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Vol. 58, Issue 4, 747-755, October 2000
Centre for Addictions and Mental Health (Y.R., E.H., M.Zi., L.B.,
E.M.S., R.F.T.), Centre for Research in Women's Health (M.Ze., E.M.S.,
R.F.T.), and Departments of Pharmacology (Y.R., E.H., M.Zi., L.B.,
E.M.S., R.F.T.), Psychiatry (E.M.S.), and Medicine (E.M.S.), University
of Toronto, Toronto, Canada
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.
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