Lipid hydroperoxide-mediated DNA damage

Lipid hydroperoxides are formed in vivo through free radical pathways from the action of reactive oxygen species on polyunsaturated fatty acids. They are also formed as specific products of lipoxygenases and cyclooxygenases. Homolytic: decomposition of lipid hydroperoxides to the alpha,beta -unsaturated aldehyde genotoxins, 4-oxo-2-nonenal, 4,5-epoxy-2(E)-decenal, and 4-hydroxy-2-nonenal occurs through two quite distinct pathways. One pathway involves a complex rearrangement of the alkoxy radical derived from the lipid hydroperoxide and the other pathway involves the intermediate formation of another potential genotoxin, 4-hydroperoxy-2-nonenal. 4,5-Epoxy-2(E)-decenal forms the unsubstituted etheno-2-deoxyadenosine adduct with DNA, a mutagenic lesion which has been observed in human tissue DNA samples. Several new ethano- and etheno-DNAadducts have been identified from the reaction of 4-oxo-2-nonenal with DNA. 4-Hydroxy-2-nonenal forms propano adducts with 2'-deoxyguanosine. It can also up-regulate cyclooxygenase-2 expression. As cyclooxygenase-2 converts linoleic acid into lipid hydroperoxides, this provides a potential mechanism for increased production of genotoxic bifunctional electrophiles. Malondialdehyde (beta -hydroxy-acrolein), another genotoxic bifunctional electrophile, is formed during homolytic decomposition of lipid hydroperoxides that contain more than two double bonds. Other sources of malondialdehyde include, hydroxyl radical-mediated decomposition of the 2'-deoxyribose DNA backbone and formation as a side-product during the biosynthesis of thromboxane A(2). Malondialdehyde reacts with DNA to form primarily a propano adduct with 2'-deoxyguanosine (M(1)G-dR). Significant advances in the characterization and analysis of lipid hydroperoxide-derived endogenous DNA-adducts have been made over the last decade so that dosimetry studies of human populations are now possible. Such studies will help elucidate the role of lipid hydroperoxide-derived endogenous DNA as mediators of cancer, cardiovascular disease, and neurodegeneration, the three most prevalent diseases of aging. (C) 2001 Elsevier Science Inc. All rights reserved.