Hydroperoxide-induced DNA damage and mutations

Hydroperoxides (ROOH) are believed to play an important role in the generat ion of free radical damage in biology. Hydrogen peroxide (R = H) is produce d by endogenous metabolic and catabolic processes in cells, while alkyl hyd roperoxides (R = Lipid, protein, DNA) are produced by free radical chain re actions involving molecular oxygen (autooxidation). The role of metal ions in generating DNA damage from hydroperoxides has long been recognized, and several distinct, biologically relevant mechanisms have been identified. Id entification of the mechanistic pathways is important since it will largely determine the types of free radicals generated, which will largely determi ne the spectrum of DNA damage produced. Some mechanistic aspects of the rea ctions of low valent transition metal ions with ROOH and their role in muta genesis are reviewed with a perspective on their possible role in the biolo gical generation of DNA damage. A survey of hydroperoxide-induced mutagenes is studies is also presented. In vitro footprinting of DNA damage induced b y hydroperoxides provides relevant information on sequence context dependen t reactivity, and is valuable for the interpretation of mutation spectra si nce it represents the damage pattern prior to cellular repair. Efforts in t his area are also reviewed. (C) 2000 Elsevier Science B.V. All rights reser ved.