基化率的相关系数均高于CYP3A4，尽管CYP3A5与咪达唑仑4-羟基化率的值与CYP3A4相似。动力学分析显示携带 (*)1 等位基因的受试者的肝微粒体中存在双相地尔硫卓 N-去甲基化。重组CYP3A5的表观V(max)/K(m)值表明与CYP3A4相比，对地尔硫卓N-去甲基化和咪达唑仑1'-羟基化的贡献更大。这些结果表明，多态性 CYP3A5 对日本受试者肝微粒体的药物氧化，尤其是地尔硫卓 N-去甲基化、咪达唑仑 1'-羟基化和睾酮 6β-羟基化有显着贡献。
The purpose of this study was to evaluate a contribution of polymorphic cytochrome P450 (CYP) 3A5 to the oxidation of diltiazem, midazolam and testosterone by liver microsomes from Japanese subjects. Twenty-seven liver samples were classified into three groups according to the CYP3A5 genotypes; CYP3A5(*)1/(*)1 (n=3), (*)1/(*)3 (n=12) and (*)3/(*)3 (n=12). The results of genotyping and immunochemical quantitation of CYP3A5 protein showed a good accordance between the CYP3A5 genotype and CYP3A5 content but not CYP3A4 content in liver microsomes. The expression levels of hepatic CYP3A5 protein ranged from 20 to 60% of the sum of CYP3A4 and CYP3A5 contents in subjects with at least one wild type allele ((*)1). The CYP3A5 contents correlated well with liver microsomal activities of diltiazem N-demethylation, midazolam 1'- and 4-hydroxylations and testosterone 6beta-hydroxylation among subjects carrying at least one (*)1 allele. In addition, the correlation coefficients of CYP3A5 contents with the rates of diltiazem N-demethylation, midazolam 1'-hydroxylation and testosterone 6beta- hydroxylation were higher than those of CYP3A4, although the value of CYP3A5 with the midazolam 4-hydroxylation rate was similar to that of CYP3A4. Kinetic analyses revealed a biphasic diltiazem N-demethylation in liver microsomes from subjects carrying the (*)1 allele. The apparent V(max)/K(m) values for recombinant CYP3A5 indicated the greater contributions to diltiazem N-demethylation and midazolam 1'-hydroxylation as compared with CYP3A4. These results suggest that polymorphic CYP3A5 contributes markedly to the drug oxidations, particularly diltiazem N-demethylation, midazolam 1'- hydroxylation and testosterone 6beta-hydroxylation by liver microsomes from Japanese subjects.