Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking.
In humans, 80% of nicotine is metabolized to the inactive metabolite cotinine by the enzyme CYP2A6, which can also activate tobacco smoke procarcinogens (e.g., 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone). Previously, we demonstrated that individuals who are nicotine-dependent and have defective CYP2A6 alleles (*2, *3) smoked fewer cigarettes; however, we recognize that the genotyping method used for the CYP2A6*3 allele gave a high false-positive rate. In the current study we used improved genotyping methods to examine the effects of the defective CYP2A6*2 and CYP2A6*4 alleles on smoking behavior. We found that those with the defective alleles (N = 14) smoked fewer cigarettes per day than those homozygous (N = 277) for wild-type alleles (19 versus 28 cigarettes per day, P <.001). In addition, we identified a duplicated form of the CYP2A6 gene, corresponding to the gene deletion CYP2A6*4 allele, developed a genotyping assay, assessed the gene copy number, and examined its prevalence in Caucasian smokers (N = 296). We observed an ascending rank order for plasma cotinine and breath carbon monoxide levels (an index of smoke inhalation) in individuals with null (CYP2A6*2 and CYP2A6*4) alleles (N = 14), those homozygous for wild-type (CYP2A6*1/*1) alleles (N = 277), and those with our newly identified CYP2A6 gene duplication (N = 5). The phenotype, as determined by plasma nicotine/cotinine ratios, had a descending rank order for these three genotype groups that did not reach significance. Although further characterization is required for the duplication gene variant, these results extend our previous findings and suggest a substantial influence of CYP2A6 genotype and phenotype on smoking behavior.
Rao
Y
Y
Centre for Addictions and Mental Health, University of Toronto, Toronto, Canada.
Hoffmann
E
E
Zia
M
M
Bodin
L
L
Zeman
M
M
Sellers
E M
EM
Tyndale
R F
RF
D000293:Adolescent; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D002248:Carbon Monoxide / Q000378:metabolism; D003367:Cotinine / Q000097:blood; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004247:DNA / Q000032:analysis; D005260:Female; D020440:Gene Duplication; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008969:Molecular Sequence Data; D009538:Nicotine / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D012907:Smoking / Q000097:blood / Q000235:genetics*; D044465:White People / Q000235:genetics
D009538:Nicotine; D002248:Carbon Monoxide; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D003367:Cotinine