BIOMARKERS FOR HUMAN UPTAKE AND METABOLIC-ACTIVATION OF TOBACCO-SPECIFIC NITROSAMINES

Tobacco-specific nitrosamines are a group of carcinogens formed from n icotine and related tobacco alkaloids. Two of these compounds, 4-(meth ylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotin e, are believed to be involved as causative agents for cancers of the lung, oral cavity, esophagus, and pancreas associated with the use of tobacco products. The goal of the studies described here is to develop biomarkers which will allow us to understand the uptake, metabolic ac tivation, and detoxification of these carcinogens in humans. Two metab olites of NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its g lucuronide, have been identified and quantified in human urine. These metabolites allow assessment of NNK uptake in smokers, tobacco chewers , and people exposed to environmental tobacco smoke. NNK and N-nitroso nornicotine form hemoglobin and DNA adducts upon metabolic activation by alpha-hydroxylation. These adducts release 4-hydroxy-1-(3-pyridyl)- 1-butanone (HPB) upon hydrolysis. The released 4-hydroxy-1-(3-pyridyl) -1-butanone can be quantified by gas chromatography-mass spectrometry. A subset of smokers and most tobacco chewers have hemoglobin adduct l evels which are higher than detected in nonsmokers. 4-Hydroxy-1-(3-pyr idyl)-1-butanone-releasing DNA adducts are higher in lung tissue from smokers than from nonsmokers. These data indicate that some smokers an d tobacco chewers are capable of metabolically activating NNK or N-nit rosonornicotine to intermediates which bind to cellular macromolecules and are, therefore, at potentially higher risk for cancer development . The application of these biomarkers to studies on cancer induction b y tobacco products is discussed.