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 致癌物通常是环境或工作条件、饮食或 抽烟。最近，基因毒素引起了人们的极大关注。 是由于氧化应激而内源性形成的。暴露在这些环境中 化合物是不可避免的。有新的证据表明， 香烟烟雾会刺激氧化应激，导致体内 脂质过氧化产物。脂质的过氧化作用形成了一个复杂的排列 亲电性的物种。一些相对简单的不饱和醛 (2-烯醛)已被鉴定，并被证明与DNA碱基反应形成 羟丙基加合物。这些肠还可以进一步氧化为 与DNA反应生成亚乙基加合物的2，3-环氧醛。这个 环氧醛已被证明是比母体更强的遗传毒素。 肠系膜。这一计划的长期目标是为 碱基已存在的寡核苷酸的定点合成 被脂质过氧化产物修饰以形成复杂的乙烯加合物。这个 核酸基的修饰经常产生新的立体产生中心，这 将由我们的合成方法控制。因此，我们的目标不仅是 以立体化学方法合成定点修饰的寡核苷酸 还定义了加合物。在我们的研究过程中，对映体选择性 脂质过氧化产物的合成也将实现。 已经建立了合作来检查细胞的结构和生物学 诱变剂。将使用多维核磁共振进行结构研究 方法：研究方法。结合诱变实验，我们希望建立 这些诱变损伤的构效关系。合作以实现 检测各种脂质过氧化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 被追捕。

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.