Abstract
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 defectiveCYP2A6*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 CYP2A6gene, corresponding to the gene deletion CYP2A6*4allele, 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 andCYP2A6*4) alleles (N = 14), those homozygous for wild-type (CYP2A6*1/*1) alleles (N = 277), and those with our newly identifiedCYP2A6 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 CYP2A6genotype and phenotype on smoking behavior.
Footnotes
- Received November 8, 1999.
- Accepted June 30, 2000.
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Send reprint requests to: R. F. Tyndale, Ph.D., Rm. 4336, Department of Pharmacology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. E-mail:r.tyndale{at}utoronto.ca
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Supported in part by Grant DA06889 from the National Institute of Drug Abuse, Nicogen Research Inc., and the Centre for Addictions and Mental Health (Toronto, Canada).
- The American Society for Pharmacology and Experimental Therapeutics
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