83 - Metal-independent Hydroxyl Radical Production and DNA Damage by Sunlight-Irradiation of Hydroxamic Acid Carcinogens

Abstract

The hydroxyl radical (•OH) has been considered to be one of the most reactive oxygen species produced in biological systems, which can cause DNA, protein, and lipid oxidation. N-hydroxy-2-acetamidofluorene (N-OH-AAF) has been identified as a major genotoxic metabolite of 2-nitroflurene, a polyaromatic amine carcinogen commonly found in diesel exhaust. The carcinogenicity of N-OH-AAF has been mainly attributed to the formation of DNA adducts via aryl nitrenium ion. Recently, we found, unexpectedly, that exposure of N-OH-AAF to sunlight can induce the formation of not only DNA single and double strand breaks, but also 8-OHdG, both of which were inhibited by the typical •OH scavengers (DMSO and ethanol), but not by the classic iron and copper chelating agents. ESR secondary radical spin-trapping with DMPO and fluorescent studies with terephthalic acid confirmed that •OH was indeed generated from N-OH-AAF photolysis, with the formation of the characteristic DMPO/•OH and the fluorescent 2-hydroxyterephthalic acid, respectively. This is the first report that the highly reactive •OH can be readily produced via homolysis of N-OH-AAF by sunlight, which represents a new mechanism of •OH production that does not require redox-active metal ions, and provide a new perspective to understand the molecular mechanism for the carcinogenicity of polycyclic aromatic amines.