Two Novel CYP2D6*10 Haplotypes As Possible Causes of a Poor Metabolic Phenotype in Japanese
Two Novel CYP2D6*10 Haplotypes As Possible Causes of a Poor Metabolic Phenotype in Japanese
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DOI：
10.1124/dmd.108.026096
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发表时间：
2009-04
影响因子：
3.9
通讯作者：
Masayuki Matsunaga;H. Yamazaki;K. Kiyotani;S. Iwano;J. Saruwatari;K. Nakagawa;A. Soyama;S. Ozawa;J. Sawada;E. Kashiyama;M. Kinoshita;T. Kamataki
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文献类型：
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作者：
Masayuki Matsunaga;H. Yamazaki;K. Kiyotani;S. Iwano;J. Saruwatari;K. Nakagawa;A. Soyama;S. Ozawa;J. Sawada;E. Kashiyama;M. Kinoshita;T. Kamataki
在对CYP 2D 6基因进行测序的过程中，我们发现了一个新的与CYP 2D 6 *10相关的单核苷酸多态性g.3318G>A（E383 K），称为CYP 2D 6 *72。我们还在CYP 2D 6 *49中发现了g.1611T>A（F120 I），该基因先前在独立的日本人群中被鉴定为CYP 2D 6 *10相关等位基因。为了阐明这些新的CYP 2D 6 *10单倍型对CYP 2D 6功能的影响，使用大肠杆菌表达系统和人肝微粒体对美沙芬O-去甲基化进行动力学分析。与CYP2D6.1催化的相比，CYP 2D 6 *10、CYP 2D 6 *49和CYP 2D 6 *72编码的重组CYP 2D 6形式催化的美沙芬O-去甲基化的Vmax/Km值分别为3.0、0.5和1.3%。来自基因分型为CYP 2D 6 *10/*49的人类受试者的肝微粒体也显示出美沙芬O-脱甲基酶活性降低。CYP2D6.49形成7-羟基双甲吗喃，其Vmax/Km值与O-去甲基化的Vmax/Km值大致相似。这些结果表明，这两种CYP 2D 6 *10单倍型可能是导致CYP 2D 6活性和底物特异性个体间差异的原因。
During the course of sequencing for the CYP2D6 gene, we found a novel single nucleotide polymorphism of g.3318G>A (E383K) associated with CYP2D6*10, termed as CYP2D6*72. We also found a g.1611T>A (F120I) in the CYP2D6*49, which was previously identified as a CYP2D6*10-associated allele in an independent Japanese population. To clarify the effects of these novel CYP2D6*10 haplotypes on the functions of CYP2D6, kinetic analysis for dextromethorphan O-demethylation was performed using the Escherichia coli expression system and human liver microsomes. The Vmax/Km values for dextromethorphan O-demethylation catalyzed by recombinant CYP2D6 forms encoded by CYP2D6*10, CYP2D6*49, and CYP2D6*72 were 3.0, 0.5, and 1.3%, respectively, compared with that catalyzed by CYP2D6.1. Liver microsomes from a human subject genotyped as CYP2D6*10/*49 also showed a reduced dextromethorphan O-demethylase activity. CYP2D6.49 formed a 7-hydroxydextromethorphan, with a roughly similar Vmax/Km value to that of O-demethylation. These results suggest that these two CYP2D6*10 haplotypes are possible causes of interindividual variation in the activities and the substrate specificity of CYP2D6.