Individual differences in urinary cotinine levels in Japanese smokers: Relation to genetic polymorphism of drug-metabolizing enzymes

Urinary cotinine, one of the main metabolites of nicotine, has been widely used as a biomarker for assessment of direct or passive exposure to cigarette smoke. However, there is wide variation of the cotinine level among smokers who smoke the same number of cigarettes. To use urinary cotinine as a proper exposure-biomarker for cigarette smoke, interindividual variations of cotinine formation must be considered. Therefore, we studied the effects of genetic polymorphisms in drug metabolic enzymes on urinary cotinine levels among 190 male Japanese smokers (ages 19-66 years; mean, 40.6 years). Genetic polymorphisms in cytochrome P-450s (CYP1A1, CYP2A6, CYP2E1), and aldehyde dehydrogenase 2 (ALDH2) were determined by analyzing DNA isolated from peripheral blood. Cotinine in morning spot urine was analyzed by high-performance liquid chromatography. Lifestyle, i.e., smoking, alcohol consumption, and intake of coffee or tea, was examined using a questionnaire. The number of cigarettes smoked and CYP2A6 polymorphism were significantly associated with the urinary cotinine level. Especially, the urinary cotinine levels was drastically lower in CYP2A6-deleted homozygous (CYP2A6*4/*4) subjects than in CYP2A6*1 allele-positive subjects. The polymorphism in the CYP2E1 5′-flanking region was related to the urinary cotinine level in intermediate smokers (who smoke 11-20 cigarettes/day; P < 0.01). Polymorphisms in CYP1A1 or ALDH2, and consumption of alcohol, coffee, or tea were not associated with the urinary cotinine level.