Iron complexes of deferiprone and dietary plant catechols as cytoprotective superoxide radical scavengers(1).

Abstract

Superoxide radicals have been implicated in the pathogenesis of aging, cataract, ischemia-reperfusion, cancer and inflammatory diseases. In the present work, we found that deferiprone (L1), an iron-chelating drug, and dietary dihydroxycinnamic acids (catechols) were much more effective at protecting isolated rat hepatocytes against hypoxia-reoxygenation injury if complexed with Fe(3+). Furthermore, the 2:1 catechol-metal complexes with Cu(2+), Fe(2+), and Fe(3+) were also more effective than uncomplexed catechols in scavenging superoxide radicals generated enzymically (xanthine oxidase/hypoxanthine). The 2:1 deferiprone:Fe(3+) complex was less effective at scavenging enzymically generated superoxide radicals even though it was effective at preventing hepatocyte hypoxia-reoxygenation injury. On the other hand, the 1:1 deferoxamine:Fe(3+) complex, another iron-chelating drug, did not prevent hepatocyte hypoxia-reoxygenation injury and did not scavenge enzymically generated superoxide radicals. Furthermore, hepatocytes readily reduced the 2:1 deferiprone:Fe(3+) complex but not the deferoxamine:Fe(3+) complex. These results suggest that the initial step in superoxide radical scavenging (SRS) activity is the formation of a redox complex between Fe(3+) and deferiprone or catechols. The [deferiprone:Fe(3+)] complex was more cytoprotective than would be expected from its SRS activity. This suggests that [deferiprone:Fe(3+)] complex is reduced by a ferrireductase present on the hepatocyte membrane to form [deferiprone:Fe(2+)] complex, which then scavenges superoxide radicals. Therefore, the clinically used deferiprone (L1) may have therapeutic advantages over deferoxamine in having a double role therapeutically: (a) it chelates iron to alleviate iron overload pathology, and (b) the readily formed iron complex protects hepatocytes from superoxide radical-mediated hypoxia-reoxygenation injury.

• Authors: M Y Moridani, P J O'Brien
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 62 Issue 12 Pg. 1579-85 (Dec 15 2001) ISSN: 0006-2952 [Print] England
• PMID: 11755110 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Catechols
• Free Radical Scavengers
• Iron Chelating Agents
• Protective Agents
• Pyridones
• Superoxides
• Deferiprone
• Copper
• Iron

Topics

• Animals
• Antioxidants (pharmacology, therapeutic use)
• Catechols (pharmacology, therapeutic use)
• Copper (metabolism)
• Deferiprone
• Disease Models, Animal
• Free Radical Scavengers (pharmacology, therapeutic use)
• Iron (metabolism)
• Iron Chelating Agents (pharmacology)
• Male
• Protective Agents (pharmacology, therapeutic use)
• Pyridones (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (prevention & control)
• Superoxides (metabolism)