DNA Adducts of Lipid Peroxidation Products

脂质过氧化产物的 DNA 加合物

• 批准号: 6685891
• 负责人: Carmelo J Rizzo
• 金额: $ 26.43万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6685891
• 关键词: DNA damage; adduct; chemical structure function; enzyme activity; epoxide hydrolase; glutathione transferase; lipid peroxides; method development; nucleic acid chemical synthesis; oligonucleotides; peroxidation; stereochemistry

DESCRIPTION: (PROVIDED BY APPLICANT) The covalent modification of DNA is believed to be the initial step in chemical carcinogenesis. Exposure to carcinogens is often a result of environmental or work conditions, diet or smoking. Recently, considerable attention has been focused on genotoxins that are formed endogenously as a result of oxidative stress. Exposure to these compounds is unavoidable. There is emerging evidence that constituents of cigarette smoke stimulate oxidative stress, resulting in elevated levels of lipid peroxidation products. The peroxidation of lipids gives a complex array of electrophilic species. A number of relatively simple unsaturated aldehydes (2-enals) have been identified and shown to react with DNA bases to form hydroxypropano adducts. These enals can also undergo further oxidation to 2,3-epoxyaldehydes which react with DNA to give etheno adducts. The epoxyaldehydes have been shown to be more potent genotoxins than the parent enals. The long-term goal of this program is to develop strategies for the site-specific synthesis of oligonucleotides in which nucleobases have been modified by lipid peroxidation products to form complex etheno adducts. The modification of the nucleobase often generates new stereogenic centers, which will be controlled by our synthetic approaches. Thus, our aim is to not only to synthesize site-specifically modified oligonucleotides, but stereochemically defined adducts as well. During the course of our studies, enantioselective syntheses of the lipid peroxidation products will also be achieved. Collaborations have been established to examine the structure and biology of the mutagens. Structural studies will be performed using multi-dimensional NMR methods. In combination with mutagenesis experiments, we hope to establish structure-activity relationships of these mutagenic lesions. A collaboration to examine the detoxification of the various stereoisomers of lipid peroxidation products with epoxide hydrolase and glutathione transferase will also be pursued.

描述：（由申请人提供）DNA 的共价修饰是 被认为是化学致癌的第一步。接触 致癌物通常是环境或工作条件、饮食或 吸烟。最近，基因毒素引起了人们的极大关注。 由于氧化应激而内源性形成。接触这些 化合物是不可避免的。越来越多的证据表明， 香烟烟雾会刺激氧化应激，导致氧化应激水平升高 脂质过氧化产物。脂质的过氧化产生复杂的阵列 亲电物种。一些相对简单的不饱和醛 (2-烯醛) 已被鉴定并显示可与 DNA 碱基反应形成 羟基丙醇加合物。这些烯醛还可以进一步氧化成 2,3-环氧醛与 DNA 反应生成乙烯加合物。这 环氧醛已被证明是比母体更有效的基因毒素 埃纳尔斯。该计划的长期目标是制定战略 寡核苷酸的位点特异性合成，其中核碱基已被 通过脂质过氧化产物修饰形成复杂的乙烯加合物。这 核碱基的修饰通常会产生新的立体中心， 将由我们的合成方法控制。因此，我们的目标不仅是 合成位点特异性修饰的寡核苷酸，但立体化学 也定义了加合物。在我们的研究过程中，对映选择性 脂质过氧化产物的合成也将实现。 已建立合作来检查其结构和生物学 诱变剂。将使用多维核磁共振进行结构研究 方法。结合诱变实验，我们希望建立 这些诱变病变的结构-活性关系。合作 检查脂质过氧化的各种立体异构体的解毒作用 含有环氧化物水解酶和谷胱甘肽转移酶的产品也将 追击。