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Nicotine Metabolism and CYP2D6 Phenotype in Smokers

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892 [N. E. C., R. T. F.]; Lombardi Cancer Research Center, Georgetown University, Washington, D.C. 20007 [C. L., J. A., N. R. B., D. M.]; Laboratory of Chemical Synthesis and Analysis, Frederick Cancer Research Center, Frederick, Maryland 21701 [H. J. I., B. U.]; and Laboratory of Human Carcinogenesis, Division of Cancer Etiology, NIH, National Cancer Institute, Bethesda, Maryland 20892 [P. S.]

We tested the hypothesis that the polymorphic enzyme CYP2D6 is related to nicotine metabolism in 261 healthy subjects enrolling in a smoking cessation clinic. Subjects completed a questionnaire, were given dextromethorphan, and contributed a urine and blood sample. The CYP2D6 phenotype (based on a determination of dextromethorphan and metabolites in an aliquot of overnight urine) and genotype (based on characterization of CYP2D6 variant alleles by a PCR-based method on a subset) were determined. Seventeen poor metabolizers (6.5%) were observed among 261 phenotyped smokers. Nicotine and it chief metabolites, cotinine and trans-3'-hydroxycotinine were measured in the urine and adjusted for pH. All of the nicotine metabolite levels were significantly related to usual and recent smoking. Neither levels of smoking nor nicotine metabolites overall exhibited a relationship to the CYP2D6-deficient metabolizer phenotype. The ratio of nicotine:cotinine + trans-3'-hydroxycotinine, stratified by time since the last cigarette, was unrelated to gender, age, education, race (white/African American), recent alcohol or caffeine consumption, or smoking practices. Subjects in either the lowest quintile or decile metabolic ratio (ultrametabolizers) exhibited a significantly lower nicotine:cotinine + trans-3'-hydroxycotinine ratio after adjustment for recent smoking, pH, and other factors. These data suggest that the polymorphic CYP2D6 gene is not a major contributor to nicotine metabolism in tobacco smokers but may influence the disposition of nicotine in the small subset of the population who are CYP2D6 ultrametabolizers.

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