ClinVar

The CYP2A6 enzyme metabolizes certain drugs and precarcinogens and is the most important enzyme for nicotine metabolism. More than 10 different allelic variants cause abolished or decreased enzyme activity. Genetic polymorphism in this gene may be of particular importance for an individual's need for nicotine and for susceptibility to lung and/or liver cancer. The CYP2A6 gene is located adjacent to the inactive, very similar CYP2A7 gene, and several allelic variants of CYP2A6 have been created by unequal crossover and gene conversion reactions between these genes. Oscarson et al. (2002) identified a novel CYP2A6 allele, CYP2A6*12, which carries an unequal crossover between the CYP2A6 and CYP2A7 genes in intron 2. This results in a hybrid allele where the 5-prime regulatory region and exons 1 and 2 are of CYP2A7 origin and exons 3 through 9 are of CYP2A6 origin, resulting in 10 amino acid substitutions compared to the CYP2A6*1 allele. Phenotyping with the CYP2A6 substrate coumarin indicated that the CYP2A6*12 allele causes reduced CYP2A6 activity in vivo. Furthermore, when expressed in mammalian COS-1 cells, the enzyme variant catalyzed 7-hydroxylation of coumarin at a rate approximately 60% that of the wildtype enzyme, recapitulating a coumarin-resistant phenotype (122700). The CYP2A6*12 allele was present at an allele frequency of 2.2% among 92 unrelated Spaniards, but was absent in 97 unrelated Chinese.

This allele was designated CYP2A6*12A by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee.