Fernandez-Salguero P, Hoffman S M, Cholerton S, Mohrenweiser H, Raunio H, Rautio A, Pelkonen O, Huang J D, Evans W E, Idle J R
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Am J Hum Genet. 1995 Sep;57(3):651-60.
A group of human cytochrome P450 genes encompassing the CYP2A, CYP2B, and CYP2F subfamilies were cloned and assembled into a 350-kb contig localized on the long arm of chromosome 19. Three complete CYP2A genes--CYP2A6, CYP2A7, and CYP2A13--plus two pseudogenes truncated after exon 5, were identified and sequenced. A variant CYP2A6 allele that differed from the corresponding CYP2A6 and CYP2A7 cDNAs previously sequenced was found and was designated CYP2A6v2. Sequence differences in the CYP2A6v2 gene are restricted to regions encompassing exons 3, 6, and 8, which bear sequence relatedness with the corresponding exons of the CYP2A7 gene, located downstream and centromeric of CYP2A6v2, suggesting recent gene-conversion events. The sequencing of all the CYP2A genes allowed the design of a PCR diagnostic test for the normal CYP2A6 allele, the CYP2A6v2 allele, and a variant--designated CYP2A6v1--that encodes an enzyme with a single inactivating amino acid change. These variant alleles were found in individuals who were deficient in their ability to metabolize the CYP2A6 probe drug coumarin. The allelic frequencies of CYP2A6v1 and CYP2A6v2 differed significantly between Caucasian, Asian, and African-American populations. These studies establish the existence of a new cytochrome P450 genetic polymorphism.
一组包含CYP2A、CYP2B和CYP2F亚家族的人类细胞色素P450基因被克隆，并组装成一个位于19号染色体长臂上的350 kb重叠群。鉴定并测序了三个完整的CYP2A基因——CYP2A6、CYP2A7和CYP2A13，以及两个在第5外显子后截短的假基因。发现了一个与先前测序的相应CYP2A6和CYP2A7 cDNA不同的CYP2A6变异等位基因，命名为CYP2A6v2。CYP2A6v2基因中的序列差异仅限于包含第3、6和8外显子的区域，这些区域与位于CYP2A6v2下游和着丝粒方向的CYP2A7基因的相应外显子具有序列相关性，提示近期发生了基因转换事件。对所有CYP2A基因的测序使得能够设计一种针对正常CYP2A6等位基因、CYP2A6v2等位基因以及一种变异体（命名为CYP2A6v1）的PCR诊断试验，该变异体编码一种具有单个失活氨基酸变化的酶。这些变异等位基因在代谢CYP2A6探针药物香豆素能力不足的个体中被发现。CYP2A6v1和CYP2A6v2的等位基因频率在白种人、亚洲人和非裔美国人种群之间存在显著差异。这些研究证实了一种新的细胞色素P450基因多态性的存在。
