UDP-GLUCURONOSYLTRANSFERASE GENOTYPE AND CANCER RISK

描述（由申请方提供）：葡萄糖醛酸化在多种致癌物和与癌症风险增加相关的内源性因素的代谢和消除中起着极其重要的作用。我们在该奖项前五年的研究强烈表明，两种UGT-UGT 1A 10和UGT 2B 17-在癌症易感性中发挥关键作用。我们已经确定了UGT 1A 10和UGT 2B 17的普遍缺失多态性，包括近端启动子区的一部分或编码序列的大部分，并且全基因UGT 2B 17 *2缺失等位基因与肝微粒体葡萄糖醛酸化活性显著降低和肺腺癌风险增加相关。这两种酶都是：（1）存在于烟草相关癌症的靶部位，包括呼吸消化道和肺部，并且对烟草烟雾致癌物的许多重要代谢物（包括BaP和NNK）具有活性，（2）UGT 1A 10对相关C18类固醇（如雌二醇）具有高度活性，并且在激素相关组织中广泛表达，（3）UGT 2B 17存在于前列腺中，并且对包括睾酮和双氢睾酮在内的相关C19类固醇具有高度活性。因此，这两种酶可能在所有上述位点的相关底物的解毒中发挥重要作用，而UGT基因变异（如基因缺失）可能对癌症风险产生重大影响。我们假设UGT 1A 10和UGT 2B 17多态性显著改变了对外源性外源性生物质（如烟草致癌物）或内源性化合物（如C18或C19类固醇）的活性，与葡萄糖醛酸化表型改变相关，并且它们在癌症风险中发挥重要作用。本提案的目标是：（1）表征这两个基因中的这些和其他潜在多态性，（2）评估它们对体外和基因型：表型测定中酶功能或表达的影响，以及（3）进行初步研究，检查它们在癌症风险中的作用。这些研究将与仔细评估UGT 1A 10-和UGT 2B 17-葡萄糖醛酸化活性对各种烟草烟雾致癌物或其代谢产物的总体重要性相结合。这些研究将对癌症遗传学和流行病学领域产生重大影响，因为它们将使我们能够更好地评估葡萄糖醛酸化途径和癌症诱导中变异的作用。

DESCRIPTION (provided by applicant): 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.