Nicotine metabolism and CYP2D6 phenotype in smokers

We tested the hypothesis that the polymorphic enzyme CYP2D6 is related to n icotine metabolism in 261 healthy subjects enrolling in a smoking cessation clinic. Subjects completed a questionnaire, were given dextromethorphan, a nd contributed a urine and blood sample. The CYP2D6 phenotype (based on a d etermination of dextromethorphan and metabolites in an aliquot of overnight urine) and genotype (based on characterization of CYP2D6 variant alleles b y a PCR-based method on a subset) were determined. Seventeen poor metaboliz ers (6.5%) were observed among 261 phenotyped smokers. Nicotine and it chie f metabolites, cotinine and trans-3'-hydroxycotinine were measured in the u rine and adjusted for pH. All of the nicotine metabolite levels were signif icantly related to usual and recent smoking. Neither levels of smoking nor nicotine metabolites overall exhibited a relationship to the CYP2D6-deficie nt metabolizer phenotype, The ratio of nicotine:cotinine + trans-3'-hydroxy cotinine, stratified by time since the last cigarette, was unrelated to gen der, age, education, race (white/African American), recent alcohol or caffe ine consumption, or smoking practices. Subjects in either the Lowest quinti le or decile metabolic ratio (ultrametabolizers) exhibited a significantly lower nicotine:cotinine + trans-3'-hydroxycotinine ratio after adjustment f or recent smoking, pH, and other factors. These data suggest that the polym orphic CYP2D6 gene is not a major contributor to nicotine metabolism in tob acco smokers but may influence the disposition of nicotine in the small sub set of the population who are CYP2D6 ultrametabolizers.