Iron complexes of deferiprone and dietary plant catechols as cytoprotective superoxide radical scavengers(1).
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.
Moridani
M Y
MY
Faculty of Pharmacy, University of Toronto, M5S 2S2, Toronto, Ontario, Canada.
O'Brien
P J
PJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002396:Catechols / Q000494:pharmacology* / Q000627:therapeutic use; D003300:Copper / Q000378:metabolism; D000077543:Deferiprone; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000627:therapeutic use; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D008297:Male; D020011:Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control; D013481:Superoxides / Q000378:metabolism*
D000975:Antioxidants; D002396:Catechols; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D020011:Protective Agents; D011728:Pyridones; D013481:Superoxides; D000077543:Deferiprone; D003300:Copper; D007501:Iron