Intraindividual and Interindividual Differences in Metabolites of the Tobacco-Specific Lung Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in Smokers' Urine

This study describes quantitation in smokers' urine of two metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-l-(3-pyridyl)-1 -butanone (NNK). The metabolites are 4-(methylnitrosamino)-l-(3-pyridyl)- 1-butanol (NNAL), which is also a lung carcinogen, and its O-glucuronide (NNAL-Gluc), a presumed detoxification product of NNK. Using updated methodology, levels of NNAL, NNAL-Gluc, and cotinine were determined in the urine of 61 smokers. The NNAL-Gluc:NNAL ratio, a potential marker for NNK detoxification potential, varied 16-fold in this group. Two phenotypes of this ratio were apparent; one ranging from 0 to 6 and found in 85% of the smokers and a second ranging from 6 to 11. The short-term and long-term consistency of the ratio was investigated. Studies carried out over a 4-5-day period indicated that the NNAL-Gluc: NNAL ratio was reasonably stable. Subjects who donated urine samples on two occasions separated by 4-16 months were classified in the same group (ratio range, 0-6 or 6-11) each time. Different urine collection protocols appeared to have little influence on the NNAL-Gluc:NNAL ratio. Thus, intraindividual differences in the NNAL-Gluc:NNAL ratio were generally small, whereas interindividual differences were large. Amounts of NNAL, NNAL-Gluc, and cotinine excreted by smokers were constant in 24-h samples obtained over a 3-day period of constant cigarette intake and controlled diet. Levels of NNAL, NNAL-Gluc, and NNAL plus NNAL-Gluc correlated with cotinine in a study of 61 smokers without controlled diet or smoking (r = 0.58; P < 0.0001). The results of this study indicate that urinary NNAL and NNAL-Gluc can be reliably quantified in smokers' urine, and that the NNAL-Gluc:NNAL ratio may be a useful biomarker for NNK detoxification in smokers.