Metabolism of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone to its biomarker total NNAL in smokeless tobacco users

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) is one of the most abundant carcinogens in smokeless tobacco products. NNK uptake by measurement of the urinary metabolites 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL) has been reported in many studies, but there are no data in the literature on the percentage of the NNK dose that is converted to NNAL in smokeless tobacco users. In this study, 15 male subjects abstained from tobacco use for 3 weeks before placing 2 g smokeless tobacco between their cheeks and gums for 30 min. They then continued abstinence and collected three consecutive 24-h urine samples. The amount of NNK in the tobacco before and after use was determined along with the amount in expectorated saliva. The NNK dose thus calculated was compared with the amount of total NNAL excreted in the next 72 h. These data, taken together with previous pharmacokinetic data, show that the percent conversion of NNK to total NNAL in smokeless tobacco users is ∼14% to 17%. This figure can be used to calculate daily exposure to NNK in smokeless tobacco users (∼6 μg). The results of this study also indicate that metabolic activation of NNK to intermediates that can react with DNA is its major pathway of metabolism in smokeless tobacco users.