University of Connecticut, Storrs, USA.
J Toxicol Environ Health B Crit Rev. 2009;12(5-6):334-61. doi: 10.1080/10937400903158342.
Cytochrome P-450 2D6 (CYP2D6) is involved in the metabolism of many therapeutic drugs even though the enzyme represents a small proportion of the total CYP content of human liver. In vivo phenotyping with probe drug substrates such as debrisoquine and dextromethorphan showed a clear separation between poor metabolizers (PM) and extensive metabolizers (EM). This polymorphism may affect susceptibility to environmental disease, as suggested by molecular epidemiologic studies that found an association between CYP2D6 metabolizer phenotype and cancer risk; however, this association is not consistent. There are only a few examples of CYP2D6 involvement in toxicant mechanism of action, but this has not been extensively studied. Gene probe studies documented a number of genetic polymorphisms that underlie CYP2D6 metabolizer phenotypes. The EM group carries the wild-type (*1) or active (*2) variant alleles, while the PM group carries the *3, *4, *5, or *6 alleles, all of which code for a protein that has lower or null CYP2D6 activity. The current analysis characterizes (a) influence of genotype on phenotype based upon in vivo metabolism studies of probe drugs and (b) frequency of the major genotypes in different population groups is also characterized. These data were then incorporated into Monte Carlo modeling to simulate population distributions of CYP2D6 activity. This analysis reproduced the bimodal distributions commonly seen in phenotyping studies of Caucasians and found extensive population variability in enzyme activity, as indicated by the 9- to 56-fold difference between the PM modal median and the total population median CYP2D6 activity. This substantial degree of interindividual variability in CYP function indicates that assessments involving CYP2D6 substrates need to consider the full distribution of enzyme activity in refining estimates of internal dose in health assessments of xenobiotics.
细胞色素 P-450 2D6（CYP2D6）参与许多治疗药物的代谢，尽管该酶仅占人类肝脏总 CYP 含量的一小部分。使用探针药物底物（如地昔帕明和右美沙芬）进行体内表型研究表明，弱代谢者（PM）和广泛代谢者（EM）之间存在明显差异。这种多态性可能会影响对环境疾病的易感性，正如分子流行病学研究表明 CYP2D6 代谢表型与癌症风险之间存在关联所表明的那样；然而，这种关联并不一致。只有少数 CYP2D6 参与毒物作用机制的例子，但这并没有得到广泛研究。基因探针研究记录了许多导致 CYP2D6 代谢表型的遗传多态性。EM 组携带野生型（*1）或活性（2）变体等位基因，而 PM 组携带3、*4、5 或6 等位基因，所有这些等位基因编码的蛋白质均具有较低或无 CYP2D6 活性。目前的分析描述了（a）基于探针药物体内代谢研究的基因型对表型的影响，以及（b）不同人群群体中主要基因型的频率特征。然后将这些数据纳入蒙特卡罗建模中，以模拟 CYP2D6 活性的人群分布。该分析再现了在白种人表型研究中常见的双峰分布，并发现了酶活性的广泛人群变异性，这表明 PM 模态中位数和总人群 CYP2D6 活性中位数之间的差异高达 9 至 56 倍。CYP 功能的这种显著个体间变异性表明，涉及 CYP2D6 底物的评估需要考虑酶活性的全部分布，以在对外源物健康评估中的内剂量估计中细化评估。
