Luo Huai-Rong, Gaedigk Andrea, Aloumanis Vasileios, Wan Yu-Jui Yvonne
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Mail Stop 1018, Breidenthal Building, 3901 Rainbow Blvd., Kansas City, KS 66160-7417, USA.
Eur J Clin Pharmacol. 2005 Dec;61(11):797-802. doi: 10.1007/s00228-005-0044-4. Epub 2005 Nov 8.
To extend the genotyping analysis of the CYP2D6 gene and further explain variability of CYP2D6 activity in Mexican Americans by genetic factors.
CYP2D6 gene sequence variations associated with *6, *7, *8, *9, *11, *14, *29, *41, *45, and 46 alleles as well as the 2988G>A SNP were examined in 264 Mexican Americans; 236 had previously been phenotyped with dextromethorphan. All subjects were previously genotyped for CYP2D62, *3, *4, *5, *10, *17, and the presence of a gene duplication. Associations between genotype and CYP2D6 activity were determined.
Mexican Americans revealed a high frequency of functional alleles (CYP2D6*1 and 2; 73.1%), followed by CYP2D64 (non-functional, 10.0%) and the reduced-function allele 41 (9.5%). The frequencies of CYP2D65, *6, *9, 10, duplication, and 2988A were 1.7%, 0.4%, 1.1%, 2.8%, 0.8%, and 5.7%, respectively. CYP2D63, *17, and 29 were found only in one individual (CYP2D62/*3, *1/*17, and *4/29), while CYP2D67, *8, *11, *14, *45, and *46 were absent in this study population. Decreased CYP2D6 activity was more accurately predicted by the presence *41[-1584C] compared to 41[2988A]. One genotype/phenotype discordant subject was resolved by the presence of a CYP2D66 allele (*4/*6), while two other cases remained discordant (*41/*41 and *1/*1).
The CYP2D6*4, *5, and *6 null alleles along the reduced function alleles *9, *10, and *41 are the major cause for diminished dextromethorphan oxidative capacity in Mexican Americans. These findings may have implications for the safety and efficacy of CYP2D6 substrates taken by Mexican Americans.
扩展CYP2D6基因的基因分型分析，并通过遗传因素进一步解释墨西哥裔美国人中CYP2D6活性的变异性。
在264名墨西哥裔美国人中检测了与*6、*7、*8、*9、*11、*14、*29、41、45和46等位基因以及2988G>A单核苷酸多态性相关的CYP2D6基因序列变异；236人之前已用右美沙芬进行了表型分析。所有受试者之前都已对CYP2D62、*3、*4、*5、*10、*17以及基因重复情况进行了基因分型。确定了基因型与CYP2D6活性之间的关联。
墨西哥裔美国人中功能性等位基因（CYP2D61和2；73.1%）的频率较高，其次是CYP2D64（无功能，10.0%）和功能降低的等位基因41（9.5%）。CYP2D6*5、*6、9、10、基因重复以及2988A的频率分别为1.7%、0.4%、1.1%、2.8%、0.8%和5.7%。仅在一名个体中发现了CYP2D63、17和29（CYP2D62/*3、*1/17和4/29），而在本研究人群中未发现CYP2D67、*8、*11、14、45和46。与41[2988A]相比，41[-1584C]的存在能更准确地预测CYP2D6活性降低。一名基因型/表型不一致的受试者通过存在CYP2D66等位基因（*4/*6）得到了解决，而另外两例仍不一致（*41/41和1/*1）。
CYP2D64、5和6无效等位基因以及功能降低的等位基因9、10和41是墨西哥裔美国人右美沙芬氧化能力降低的主要原因。这些发现可能对墨西哥裔美国人服用的CYP2D6底物的安全性和有效性有影响。
