A genetic polymorphism in coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles.
A genetic polymorphism in coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles.
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发表时间：
1995-09
影响因子：
9.8
通讯作者：
Pedro Fernandez-Salguero;Susan M. G. Hoffman;Suzanne Cholerton;Harvey Mohrenweiser;Hannu Raunio;Arja Rautio;O. Pelkonen;Jin-ding Huang;William E. Evans;Jeffrey;-R.;Idle;Frank;-J.;Gonzalez
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文献类型：
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作者：
Pedro Fernandez-Salguero;Susan M. G. Hoffman;Suzanne Cholerton;Harvey Mohrenweiser;Hannu Raunio;Arja Rautio;O. Pelkonen;Jin-ding Huang;William E. Evans;Jeffrey;-R.;Idle;Frank;-J.;Gonzalez
克隆了一组人细胞色素P450基因，包括细胞色素P450、细胞色素P450和细胞色素P450亚家族，并将其组装成位于19号染色体长臂上的350kb的重叠群。发现了一个不同于先前测序的相应的CYP2A6和CYP2A7基因的变异等位基因，命名为CYP2A6v2。CYP2A6v2基因的序列差异仅限于包含外显子3、6和8的区域，这些外显子与位于CYP2A6v2下游和着丝粒的相应外显子具有序列相关性，提示最近发生了基因转换事件。通过对所有CYP2A基因的测序，可以设计一种针对正常的CYP2A6等位基因、CYP2A6v2等位基因和一种名为CYP2A6v1的变体的PCR诊断测试，该变体编码一种带有单一失活氨基酸变化的酶。这些变异等位基因是在代谢CYP2A6探针药物香豆素的能力不足的个体中发现的。高加索人、亚洲人和非裔美国人之间的等位基因频率存在显著差异。这些研究证实了一种新的细胞色素P450基因多态性的存在。
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.