) UGTs play an extremely important role as genoprotective enzymes in the cell by preventing the accumulation of carcin-ogenic compounds which could react with cellular macromolecules and the oxidation of xenobiotics into active carcinogenic electrophiles. For example, several major tobacco procarcinogens, such as metabolites of the polycyclic aromatic hydrocarbons (PAHS) like benzoapyrene (BaP) and tobacco-specific nitrosamines (TSNAs) like 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK), are detoxified via UDP-glucuronosyltransferase (UGT)-induced glucuronidation by increasing the hydrophilicity of these agents, rendering them more water soluble, more easily excreted and less active. The major goal of the present proposal is to examine detoxification by UGTs as a mechanism for differential susceptibility to tobacco-induced cancers, specifically focusing on the glucuronidation of the major NNK metabolite, 4-(methyinitrosamino)-1-(3-pyridyl)-1-butanone (NNL). NNK and NNAL are considered to be major contributors to the induction of lung and other aerodigestive tract cancers. Large inter-individual variability in the ratio of the glucuronidated form of NNAL (NNAL-gluc):free NNAL suggests that individuals may differ greatly in their ability to glucuronidate NNK metabolites and to detoxify NNK. This is consistent with recent studies suggesting that racial differences in lung cancer risk may, in part, be explained by differences in the ability of individual subjects to detoxify NNK via NNAL glucuronidation. In our preliminary studies, we have identified at least one human UGT (UGT1*9) which possesses NNAL-glucuronidating activity and demonstrate that this activity is inducible by Phenobarbitol and phenolic antioxidants in rats. As the balance between metabolic activation and detoxification of carcinogens such as NNK may be influenced by the balance of host expression of enzymes involved in tobacco carcinogen activation or deactivation, we have hypothesized that an individual's ability to glucuronidate NNAL will be correlated and that individual's risk for lung and potentially other aerodigestive tract cancers. The objective of this proposal will be to, (I) fully characterize the NNAL glucuronidation pathway in humans by determining the major UGT isoenzyme(s) responsible for the glucuronidation of NNAL, (ii) elucidate and functionally assess potentially important genetic polymorphism's in the human UGT gene which may reflect on an individual?s capacity to convert NNAL to NNAL-gluc as a measure of one's ability to detoxify NNK, and (iii) examine the importance of these polymorphic genotypes in a case:control study of lung cancer susceptibility. These studies should enable us to elucidate potentially important genetic biomarkers which may reflect upon an individual?s risk for tobacco-related cancers.
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