DNA Adducts of Lipid Peroxidation Products

描述：（申请人提供）DNA的共价修饰是 被认为是化学致癌的第一步。暴露于 致癌物质通常是环境或工作条件，饮食或 smoking.最近，相当多的注意力集中在遗传毒素， 是氧化应激的结果。暴露于这些 化合物是不可避免的。有新的证据表明， 香烟烟雾刺激氧化应激，导致 脂质过氧化产物。脂质的过氧化作用产生了一系列复杂的 亲电物种的一些相对简单的不饱和醛 （2-烯醛）已被鉴定并显示与DNA碱基反应形成 羟基丙加合物。这些烯醛还可以进一步氧化， 2，3-环氧醛与DNA反应生成乙烯加合物。的 环氧醛已被证明是比母体更有效的遗传毒素 enals。该计划的长期目标是制定战略， 位点特异性合成寡核苷酸，其中核碱基已经 被脂质过氧化产物修饰，形成复杂的乙烯加合物。的 核碱基的修饰通常产生新的立体中心， 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，但是立体化学地 加合物的定义。在我们的研究过程中， 也将实现脂质过氧化产物的合成。 已经建立了合作，以研究 变异原将使用多维NMR进行结构研究 方法.结合诱变实验，我们希望建立 这些致突变病变的结构-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 环氧化物水解酶和谷胱甘肽转移酶的产品也将 追求。

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.