UDP glucuronosyltransferases (UGTs) may play important roles in cells as genoprotective enzymes by preventing the accumulation of carcinogenic compounds which could react with cellular macromolecules causing the oxidation of xenobiotics into active carcinogenic electrophiles. Several major tobacco procarcinogens, such as metabolites of the polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (BaP) and tobacco-specific nitrosamines (TSNAs) like 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), are detoxified via UGT-induced glucuronidation by increasing the hydrophilicity of these agents, thus rendering them more water-soluble, more easily excreted, and less bioactive. The major goal of the proposed work is to examine detoxification by UGTs as a mechanism for differential susceptibility to oral cancer, specifically focusing on the glucuronidation of the major NNK metabolite, 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol (NNAL). NNK and NNAL are considered to be major contributors to the induction of cancers of the oral cavity and lung. 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 which suggest that racial differences in morbidity and mortality of lung and potentially oral cancer may, in part, be explained by differences in the ability of individual subjects to detoxify NNK via NNAL glucuronidation. Preliminary studies have identified at least two human UGTs (1A9 and 2B7) which possess NNAL-glucoronidating 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, the hypothesis was created that an individual's ability to glucuronidate NNAL is correlated with that individual's risk for oral cancer as well as for other aerodigestive tract cancers. Therefore, the objective of this proposed work is to (1) fully characterize the NNAL glucuronidation pathway in humans, (2) to elucidate, functionally assess, and determine the prevalence of potentially important genetic polymorphisms in the human UGT gene which may reflect an individual's capacity to convert NNAL to NNAL-gluc as a measure of one's ability to detoxify NNK, and (3) to examine the importance of these polymorphic genotypes in a case-control study of susceptibility to oral cancer. These studies may provide potentially important genetic biomarkers which may reflect upon an individual's risk for oral and potentially other tobacco-related cancers.
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