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Abstract
CYP2A6 (cytochrome P450 2A6), which was first identified as the human coumarin 7-hydroxylase,
is the most important enzyme in nicotine C-oxidation. The enzyme also metabolically
activates the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) in vitro. Polymorphisms in the CYP2A6 gene may thus impact on both smoking behavior
and lung cancer susceptibility. Several different genotyping methods have been reported
with conflicting results in the frequencies of CYP2A6 polymorphic variants. Thus we
decided to perform a sequence analysis of the entire CYP2A6 gene. Sequencing confirmed
the published CYP2A6 cDNA sequence. However, intron sequences differed considerably
from the reported sequence of the CYP2A6*3 (v2) variant. Our analyses revealed that
parts of introns shared homologies with the published sequence of CYP2A13. Based on
our sequence data we developed a one step protocol for specific amplification of exon
3 of CYP2A6. The resulting PCR product can be used directly for restriction endonuclease
digestion with XcmI and DdeI to determine the frequencies of the reported variant
alleles CYP2A6*2 and CYP2A6*3. In a population of 305 African-Americans and 145 Caucasians,
we found allele frequencies of 0.003 (2/610) for CYP2A6*2 and 0 (0/610) for CYP2A6*3
in African-Americans and allele frequencies of 0.014 (4/290) and 0 (0/290) in Caucasians.
We conclude that both alleles are considerably less frequent in populations than previously
reported.