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 ferro us iron and dioxygen has been evaluated. Maximal single-strand breaks in pl asmid DNA were obtained with a metal to ligand ratio 1:3. Instantaneous oxi dation of Fe2+ in presence of orellanine under air was responsible for oxy- radical production concomitant to a stable ferric complex Fe(III)Or(3) form ation, leading to oxidative DNA breakage at physiological pH. DNA damage wa s 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 Fe2and O-2 using a combination of spin-trapping and DNA-nicking experiments, n one of which were able to chelate iron and induce damage at pH 7. Both cate cholic moieties and aminoxide groups are required for observing breakage at physiological pH.