Oxidative damage to human red cells induced by copper and iron complexes in the presence of ascorbate.
The role of trace metals in the generation of free radical mediated oxidative stress in normal human red cells was studied. Ascorbate and either soluble complexes of Cu(II) or Fe(III) provoked changes in red cell morphology, alteration in the polypeptide pattern of membrane proteins, and significant increases in methemoglobin. Neither ascorbate nor the metal complexes alone caused significant changes to the cells. The rate of methemoglobin formation was a function of ascorbate and metal concentrations, and the chemical nature of the chelate. Cu(II) was about 10-times more effective than Fe(III) in the formation of methemoglobin. Several metals were tested for their ability to compete with Cu(II) and Fe(III). Only zinc caused a significant inhibition of methemoglobin formation by Fe(III)-fructose. These observations suggest that site-specific as well as general free radical damage is induced by redox metals when the metals are either bound to membrane proteins or to macromolecules in the cytoplasm. The Cu(II) and Fe(III) function in two catalytic capacities: (1) oxidation of ascorbate by O2 to yield H2O2, and (2) generation of hydroxyl radicals from H2O2 in a Fenton reaction. These mechanisms are different from the known damage to red cells caused by the binding of Fe(III) or Cu(II) to the thiol groups of glucose-6-phosphate dehydrogenase. Our system may be a useful model for understanding the mechanisms for oxidative damage associated with thalassemia and other congenital hemolytic anemias.
Shinar
E
E
Department of Hematology, Hadassah Medical Center, Jerusalem, Israel.
Rachmilewitz
E A
EA
Shifter
A
A
Rahamim
E
E
Saltman
P
P
D001205:Ascorbic Acid / Q000494:pharmacology*; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000633:toxicity*; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects*; D005609:Free Radicals; D005632:Fructose / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007501:Iron / Q000633:toxicity*; D008565:Membrane Proteins / Q000097:blood; D008706:Methemoglobin / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D010084:Oxidation-Reduction; D013997:Time Factors; D015032:Zinc / Q000494:pharmacology
D002614:Chelating Agents; D005609:Free Radicals; D008565:Membrane Proteins; D005632:Fructose; D003300:Copper; D008706:Methemoglobin; D007501:Iron; D015032:Zinc; D001205:Ascorbic Acid