Shen Hongwu, He Minxia M, Liu Houfu, Wrighton Steven A, Wang Li, Guo Bin, Li Chuan
Shanghai Institute of Materia Medica, Graduate School, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai, China.
Drug Metab Dispos. 2007 Aug;35(8):1292-300. doi: 10.1124/dmd.107.015354. Epub 2007 Apr 30.
Polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene are a major cause of pharmacokinetic variability in human. Although the poor metabolizer phenotype is known to be caused by two null alleles leading to absence of functional CYP2D6 protein, the large variability among individuals with functional alleles remains mostly unexplained. Thus, the goal of this study was to examine the intrinsic enzymatic differences that exist among the several active CYP2D6 allelic variants. The relative catalytic activities (enzyme kinetics) of three functionally active human CYP2D6 allelic variants, CYP2D6.1, CYP2D6.10, and CYP2D6.17, were systematically investigated for their ability to metabolize a structurally diverse set of clinically important CYP2D6-metabolized drugs [atomoxetine, bufuralol, codeine, debrisoquine, dextromethorphan, (S)-fluoxetine, nortriptyline, and tramadol] and the effects of various CYP2D6-inhibitors [cocaine, (S)-fluoxetine, (S)-norfluoxetine, imipramine, quinidine, and thioridazine] on these three variants. The most significant difference observed was a consistent but substrate-dependent decease in the catalytic efficiencies of cDNA-expressed CYP2D6.10 and CYP2D6.17 compared with CYP2D6.1, yielding 1.32 to 27.9 and 7.33 to 80.4% of the efficiency of CYP2D6.1, respectively. The most important finding from this study is that there are mixed effects on the functionally reduced allelic variants in enzyme-substrate affinity or enzyme-inhibitor affinity, which is lower, higher, or comparable to that for CYP2D6.1. Considering the rather high frequencies of CYP2D610 and CYP2D617 alleles for Asians and African Americans, respectively, these data provide further insight into ethnic differences in CYP2D6-mediated drug metabolism. However, as with all in vitro to in vivo extrapolations, caution should be applied to the clinical consequences.
细胞色素P450 2D6（CYP2D6）基因多态性是人类药代动力学变异性的主要原因。虽然已知代谢不良表型是由两个导致功能性CYP2D6蛋白缺失的无效等位基因引起的，但具有功能性等位基因的个体之间的巨大变异性在很大程度上仍无法解释。因此，本研究的目的是研究几种活性CYP2D6等位基因变体之间存在的内在酶学差异。系统研究了三种具有功能活性的人类CYP2D6等位基因变体CYP2D6.1、CYP2D6.10和CYP2D6.17代谢一组结构多样的临床重要CYP2D6代谢药物[托莫西汀、丁呋洛尔、可待因、异喹胍、右美沙芬、（S）-氟西汀、去甲替林和曲马多]的相对催化活性（酶动力学），以及各种CYP2D6抑制剂[可卡因、（S）-氟西汀、（S）-去甲氟西汀、丙咪嗪、奎尼丁和硫利达嗪]对这三种变体的影响。观察到的最显著差异是与CYP2D6.1相比，cDNA表达的CYP2D6.10和CYP2D6.17的催化效率一致但依赖于底物地降低，分别为CYP2D6.1效率的1.32%至27.9%和7.33%至80.4%。本研究最重要的发现是，在酶-底物亲和力或酶-抑制剂亲和力方面，对功能降低的等位基因变体存在混合效应，其低于、高于或与CYP2D6.1相当。考虑到亚洲人和非裔美国人中CYP2D610和CYP2D617等位基因的频率分别相当高，这些数据为CYP2D6介导的药物代谢中的种族差异提供了进一步的见解。然而，与所有从体外到体内的推断一样，应谨慎对待其临床后果。
