) UDP-Glucuronyltransferases (UGT) play an extremely important role as genoprotective enzymes by preventing the accumulation of carcinogenic compounds which could react with cellular macromolecules and the oxidation of xenobiotics into active carcinogenic electrophiles. For example, several major tobacco pro-carcinogens, such as metabolites of the polycyclic aromatic hydrocarbons(PAHs) like benz[a]pyrene (BaP) and tobacco-specific nitrosamines (TSNAs) like 4-(methylnitrosamino)-1- (3,l)-butanone (NNK), are detoxified via glucuronidation by increasing hydrophilicity of these agents, rendering them more water soluble, and therefore 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 lung cancer, specifically focusing on the glucuronidation of the major NNK metabolite, 4-(methylnitrosamino)- 1-(3-pyridyl)- l(NNAL). NNK and NNAL are considered to be major contributors to the induction of lung and other aerodigestive cancers. Large inter-individual variability in the ratio of the glucuronidated form of NNAL (NNAL-gluc):free NNAL suggests that individuals differ greatly in their ability to glucuronidate NNK metabolites and to detoxify NNK. This is consistent with recent studies suggesting that racial differences in risk for lung cancer may, in part, be explained by differences in the ability of individual subjects to detoxify NNK via NNAL glucuronidation. In our preliminary studies, we identified several human UGTs, including UGT1A9, which appear to possess NNAL-glucuronidating activity and demonstrate that this activity is inducible by phenobarbitol and phenolic antioxidants in rats. As the balance between 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 hypothesize that an individual's ability to glucoronidate NNAL will be correlated with that individual's risk for lung and potentially other aerodigestive tract cancers. The objective of this application 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 polymorphisms in the human UGT gene which may reflect on an individual's capacity to convert 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 biomarkers which may reflect upon an individual's risk for lung and potentially other tobacco-related cancers.
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