Polymorphic cytochrome p450 2D6: Humanized mouse model and endogenous substrates
Polymorphic cytochrome p450 2D6: Humanized mouse model and endogenous substrates
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DOI：
10.1081/dmr-120034000
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发表时间：
2004-05-01
影响因子：
5.9
通讯作者：
Gonzalez, FJ
中科院分区：
文献类型：
--
作者：
Yu, AM;Idle, JR;Gonzalez, FJ
细胞色素P450 2D6(CYP2D6)是第一个被鉴定的多态的I相药物代谢酶，位于人类染色体22q13.1上，已被鉴定出80多个等位变异。人类脱氢异喹和司马汀的代谢被细分为两种主要的表型-广泛代谢者和不良代谢者-这两种表型来自不同的CYP2D6基因。据估计，CYP2D6参与了超过20%的处方药的代谢和处置，其中大部分作用于中枢神经系统或心脏。这些药物底物的特征是含有一个氮原子的有机碱，与氧化部位的距离约为5、7或10埃。通过静电作用，确定天冬氨酸301和谷氨酸216是底物-酶结合的关键酸性残基。使用包含完整野生型CYP2D6基因的Lambda噬菌体克隆产生的CYP2D6转基因小鼠，显示出增强的去布列异喹的代谢和处置。该转基因小鼠品系及其野生型对照分别是人类广泛代谢者和弱代谢者的模型，在药物发现和开发以及个体化药物治疗的临床实践中将有广泛的应用前景。从5-羟色胺衍生的内源5-甲氧基吲哚-乙胺被鉴定为催化其O-脱甲基化的高亲和力底物，具有很高的酶活性和特异性。因此，多态的CYP2D6可能在这些精神活性色胺的相互转化中发挥重要作用，包括在5-羟色胺-褪黑素循环中的关键步骤。
Cytochrome P450 2D6 (CYP2D6) is the first well-characterized polymorphic phase I drug-metabolizing enzyme, and more than 80 allelic variants have been identified for the CYP2D6 gene, located on human chromosome 22q13.1. Human debrisoquine and sparteine metabolism is subdivided into two principal phenotypes-extensive metabolizer and poor metabolizer-that arise from variant CYP2D6 genotypes. It has been estimated that CYP2D6 is involved in the metabolism and disposition of more than 20% of prescribed drugs, and most of them act in the central nervous system or on the heart. These drug substrates are characterized as organic bases containing one nitrogen atom with a distance about 5, 7, or 10 Angstrom from the oxidation site. Aspartic acid 301 and glutamic acid 216 were determined as the key acidic residues for substrate-enzyme binding through electrostatic interactions. CYP2D6 transgenic mice, generated using a lambda phage clone containing the complete wildtype CYP2D6 gene, exhibits enhanced metabolism and disposition of debrisoquine. This transgenic mouse line and its wild-type control are models for human extensive metabolizers and poor metabolizers, respectively, and would have broad application in the study of CYP2D6 polymorphism in drug discovery and development, and in clinical practice toward individualized drug therapy. Endogenous 5-methoxyindole-thylamines derived from 5-hydroxytryptamine were identified as high-affinity substrates of CYP2D6 that catalyzes their O-demethylations with high enzymatic capacity and specificity. Thus, polymorphic CYP2D6 may play an important role in the interconversions of these psychoactive tryptamines, including a crucial step in a serotonin-melatonin cycle.