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RESEARCH PRODUCT

Oxidative DNA Damage Profiles in Mammalian Cells

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Reactive oxygen species (ROS) are formed inside cells not only under the influence of exogenous agents (visible light, ionizing radiation, and many oxidants such as peroxides or quinones), but also under normal (physiological) conditions as byproducts of oxygen metabolism and other cellular redox reactions (Pryor 1986; Halliwell and Gutteridge 1986; Sies 1986; Clayson et al. 1994). ROS such as hydroxyl radicals and singlet oxygen are a serious threat to the integrity of the cellular genome, since they efficiently react with DNA to generate many types of DNA modifications, at least some of which are pre- mutagenic (Breimer 1990; Halliwell and Aruoma 1991; Epe 1991; Feig et al. 1994). Steady-state levels of 8-hydroxyguanine (8-oxoG) and other oxidative DNA base modifications observed in untreated cells indicate that the various cellular defense and DNA repair systems (Demple and Harrison 1994) do not completely eliminate the mutagenic risk associated with ROS formation even under normal growth conditions. This led to the assumption that oxidative DNA damage is a causal or ancillary risk factor for the development of cancer and several age-correlated degenerative diseases (Ames 1983; Wallace 1992; Gutteridge 1993). A strategy to verify this hypothesis and to quantify the mutagenic risk associated with oxidative DNA damage could be to determine (a) what type of oxidative DNA damage profile (pattern of DNA modifications) is generated in the cells under the conditions of interest and (b) the mutagenicity associated with this damage profile. Then, the quantification of any suitable marker modification of this damage profile should allow an estimation of the mutagenicity to be expected.