Glucuronidation plays an extremely important role in the metabolism and elimination of a variety of carcinogens and endogenous factors associated with increased risk for cancer. Our studies over the first five years of this award strongly suggest that two UGTs - UGT1A10 and UGT2B17 - play key roles in cancer susceptibility. We have identified prevalent deletion polymorphisms for both UGT1A10 and UGT2B17 that include either part of the proximal promoter region or a large part of the coding sequence, and that the whole-gene UGT2B17*2 deletion allele is associated with significant decreases in liver microsome glucuronidating activities and increased risk for lung adenocarcinoma. Both enzymes are, (1) present in target sites for tobacco-related cancers including the aerodigestive tract and lung and are active against many important metabolites of tobacco smoke carcinogens including BaP and NNK, (2) UGT1A10 is highly active against relevant C18 steroids like estradiol and is widely-expressed in hormone-related tissues, and (3) UGT2B17 is present in prostate and is highly active against relevant C19 steroids including testosterone and dihydrotestosterone. Therefore, both enzymes could potentially play a significant role in the detoxification of relevant substrates in all of these aforementioned sites, and UGT genetic variations like gene deletions could have a significant impact on cancer risk. We hypothesize that UGT1A10 and UGT2B17 polymorphisms that significantly alter activities against exogenous xenobiotics like tobacco carcinogens or endogenous compounds like C18 or C19 steroids are correlated with altered glucuronidation phenotypes, and that they play an important role in cancer risk. It is the goal of this proposal to, (1) characterize these and other potential polymorphisms in the two genes, (2) assess their effect on enzyme function or expression both in vitro and in genotype:phenotype assays, and (3) perform preliminary studies examining their role in cancer risk. These studies will be combined with a careful assessment of the overall importance of UGT1A10- and UGT2B17-glucuronidating activities against a variety of tobacco smoke carcinogens or their metabolites. These studies should significantly impact on the field of cancer genetics and epidemiology as they will enable us to better assess the role of variation in glucuronidation pathways and cancer induction. ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
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