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Mechanisms of Free Radical Damage to DNA



M Miral Dizdar


1.1 Reactions of Free Radicals with DNAFree radicals produce a number of lesions in DNA such as base lesions, sugar lesions, DNA-protein cross-links, single-strand breaks, double-strand breaks and abasic sites by a variety of mechanisms (Teoule and Cadet 1978, von Sonntag 1987, Oleinick et al 1987, Steenken 1989, Halliwell and Aruoma 1991, Dizdaroglu 1992, Breen and Murphy 1995). 1.1.1 Reactions with the Base Moieties of DNAHydroxyl radical (OH ), eaq) and H atom react with the heterocyclic bases in DNA by addition. Hydroxyl radical adds to the C5-C6 double bound of pyrimidines at almost diffusion-controlled rates ((5 x 109 M-1 s -1) (von Sonntag 1987), giving rise to the formation of 5-hydroxy-6-yl and 6-hydroxy-5-yl radicals. The C5-position of pyrimidines with the highest electron density is the preferred site of attack by OH because of the electrophilic nature of OH?. With thymine and cytosine, OH adds to the C5-position to the extent of 60% and 90%, respectively, and to the C6-position to the extent of 30% and 10%, respectively (Fujita and Steenken 1981, Hazra and Steenken 1981, Hazra and Steenken 1983). Abstraction by OH of an H atom from the methyl group of thymine also occurs and amounts to 10% contribution (Fujita and Steenken 1981). Figure 1.1 illustrates the structures of thymine radicals. The OH-adduct radicals of pyrimidines differ with respect to their redox properties. The 5-hydroxy-6-yl radicals have reducing properties, whereas the 6-hydroxy-5yl radicals have oxidizing properties (Steenken 1987). Reactions of eaqu-^ with thymine and cytosine occur at diffusion-controlled rates (calculated rate constants of 1.3 1.7 x 1010M-1s-1) (von Sonntag 1987) and electron adducts are produced in these reactions. Electron adducts (radical anions) generally protonate in water to give 6-hydro-5-yl radicals (Hissung and von Sonntag 1979, Das et al 1984, Novais and Steenken 1986). Figure 1.2 illustrates these reactions in the case of thymine. Similar H-adduct radicals are also formed by reactions of H atom with pyrimidines (Das et al 1985). These reactions are considerably slower than those of OH and eaq- and are in the order of 1 5 x 108 M -1 s -1 (von Sonntag 1987). In the oxygenated systems, adduct radicals of pyrimidines are converted into corresponding peroxyl radicals in diffusion-controlled reactions with oxygen:Pyr +O2 PyrO2 Hydroxyl radicals reacts with purines at diffusion-controlled rates (5-9 x 109M-1s-1) (von Sonntag 1987). Addition to C4-, C5- and C8-positions results in equal amounts of oxidizing and reducing types of adduct radicals (O Neill 1983). As an example, Figure 1.3 illustrates the structures of the OH-adduct radicals of guanine. These adduct radicals demonstrate a redox ambivalence meaning that different mesomeric structures of the same adduct radical can have oxidizing or reducing properties (Steenken 1989). The C4-OH- and C5-OH-adduct radicals dehydrate and are converted into radicals with oxidizing properties (Steenken 1987, Vieira and Steenken 1987, 1990). The C8-OH adduct radicals of purines can undergo unimolecular opening of the imidazole ring (Steenken 1989). Hydrated electrons react with purines at diffusion-controlled rates (0.9 1.3 x 1010M-1s-1) (von Sonntag 1987), to form electron adducts which undergo protonation reactions (Steenken 1989). Reactions of oxygen with adduct radicals of purines are not as well understood as those with adduct radicals of pyrimidines. The majority of purine-derived adduct radicals may not react with oxygen (von Sonntag 1987, Steenken 1989). There is evidence that 5-OH- and 8-OH-adduct radicals of adenine react with oxygen to form peroxyl radicals undergo elimination of O2- to give cations (Vieira and Steenken 1987):HO-ADe + O2 -> HO-AdeO2- -> HO-Ade+ + O2-
DNA and Free Radicals: Techniques, Mechanisms and Applications
Publisher Info
OICA International (UK) Ltd., London, -1


8, 5' - cyclopurine-2' -deo, 8-hydroxyguanine, hydroxyl radical, modified bases, modified sugars, oxidative DNA damage


, M. (1998), Mechanisms of Free Radical Damage to DNA, OICA International (UK) Ltd., London, -1 (Accessed April 15, 2024)
Created January 1, 1998, Updated February 19, 2017