Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
Hydroxyl radicals and DNA base damage
Introduction
Various reactive oxygen species including hydroxyl radical, hydrogen peroxide and singlet oxygen together with one-electron process are likely to be involved in mutagenesis and carcinogenesis and possibly in aging 1, 2, 3, 4. In this respect, hydroxyl radical may be considered the main contributing reactive oxygen species to endogenous oxidation of cellular DNA. This is likely to occur from the initial formation of superoxide radical as a side product, for example, of the respiratory burst in mitochondria. Exposure of cells to chemicals including various carcinogens and physical agents such as ionizing and solar radiations may promote the formation of both superoxide radical and hydroxyl radical. It should be noted that superoxide radical which by itself is rather unreactive towards DNA may be involved in several biochemical reactions. These include the formation of peroxynitrite with nitric oxide 5, 6together with the reduction of the thymine hydroperoxyl radicals (vide infra) and oxidized forms of transition metals. Superoxide radical may also be either spontaneously or catalytically dismutated into hydrogen peroxide. The latter chemical which is almost inert towards DNA with the exception of a selective N-oxidation of adenine [7]may be converted into the highly reactive hydroxyl radical through a Fenton type reaction involving reduced transition metals. It is important to keep in mind that the rate of the reactions of radical is controlled by diffusion. Therefore, the oxidation processes mediated by the latter highly reactive and rather non-specific oxygen species are occurring at the sites of its formation. At least, five main classes of -mediated oxidative damage may be generated, including oxidized bases, abasic sites, DNA–DNA intrastrand adducts 8, 9, DNA strand breaks and DNA–protein cross-links 7, 10. In the present survey, the currently available information on the structural aspects of oxidized DNA bases and their mechanism of formation is reviewed. Emphasis has been placed on the hydroxyl radical-mediated decomposition products of the thymine and guanine moieties of both DNA and model compounds. Information on the main oxidation products of adenine [11], cytosine [12]and 5-methylcytosine [13]has been reported elsewhere. The second part of the chapter is devoted to a critical review of the available assays aimed at monitoring the formation of oxidized bases within cellular DNA, tissue and biological fluids.
Section snippets
Reactions of radicals with the thymine and the guanine moieties of isolated DNA and model compounds: final products and mechanistic aspects
The major endogenous source of oxidizing agents within cells is provided by transition metal-driven Fenton reactions as the result of initially generated superoxide radicals. This leads to the formation of either highly reactive hydroxyl radicals or related oxidizing species such as perferryl ions. It should be noted that hydroxyl radical is efficiently involved in the abstraction of hydrogen atom from various sites of the sugar moiety with the exception of the C2′ 14, 15. In most cases, the
Measurement of oxidative base damage in cellular DNA and biological fluids
Major efforts were devoted during the last decade to the development of chemical and biochemical assays aimed at monitoring the formation of oxidative base damage to DNA within both cells and individuals (for comprehensive reviews, see Refs. 48, 49). The measurement of oxidative DNA base damage in biological samples has to meet several major requirements [49]. Among them, the threshold of detection for the assays should be, at least, of one single lesion per 105–106 normal bases in a sample
Oxidative base damage to cellular DNA
The main problems associated with the measurement of oxidized bases within cellular DNA are now well identified. Prepurification of DNA components is a requisite prior to the silylation and enzymic phosphorylation steps in the improved GC–MS and -postlabeling assays, respectively [51]. As already mentioned, prevention of the artefactual induction of oxidation during DNA extraction and subsequent enzymatic digestion in most of the chromatographic assays is still a major objective to be
Conclusion
Significant progress was made during the last decade for a better understanding of the mechanisms of formation of oxidative damage to DNA. However, as already outlined, there is still a paucity of data on the formation of most of the oxidative base lesions within cellular DNA at the exception of 8-oxodGuo (23) and to a lesser extent to 5-hydroxy-2′-deoxycytidine. This would require both the improvement of existing assays and the development of new methods with emphasis on the prevention of the
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