Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, Sendai, Japan.
Pharmacogenet Genomics. 2010 Jul;20(7):459-62. doi: 10.1097/FPC.0b013e32833bba0e.
Cytochrome P450 2B6 (CYP2B6) is a potentially important enzyme for the metabolism of clinical drugs, and it exhibits genetic polymorphism. Thus far, 29 allelic variants of CYP2B6 (CYP2B61-CYP2B629) have been identified. This study aimed to investigate whether 26 of the variant alleles of CYP2B6 (CYP2B62-CYP2B621 and CYP2B623-CYP2B628) affect its kinetics in the metabolism of 7-ethoxy-4-trifluoromethylcoumarin (7-EFC) and selegiline. Wild-type CYP2B6.1 and the allelic variants were heterologously expressed in COS-7 cells. In-vitro kinetic analysis revealed that when compared with the wild-type protein CYP2B6.1, CYP2B6.10 and CYP2B6.14 exhibited significantly lower V(max)/K(m) values for selegiline N-demethylation. The kinetic parameters of CYP2B6.8, CYP2B6.11, CYP2B6.12, CYP2B6.13, CYP2B6.15, CYP2B6.18, CYP2B6.21, CYP2B6.24, and CYP2B6.28 could not be determined because these enzymes were inactive in the deethylation of 7-EFC and the N-demethylation/N-depropagylation of selegiline. These findings provide useful information for further genotype-phenotype studies on interindividual differences in the metabolism of CYP2B6 substrate drugs.
细胞色素 P450 2B6（CYP2B6）是临床药物代谢的重要酶，具有遗传多态性。迄今为止，已鉴定出 29 种 CYP2B6 的等位基因变异体（CYP2B61-CYP2B629）。本研究旨在探讨 CYP2B6 的 26 种变异等位基因（CYP2B62-CYP2B621 和 CYP2B623-CYP2B628）是否影响其代谢 7-乙氧基-4-三氟甲基香豆素（7-EFC）和司来吉兰的动力学。野生型 CYP2B6.1 和等位基因变异体在 COS-7 细胞中异源表达。体外动力学分析显示，与野生型蛋白 CYP2B6.1 相比，CYP2B6.10 和 CYP2B6.14 对司来吉兰 N-去甲基化的 Vmax/Km 值明显较低。CYP2B6.8、CYP2B6.11、CYP2B6.12、CYP2B6.13、CYP2B6.15、CYP2B6.18、CYP2B6.21、CYP2B6.24 和 CYP2B6.28 的动力学参数无法确定，因为这些酶在 7-EFC 的去乙基化和司来吉兰的 N-去甲基化/N-去丙基化中无活性。这些发现为进一步研究 CYP2B6 底物药物代谢个体间差异的基因型-表型研究提供了有用信息。
