Comparison of cytochrome P450 2D6 and variants in terms of drug oxidation rates and substrate inhibition.
Comparison of cytochrome P450 2D6 and variants in terms of drug oxidation rates and substrate inhibition.
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DOI：
10.2174/138920011795495286
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发表时间：
2011-05
影响因子：
2.3
通讯作者：
T. Niwa;N. Murayama;H. Yamazaki
中科院分区：
文献类型：
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作者：
T. Niwa;N. Murayama;H. Yamazaki
本文就CYP 2D 6基因多态性对CYP 2D 6重要活性位点残基的识别作一综述。对报告的文献进行了荟萃分析，内容涉及（1）人细胞色素P450 2D 6及其变体和突变体介导的31种底物的41种代谢反应的米氏常数（K（m））、最大速度（V（max））和固有清除率（V（max）/K（m））值，以及（2）15种抑制剂的抑制常数（K（i））。相对于野生型的V（max）/K（m）值的平均比值（CYP2D6.1）适用于CYP2D6.2（R296C/S486T），CYP2D6.10（P34 S/S486 T），CYP2D6.17（T107 I/R296 C/S486 T），CYP2D6.31（R296 C/R440 H/S486 T）、CYP 2D6.34（R296 C）、CYP 2D6.36（P34 S/S486 T和6个其他氨基酸取代），CYP2D6.49 P34 S/F120 I/S486 T），P34 S和G42 R突变体（但非CYP2D6.39（S486 T））在0.03-0.61范围内，中位比值在0.03-0.57范围内。超过90%的CYP 2D6.10、CYP 2D6.17和CYP 2D6.36的V（max）/K（m）值小于CYP 2D6.1的一半。此外，这些变体的20-59%的V（max）/K（m）值小于野生型的十分之一。这些结果表明，CYP 2D 6多态性可能会影响许多化合物的代谢活性。然而，这些变异体和突变体的动力学行为依赖于代谢反应。许多CYP2D6.10和CYP2D6.17抑制剂的K（i）值与CYP2D6.1相当或更高。总的来说，这些发现提供了深入了解CYP 2D 6多态性对药物代谢和药物不良相互作用的贡献。
This review focuses on identification of the important active site residues of CYP2D6 in terms of CYP2D6 polymorphism. A meta-analysis was performed on the reported literature regarding (1) values of the Michaelis-Menten constant (K(m)), maximal velocity (V(max)), and intrinsic clearance (V(max)/K(m)) for 41 metabolic reactions of 31 substrates mediated by human cytochrome P450 2D6 and its variants and mutants and (2) inhibition constants (K(i)) for 15 inhibitors. The mean ratios of V(max)/K(m) values with respect to the wild type (CYP2D6.1) for CYP2D6.2 (R296C/S486T), CYP2D6.10 (P34S/S486T), CYP2D6.17 (T107I/R296C/S486T), CYP2D6.31 (R296C/R440H/S486T), CYP2D6.34 (R296C), CYP2D6.36 (P34S/S486T and 6 other amino acids substitutions), CYP2D6.49 (P34S /F120I/S486T), and P34S and G42R mutants but not CYP2D6.39 (S486T) were in the range 0.03-0.61, and the median ratios were in the range 0.03-0.57. More than 90% of V(max)/K(m) values for CYP2D6.10, CYP2D6.17, and CYP2D6.36 were less than half of those for CYP2D6.1. In addition, 20-59% of V(max)/K(m) values for these variants were less than one-tenth those of the wild type. These results suggest that the CYP2D6 polymorphism may affect the metabolic activities of many compounds. However, the kinetic behaviors of these variants and mutants depended on the metabolic reaction. The K(i) values of many of the inhibitors of CYP2D6.10 and CYP2D6.17 were comparable with or higher than those for CYP2D6.1. Collectively, these findings provide insights into the contributions of CYP2D6 polymorphisms to drug metabolism and adverse drug interactions.