DNA strand scission by the nephrotoxin [2,2'-bipyridine]-3,3',4,4'-tetrol-1,1'-dioxide and related compounds in the presence of iron.
The capacity of non-illuminated nephrotoxin orellanine ([2,2'-bipyridine]-3,3',4,4'-tetrol-1,1'-dioxide) to induce DNA damage in the presence of ferrous iron and dioxygen has been evaluated. Maximal single-strand breaks in plasmid DNA were obtained with a metal to ligand ratio 1:3. Instantaneous oxidation of Fe2+ in presence of orellanine under air was responsible for oxy-radical production concomitant to a stable ferric complex Fe(III)Or3 formation, leading to oxidative DNA breakage at physiological pH. DNA damage was lowered in the presence of SOD and catalase or DMSO, indicating a set of reactions that leads to oxy-radical generation. Iron chelators such as DTPA and EDTA had no protecting effect, Desferal slightly protected. GSH acted as an oxy-radical scavenger, whereas cysteine induced stronger damage. Closely related bipyridine compounds were also studied in presence of Fe2+ and O2 using a combination of spin-trapping and DNA-nicking experiments, none of which were able to chelate iron and induce damage at pH 7. Both catecholic moieties and aminoxide groups are required for observing breakage at physiological pH.
Cantin-Esnault
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Département de Pharmacochimie Moléculaire, UMR CNRS, France. Danielle.Esnault@ujf-grenoble.fr
Oubrahim
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H
Richard
J M
JM
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002374:Catalase / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D005296:Ferrous Compounds / Q000494:pharmacology*; D005978:Glutathione / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007502:Iron Chelating Agents / Q000494:pharmacology; D010084:Oxidation-Reduction; D004369:Pentetic Acid / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D013056:Spectrophotometry, Ultraviolet; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000494:pharmacology; D013997:Time Factors
D005296:Ferrous Compounds; D007502:Iron Chelating Agents; D013113:Spin Labels; C030076:orellanine; D015082:2,2'-Dipyridyl; D004369:Pentetic Acid; D004492:Edetic Acid; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione; D004121:Dimethyl Sulfoxide