DNA Adducts of Lipid Peroxidation Products

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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.