The carcinogenicity of N-hydroxy-2-acetamidofluorene (N-OH-AAF), the major genotoxic metabolite of classic model polyaromatic amine carcinogen 2-aminoflurene, has been attributed mainly to the formation of DNA adducts via aryl nitrenium ion intermediate upon further enzymatic activation. Here we show that exposure of N-OH-AAF to UV and sunlight can induce the formation of the well-known DNA adducts as expected; but more interestingly and unexpectedly, oxidative DNA damage was also observed as measured by the formation of DNA single/double strand breaks and 8-oxodG, which were both inhibited by the typical hydroxyl radical scavengers (DMSO and ethanol). ESR secondary radical spin-trapping and fluorescent studies unequivocally confirmed that hydroxyl radical was indeed generated from N-OH-AAF photolysis. We propose that the highly reactive hydroxyl radical can be readily produced via homolysis of N-OH-AAF by UV and sunlight, which can cause oxidative DNA damage. This represents the first report of hydroxyl radical production and DNA damage via UV and sunlight irradiation of the genotoxic hydroxamic acid intermediate, which may provide a new perspective to understand the molecular mechanism for the carcinogenicity of polycyclic aromatic amines.

Unexpected hydroxyl radical production and DNA damage via UV and sunlight irradiation of the genotoxic hydroxamic acid intermediate of polyaromatic amine carcinogen

256th National Meeting (2018)

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