title: Direct evidence for hydroxyl radical-induced damage to nucleic acids by chromium(VI)-derived species: implications for chromium carcinogenesis.
abstract: Reduction of Cr(VI) by NADH and NADPH has been shown to yield Cr(V) species, which have been detected by electron paramagnetic resonance (EPR) spectroscopy. The fine structure on the EPR signal of the Cr(V) species is consistent with the presence of two NAD(P)H ligands in a square-pyramidal arrangement with a single oxygen (oxo) group at the apex. Neither this species nor the initial Cr(VI) complex damage DNA components as evidenced by the lack of effect of these compounds on the optical and EPR signals of the Cr(VI) and Cr(V) species respectively. Addition of hydrogen peroxide to the Cr(V) species is shown to result in the formation of a further transient EPR signal, the parameters of which are consistent with an assignment to a Cr(V)-peroxide complex. Inclusion of the spin trap 5,5-dimethyl-1-pyrroline-N-oxide in this system demonstrates that hydroxyl radicals are also generated, possibly via the decomposition of the peroxide complex. Inclusion of DNA components in this system together with the spin trap 2-methyl-2-nitrosopropane results in the detection of base- and sugar-derived radicals; the characteristic EPR signals of these species have allowed both the identification of these species and their mechanism of formation to be determined. The signals from the former species are consistent with radical addition to the base, whereas the sugar-derived species are believed to be formed via hydrogen atom abstraction. In each case, this behaviour is consistent with hydroxyl radicals being the damaging species in systems where Cr(V) is generated in the presence of hydrogen peroxide. These results therefore suggest that it may be the hydroxyl radical that is the ultimate carcinogenic species in cells and systems exposed to Cr(VI).
authors.affiliation: Department of Chemistry, University of York, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Molyneux
authors.forename: M J
authors.initials: MJ
authors.lastname: Davies
mesh_terms: D002273:Carcinogens / Q000737:chemistry* / Q000633:toxicity*; D002857:Chromium / Q000737:chemistry* / Q000633:toxicity*; D003497:Cyclic N-Oxides; D004247:DNA / Q000737:chemistry* / Q000187:drug effects*; D004249:DNA Damage; D003853:Deoxyribonucleosides / Q000737:chemistry / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D004347:Drug Interactions; D004578:Electron Spin Resonance Spectroscopy; D006861:Hydrogen Peroxide / Q000737:chemistry; D017665:Hydroxyl Radical / Q000737:chemistry* / Q000633:toxicity*; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D009249:NADP / Q000737:chemistry / Q000378:metabolism; D009603:Nitroso Compounds; D010084:Oxidation-Reduction; D012313:RNA / Q000737:chemistry* / Q000187:drug effects*; D012263:Ribonucleosides / Q000737:chemistry / Q000378:metabolism; D012265:Ribonucleotides / Q000737:chemistry / Q000378:metabolism; D013113:Spin Labels
chemical_list: D002273:Carcinogens; D003497:Cyclic N-Oxides; D003853:Deoxyribonucleosides; D003854:Deoxyribonucleotides; D009603:Nitroso Compounds; D012263:Ribonucleosides; D012265:Ribonucleotides; D013113:Spin Labels; D002857:Chromium; D009243:NAD; D017665:Hydroxyl Radical; D009249:NADP; D012313:RNA; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D004247:DNA; D006861:Hydrogen Peroxide; C034526:tert-nitrosobutane