title: Manganese-mediated oxidative damage of cellular and isolated DNA by isoniazid and related hydrazines: non-Fenton-type hydroxyl radical formation.
abstract: The mechanism by which hydrazines induce damage to cellular and isolated DNA in the presence of metal ions has been investigated by pulsed-field gel electrophoresis (PFGE), DNA sequencing methods, and the ESR spin-trapping technique. For the detection of single-strand breaks by PFGE, an experimental procedure with alkali treatment has been designed. Isoniazid, hydrazine, and phenylhydrazine induced DNA single- and double-strand breaks in cells pretreated with Mn(II), whereas iproniazid did not. With isolated 32P-DNA, isoniazid produced DNA damage in the presence of Cu(II), Mn(II), or Mn(III). Iproniazid damage isolated DNA only in the presence of Cu(II). The Cu(II)-mediated DNA damage by isoniazid or iproniazid is due to active oxygen species other than hydroxyl free radical (.OH), presumably the Cu(I)-peroxide complex. Cleavage of isolated DNA by isoniazid plus Mn(II) occurred without marked site specificity. The DNA damage was inhibited by .OH scavengers and superoxide dismutase (SOD) but not by catalase, suggesting the involvement of .OH formed via O2- but not via H2O2. Consistently, in ESR experiments .OH formation was observed during Mn(II)-catalyzed autoxidation of isoniazid, and the .OH formation was inhibited by SOD, but not by catalase. Iproniazid plus Mn(II) produced no or little .OH. We propose a reaction mechanism for the .OH formation without a H2O2 intermediate during manganese-catalyzed autoxidation of hydrazine. The present and previous data raise the possibility that hydrazines plus Mn(II)-induced cellular DNA damage may occur, at least in part, through the non-Fenton-type reaction.
authors.affiliation: Department of Public Health, Faculty of Medicine, Kyoto University, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: S
authors.initials: S
authors.lastname: Kawanishi
mesh_terms: D001345:Autoradiography; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004578:Electron Spin Resonance Spectroscopy; D016521:Electrophoresis, Gel, Pulsed-Field; D016166:Free Radical Scavengers; D006834:Hydrazines / Q000633:toxicity*; D006878:Hydroxides / Q000737:chemistry*; D017665:Hydroxyl Radical; D007538:Isoniazid / Q000633:toxicity*; D008345:Manganese / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D006834:Hydrazines; D006878:Hydroxides; D017665:Hydroxyl Radical; D008345:Manganese; D004247:DNA; D010100:Oxygen; D007538:Isoniazid