DNA-DAMAGE INDUCED BY FUROCOUMARIN HYDROPEROXIDES PLUS UV (360 NM)

When irradiated at 360 nm, furocoumarins with a hydroperoxide group in a side chain efficiently give rise to a type of DNA damage that can b est be explained by a photo-induced generation of hydroxyl radicals fr om the excited photosensitizers. The observed DNA damage profiles, i.e . the ratios of single-strand breaks, sites of base loss (AP sites) an d base modifications sensitive to formamidopyrimidine - DNA glycosylas e (FPG protein) and endonuclease III, are similar to the DNA damage pr ofile produced by hydroxyl radicals generated by ionizing radiation or by xanthine and xanthine oxidase in the presence of Fe(III) - EDTA. N o such damage is observed with the corresponding furocoumarin alcohols or in the absence of near-UV radiation. The damage caused by the phot o-excited hydroperoxides is not influenced by superoxide dismutase (SO D) or catalase or by D2O as solvent. The presence of t-butanol, howeve r, reduces both the formation of single-strand breaks and of base modi fications sensitive to FPG protein. The cytotoxicity caused by one of the hydroperoxides in L5178Y mouse lymphoma cells is found to be depen dent on the near-UV irradiation and to be much higher than that of the corresponding alcohol. Therefore the new type of photo-induced damage occurs inside cells. Intercalating photosensitizers with an attached hydroperoxide group might represent a novel and versatile class of DNA damaging agents, e.g. for phototherapy.