期刊
TOXICOLOGY
卷 168, 期 3, 页码 259-268出版社
ELSEVIER SCI IRELAND LTD
DOI: 10.1016/S0300-483X(01)00470-X
关键词
human CYP2A6; genetic polymorphism; genotyping method; PCR-RFLP; allele frequency; Caucasian; African-American
资金
- NCI NIH HHS [P01-CA-72099] Funding Source: Medline
CYP2A6 (cytochrome P450 2A6), which was first identified as the human coumarin 7-hydroxylase, is the most important enzyme in nicotine C-oxidation. The enzyme also metabolically activates the tobacco specific nitrosamine 4-{methylnitrosamino)-1-(3-pyridyl)-1-butanone {NNK) in vitro. Polymorphisms in the CYP2A6 gene may thus impact on both smoking behavior and lung cancer susceptibility. Several different genotyping methods have been reported with conflicting results in the frequencies of CYP2A6 polymorphic variants. Thus we decided to perform a sequence analysis of the entire CYP2A6 gene. Sequencing confirmed the published CYP2A6 cDNA sequence. However, intron sequences differed considerably from the reported sequence of the CYP2Ab*3 (upsilon2) variant. Our analyses revealed that parts of introns shared homologies with the published sequence of CYP2A13. Based on our sequence data we developed a one step protocol for specific amplification of exon 3 of CYP2A6. The resulting PCR product can be used directly for restriction endonuclease digestion with XcmI and DdeI to determine the frequencies of the reported variant alleles CYP2A6*2 and CYP2Ab*3. In a population of 305 African-Americans and 145 Caucasians, we found allele frequencies of 0.003 (2/610) for CYP2Ab*2 and 0 (0/610) for CYP2A6*3 in African-Americans and allele frequencies of 0.014 (4/290) and 0 {0/290) in Caucasians. We conclude that both alleles are considerably less frequent in populations than previously reported. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.
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