Free radicals have been incriminated in a variety of injurious processes including the toxicity of the
herbicide paraquat and the damage following
ischemia and reperfusion of different organs. Based on the assumption that
iron and
copper could serve as mediators for the transformation of relatively low reactive species (such as
superoxide radicals,
hydrogen peroxide, ascorbate, and others) to the highly reactive species, in the site-specific
metal-mediated mechanism, two new modes for intervention have been tried out. The first is the introduction of specific
chelators that "pull" out redox-active and available metals, and by this reduce the apparent damage.
Desferrioxamine was shown to protect bacterial cells and mammals against the poisonous effects of
paraquat. Using the retrogradly perfused isolated rat heart, we have demonstrated that the
chelator neocuproine, which effectively binds both
iron and
copper provides a major protection against
hydrogen peroxide-induced cardiac damage and against
ischemia/reperfusion-induced arrhythmias. Likewise,
TPEN a
heavy metal chelator, provides almost total (greater than 90%) protection against
ischemia/reperfusion-induced arrhythmias. The other mode of intervention is the use of redox-inactive
metal ions that could compete for the binding sites of
iron and
copper, and by this "push" these
metal ions out, lead to their displacement, and divert the site of
free radical attack. Applying Zn(II) complexes provided a marked protection against
metal mediated
free radical-induced damage in the
copper-mediated
paraquat toxicity to E. coli, and in the arrhythmias induced by
ischemia and reperfusion. It is proposed that the complex
zinc-desferrioxamine would be the ultimate protector being effective by both the "pull" and "push" mechanisms.