New CYP2A6 gene deletion and conversion variants in a population of Black African descent.

AIMS

Cytochrome P450 2A6 (CYP2A6) is a human enzyme best known for metabolizing nicotine and nitrosamine precarcinogens. Our aim was to discover and characterize new CYP2A6 alleles in a population of Black African descent.

MATERIALS & METHODS: We used cloning, sequencing and genotyping of genomic DNA to discover new variants, and in vivo nicotine pharmacokinetic phenotyping to characterize the functional effect of the new alleles.

RESULTS

Four new CYP2A6 alleles, CYP2A64G, 4H, 1B4 and 1L, were discovered and characterized in a population of Black African descent. The two new deletion alleles, CYP2A64G and 4H, are distinguished by different crossover junctions at 7.9 and 7.8 kb downstream of the CYP2A6 +1ATG start site, respectively; their combined allele frequency is 1.6%. The new gene conversion alleles, CYP2A61B4 and CYP2A61L, contain 27 and 10 bp of CYP2A7 sequence in the CYP2A6 3 -flanking region, respectively; their combined allele frequency is 7.3%. CYP2A64 appears to associate with lower CYP2A6 activity in vivo, while CYP2A61L does not; however, CYP2A6*1L confounds genotyping assays that use the 2A6R3 and 2A6R4 primers.

CONCLUSION

As new variants are discovered, the relationships between CYP2A6 genotype, nicotine metabolism, smoking behaviors and tobacco-related cancer risk will be further clarified.