Zinc--a redox-inactive metal provides a novel approach for protection against metal-mediated free radical induced injury: study of paraquat toxicity in E. coli.
The essential mediatory role of copper and iron in a variety of free radical-induced injuries, including paraquat-induced biological damage has been recently demonstrated. It was postulated that these transition metals undergo cyclic redox reactions, and serve as centers for repeated production of hydroxyl radical, which are the ultimate deleterious agents. Additionally, we had presented evidence indicating efficient protection against paraquat toxicity by agents commonly employed (chelators, chemical scavengers and protecting enzymes). In this study we have used the E. coli model in order to develop a new approach for protection against paraquat-induced metal-mediated cellular injury. It entails the administration of excess zinc (up to 50 fold over copper), which results in an inhibition of the toxic effect of paraquat. Lineweaver- Burk analysis demonstrates the competitive mode of this inhibition. The suggested mechanism involves the displacement of the redox-active copper (or iron) from its binding site and by this diverting the site of repeated production of free radicals. Thus, use of redox-inactive metals, which possess high similarity of their ligand chemistry, to that of iron and copper but are of relative low toxicity by themselves, should be considered for intervention in paraquat toxicity and in other metal-mediated free radical-induced injurious processes.
Chevion
M
M
Department of Cellular Biochemistry, Hebrew University of Jerusalem, Israel.
Korbashi
P
P
Katzhandler
J
J
Saltman
P
P
D001665:Binding Sites / Q000187:drug effects; D003300:Copper / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects*; D005609:Free Radicals; D007501:Iron / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D010269:Paraquat / Q000037:antagonists & inhibitors / Q000633:toxicity*; D015032:Zinc / Q000494:pharmacology*
D005609:Free Radicals; D008024:Ligands; D003300:Copper; D007501:Iron; D015032:Zinc; D010269:Paraquat