title: A genetic polymorphism in coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles.
abstract: 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.
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: P
authors.initials: P
authors.lastname: Fernandez-Salguero
authors.forename: S M
authors.initials: SM
authors.lastname: Hoffman
authors.forename: S
authors.initials: S
authors.lastname: Cholerton
authors.forename: H
authors.initials: H
authors.lastname: Mohrenweiser
authors.forename: H
authors.initials: H
authors.lastname: Raunio
authors.forename: A
authors.initials: A
authors.lastname: Rautio
authors.forename: O
authors.initials: O
authors.lastname: Pelkonen
authors.forename: J D
authors.initials: JD
authors.lastname: Huang
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
authors.forename: J R
authors.initials: JR
authors.lastname: Idle
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D013250:Steroid Hydroxylases / Q000235:genetics*
chemical_list: D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; C022657:steroid hormone 6-beta-hydroxylase