UDP-GLUCURONOSYLTRANSFERASE GENOTYPE AND CANCER RISK

UDP-葡萄糖醛酸基转移酶基因型和癌症风险

基本信息

批准号：
8064730
负责人：
Philip Lazarus
金额：
$ 50.27万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8064730
关键词：
17p African American Alleles Androstanes Androsterone Arkansas Award Benzo(a)pyrene Biological Assay Butanones C19 steroid Carcinogens Case-Control Studies Caucasians Caucasoid Race Cell Line Chloramphenicol O-Acetyltransferase Code DNA Drug Metabolic Detoxication Eating Endogenous Factors Endometrial Carcinoma Enzymes Estradiol Funding Gene Deletion Gene Expression Genes Genetic Polymorphism Genetic Variation Genomics Genotype Glucuronosyltransferase Glycols Goals Hormones Hospitals Human In Vitro Individual Isoenzymes Kinetics Liver Liver Microsomes Luciferases Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Memorial Sloan-Kettering Cancer Center Metabolism Microsomes Mining New Jersey Oral Oral mucous membrane structure Organ Pathway interactions Phenotype Play Predisposition Prevalence Promoter Regions Prostate Proteins RNA Recruitment Activity Relative (related person)Reporter Genes Research Personnel Reverse Transcriptase Polymerase Chain Reaction Risk Role Sampling Series Site Smoke Smoker Specimen Stanolone Steroids Structure of parenchyma of lung System Testosterone Time Tissues Tobacco Tobacco smoke Tobacco-Associated Carcinogen Universities Urine Variant Xenobiotics base bilirubin uridine-diphosphoglucuronosyl transferase 1A10 cancer epidemiology cancer genetics cancer risk carcinogenesis inhibitor/antagonist man population based programs promoter

项目摘要

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.

描述（由申请人提供）：葡萄糖醛酸化在代谢和消除与癌症风险增加有关的多种致癌物和内源性因素中起着极为重要的作用。我们在该奖项的头五年中的研究强烈表明，两个UGT -UGT1A10和UGT2B17-在癌症易感性中起关键作用。我们已经确定了ugt1a10和ugt2b17的普遍缺失多态性，其中包括近端启动子区域的一部分或大部分编码序列，并且整个Gene UGT2B17*2缺失等位基因与肝脏微体体型糖体型糖体的风险和增加的风险相关。两种酶都是（1）存在于烟草相关癌症中的目标部位，包括机场消化道和肺，并且对许多重要的烟草烟雾毒素代谢物具有活性，包括BAP和NNK，（2）ugt1a10在诸如雌激素和雌激素中具有高度活性UGT2B17存在于前列腺中，并且对包括睾丸激素和二氢睾丸激素在内的相关C19类固醇具有高度活跃。因此，这两种酶在所有这些上述位点的相关底物的排毒中都可能发挥重要作用，而诸如基因缺失之类的UGT遗传变异可能会对癌症风险产生重大影响。我们假设UGT1A10和UGT2B17多态性会显着改变针对外源异种生物的活性，例如烟草致癌物或内源性化合物，例如C18或C19类固醇（例如C18或C19固醇），与葡萄糖醛酸苷化表型的改变相关，并且它们在癌症风险中起重要作用。（1）在两个基因中表征这些和其他潜在多态性的目的是（2）评估其对酶功能或基因型中的酶功能或表达的影响：表型测定法，以及（3）进行初步研究，以研究其在癌症风险中的作用。这些研究将与仔细评估UGT1A10和UGT2B17-葡萄糖醛酸化活性的整体重要性相结合，以针对各种烟草烟致癌或其代谢产物。这些研究应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的变异作用。