Characterization of a novelCYP2A7/CYP2A6 hybrid allele (CYP2A6*12) that causes reduced CYP2A6 activity

Abstract

The human CYP2A6 enzyme metabolizes certain drugs and pre-carcinogens and appears to be the most important enzyme for nicotine metabolism. At present, more than 10 different allelic variants are known that cause abolished or decreased enzyme activity. Genetic polymorphism in this gene might be of particular importance for an individual's need for nicotine and for susceptibility to lung and/or liver cancer. We have identified a new 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' regulatory region and exons 1-2 are of CYP2A7 origin and exons 3-9 are of CYP2A6 origin, resulting in 10 amino acid substitutions compared to the CYP2A6(*)1 allele. Phenotyping with the CYP2A6 substrate coumarin indicates that it 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% of that of the wild-type enzyme. The CYP2A6(*)12 allele was present at an allele frequency of 2.2% among Spaniards, but was absent in Chinese.

Impact of CYP2A6 genotype on pretreatment smoking behaviour and nicotine levels from and usage of nicotine replacement therapy

“…33,34 We investigated four CYP2A6 genetic variants, CYP2A6*2, CYP2A6*4, CYP2A6*9A and CYP2A6* 12A, which are common among Caucasians, 15 and have a known detrimental impact on enzyme function. 4,11,[35][36][37] To assess whether CYP2A6 genetic variants affect enzyme activity, smoking behaviours and plasma levels from treatments, CYP2A6 activity groups were defined based on the impact of each CYP2A6 allele. 8,11,35,[37][38][39] Thus, our study aimed to assess the impact of CYP2A6 genotypes on: (1) CYP2A6 activity using the 3HC/COT ratio derived from baseline smoking, (2) on pre-treatment baseline smoking behaviour in a treatment-seeking group and (3) on usage of nicotine patch and spray and resultant plasma nicotine and cotinine levels obtained.…”

CYP2A7 polymorphic alleles confound the genotyping of CYP2A6*4A allele

“…12 The CYP2A6*12 is a CYP2A7/CYP2A6 hybrid allele created by an unequal crossover in intron 2. 13 Recently, we developed a genotyping method to distinguish the CYP2A6*4A, CYP2A6*4D, CYP2A6*1F, and CY-P2A6*1G alleles. 14 Using this method, we found that 14 out of 187 European-American subjects heterozygously possessed the CYP2A6*4A allele, resulting in an allele frequency of 3.7%.…”

CYP2A6 genetic polymorphisms and correlation with smoking status in Brazilians

“…90% in other populations studied to date. [19][20][21][22] The second purpose of this study was to investigate whether CYP2A6 polymorphisms are associated with individual susceptibility to smoking dependence.…”