Elucidation of epoxide hydrolase polymorphisms

环氧化物水解酶多态性的阐明

• 批准号: 6515084
• 负责人: Jong Y. Park
• 金额: $ 7.25万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515084
• 关键词: African American; benzopyrenes; biotransformation; caucasian American; clinical research; enzyme activity; epoxide hydrolase; genetic polymorphism; human subject; linkage mapping; polymerase chain reaction; sequence tagged sites; single strand conformation polymorphism

DESCRIPTION: (provided by Applicant) Genetic variations in genes involved in the metabolic activation and/or detoxification of tobacco carcinogens are likely to be a major source of inter-individual and inter-racial variation in cancer susceptibility. These metabolic differences are often associated with genetic polymorphisms in genes coding for carcinogen metabolizing enzymes. Therefore, the carcinogenic capacity of tobacco and tobacco smoke may be dependent upon the genetic composition of enzymes responsible for metabolizing of these carcinogens, thereby affecting individual susceptibility to tobacco- related cancers. One of the important enzymes involved in the metabolism of major tobacco-smoke carcinogens including | polycyclic aromatic hydrocarbons like benzo[a]pyrene (BaP) is epoxide hydrolase (EH). The EH enzyme catalyzes the conversion of BaP-(7,8)-epoxide to BaP-(7,8)-diol, which is the direct precursor metabolite of BaP-(7,8)-diol-(9,10)-epoxide, the ultimate carcinogen of BaP. Previous studies have implicated EH polymorphisms in increased risk for lung as well as oral cancer in Caucasian cohorts but have not included an | assessment of EH polymorphisms and cancer risk in other racial groups. We have established the presence of other EH gene polymorphisms that could potentially play a role in EH activity. As EH plays a key role in the activation of PAHs, a full exploration of EH genetic variants must be performed and the role of polymorphic EH alleles on EH activity. Our hypothesis is that newly-identified EH genetic polymorphisms play an important role in affecting enzyme activity. The goal of the present study is to elucidate novel and examine known or newly-identified polymorphisms present in the EH gene. In this proposal, we intend to examine the prevalence of newly identified as well as known polymorphisms in Caucasians as well as African Americans. In addition, we will examine the potential role of these polymorphisms in EH activity by functional analysis of each allele. These studies will provide baseline information for future large-scale case:control studies regarding the potential of these polymorphisms to affect cancer risk and influence our strategies in terms of cancer prevention for smoking-related cancers.

描述：（由申请人提供） 烟草致癌物代谢活化和/或解毒 可能是个体间和种族间差异的主要来源， 癌症易感性 这些代谢差异通常与 致癌物代谢酶编码基因的遗传多态性。 因此，烟草和烟草烟雾的致癌能力可能是 依赖于负责代谢的酶的遗传组成， 这些致癌物质，从而影响个人对烟草的易感性- 相关癌症 参与主要烟草烟雾代谢的重要酶之一 致癌物质包括|多环芳烃，如苯并[a]芘 (BaP)是环氧化物水解酶（EH）。 EH酶催化 BaP-（7，8）-环氧化物转化为BaP-（7，8）-二醇，后者是直接前体代谢物 BaP-（7，8）-diol-（9，10）-epoxy，BaP的最终致癌物。 先前 研究表明，EH多态性与肺疾病风险增加有关， 口腔癌在高加索人队列中，但没有包括|EH评价 多态性和其他种族的癌症风险。 我们成立了 存在其他EH基因多态性，可能在 EH活性。 由于EH在多环芳烃的活化中起着关键作用， 必须进行EH遗传变异的探索， 多态性EH等位基因对EH活性的影响。 我们的假设是，新发现的EH基因多态性起着重要作用。 影响酶活性的重要作用。 本研究的目的是 阐明新的和检查已知的或新鉴定的多态性， 在EH基因中。 在这项建议中，我们打算研究 新发现的和已知的高加索人的多态性，以及 非裔美国人 此外，我们将研究这些潜在的作用， 通过对每个等位基因的功能分析，确定EH活动的多态性。这些 研究将为未来的大规模病例提供基线信息：对照 关于这些多态性影响癌症风险的潜力的研究 并影响我们在预防吸烟相关癌症方面的策略， 癌的