A nicotine C-oxidase gene (CYP2A6) polymorphism important for promoter activity.
A nicotine C-oxidase gene (CYP2A6) polymorphism important for promoter activity.
复制标题
尼古丁 C-氧化酶基因 (CYP2A6) 多态性对启动子活性很重要。
DOI：
10.1002/humu.20002
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发表时间：
2004
期刊：
影响因子：
3.9
通讯作者：
Ingelman-Sundberg,Magnus
中科院分区：
文献类型：
--
作者：
Pitarque,Marià;vonRichter,Oliver;Rodríguez-Antona,Cristina;Wang,Jue;Oscarson,Mikael;Ingelman-Sundberg,Magnus
In humans, several polymorphic variants have been described for the gene encoding the major nicotineC‐oxidase, cytochrome P450 2A6 (CYP2A6), which is to a great extent responsible for the large interindividual differences seen at the enzymatic and activity levels. Hitherto, mainly polymorphic variants in the open reading frame have been identified. In the present study, we identified a novel single nucleotide polymorphism (SNP) located in the 5′ flanking region of theCYP2A6gene. Sequencing of 1.4 kb of the 5′‐upstream region of theCYP2A6gene from eight individuals revealed a c.‐1013A>G polymorphism defining two new alleles,CYP2A6*1DandCYP2A6*1E, lacking or having also theCYP2A73′‐UTR. Analysis of genomic DNA from 32 Swedish and 109 Turkish subjects by dynamic allele‐specific hybridization (DASH) showed that, in both groups, the variants carrying the c.‐1013A>G SNP represent approximately 70% of the total number of alleles. Transfection of HepG2 cells with luciferase reporter constructs containing 1019 bp of theCYP2A65′‐regulatory sequence showed that the region between c.‐1005 and c.‐1019 elicited a strong enhancer effect and that theCYP2A6*1Dpromoter had significantly reduced expression as compared toCYP2A6*1Acarrying c.‐1013A. Electrophoretic mobility shift assays (EMSA) showed that nuclear proteins from HepG2 and B16A2 cells exhibited a higher binding affinity to the probe harboring c.‐1013A as compared to the c.‐1013G probe, although the transcription factor(s) responsible for this binding could not be identified. In conclusion, our results indicate the presence of a strong enhancer or promoter responsive element between c.‐1005 and c.‐1019 in theCYP2A6gene and that a c.‐1013A>G polymorphism in this region affectsCYP2A6transcription. Hum Mutat 23:258–266, 2004. © 2004 Wiley‐Liss, Inc.
