Iron complexes of deferiprone and dietary plant catechols as cytoprotective superoxide radical scavengers

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 Fe3+. Furthermore, the 2:1 catechol-metal complexes with Cu2+, Fe2+, and Fe3+ were also more effective than uncomplexed catechols in scavenging superoxide radicals generated enzymically (xanthine oxidase/hypoxanthine). The 2:1 deferiprone:Fe3+ 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:Fe3+ 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 31 complex. These results suggest that the initial step in superoxide radical scavenging (SRS) activity is the formation of a redox complex between Fe3+ and deferiprone or catechols. The [deferiprone: Fe3+] complex was more cytoprotective than would be expected from its SRS activity. This suggests that [deferipronc:Fe3+] complex is reduced by a ferrireductase present on the hepatocyte membrane to form [deferiprone:Fe2+] complex, which then scavenges superoxide radicals. Therefore, the clinically used deferiprone (L 1) 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. (C) 2001 Elsevier Science Inc. All rights reserved.