Ascorbic acid oxidation and DNA scission catalyzed by iron and copper chelates.
The asorbic acid (AH-) auto-oxidation rates catalyzed by copper chelates of 1,10-phenanthroline (OP) or by iron chelates of bleomycin (BLM) are only slightly higher than the oxidation rates catalyzed by the metal ions. AH- oxidation in the presence of DNA is accompanied by degradation of the DNA. The rates of DNA scission by the metal chelates are markedly higher than the rates induced by the free metal ions. AH- oxidation is slowed down in the presence of DNA which forms ternary complexes with the chelates. The ternary complexes react slowly with AH- but induce DNA double strand breaks more efficiently than the free metal chelates. With OP, DNA is degraded by the reaction of the ternary complex, DNA-(OP)2Cu(I), with H2O2. AH- oxidation in the presence of DNA was biphasic, showing a marked rate increase after DNA was cleaved. We suggest that this sigmoidal pattern of the oxidation curves reflects the low initial oxidative activity of the ternary complexes, accelerating as DNA is degraded. Using O2- produced by pulse radiolysis as a reductant, we found that AH- oxidation with (OP)2Cu(II) induced more DNA double strand breaks per single strand break than bipyridine-copper. The site specific DNA damaging reactions indicated by these results are relevant to the mechanism of cytotoxic activities of bleomycin and similar antibiotics or cytotoxic agents.
Aronovitch
J
J
Department of Molecular Biology, School of Medicine, Hebrew University Jerusalem, Israel.
Godinger
D
D
Samuni
A
A
Czapski
G
G
D001205:Ascorbic Acid / Q000378:metabolism*; D001761:Bleomycin / Q000378:metabolism / Q000031:analogs & derivatives; D002384:Catalysis; D003300:Copper / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D006861:Hydrogen Peroxide / Q000378:metabolism; D007502:Iron Chelating Agents / Q000378:metabolism*; D007700:Kinetics; D009994:Osmolar Concentration; D010084:Oxidation-Reduction; D010618:Phenanthrolines / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013481:Superoxides / Q000378:metabolism
D007502:Iron Chelating Agents; D010618:Phenanthrolines; C023503:iron bleomycin; D001761:Bleomycin; D013481:Superoxides; D003300:Copper; D004247:DNA; D006861:Hydrogen Peroxide; D001205:Ascorbic Acid; C025205:1,10-phenanthroline