Cardioprotective effect of alpha-tocopherol, ascorbate, deferoxamine, and deferiprone: mitochondrial function in cultured, iron-loaded heart cells.
Because mitochondrial inner membrane respiratory complexes are important targets of iron toxicity, we used iron-loaded rat heart cells in culture to study the beneficial effect on mitochondrial enzymes of the iron chelators deferoxamine (DFO) and deferiprone (L1) and of antioxidants and reducing agents (ascorbate and alpha-tocopherol). Reduced nicotinamide adenine dinucleotide-cytochrome c oxidoreductase (complex I-III) and succinate dehydrogenase were the most-sensitive indicators of iron toxicity and cardioprotective effect. Although at concentrations below 0.3 mmol/L the iron-mobilizing effect of L1 was less than that of DFO, both were equally effective in protecting or restoring mitochondrial respiratory enzyme activity. At 1.0 mmol/L, L1 toxicity was manifested in respiratory enzyme inhibition, whereas DFO had no such effect. Ascorbate (0.057 to 5.7 mmol/L) had a mild cardioprotective effect at the highest concentration only, in association with decreased cellular iron uptake. By contrast, alpha-tocopherol (0.023 mmol/L) completely inhibited mitochondrial iron toxicity without affecting iron uptake or release, and irrespective of whether it was used before, during, or after in vitro iron loading. These observations illustrate the usefulness and limitations of iron chelators and other agents used for preventing iron toxicity to the heart and other vital organs, and they underline the need for exploring in more detail the effects of these agents in the clinical setting.
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Department of Human Nutrition and Metabolism, Hebrew University, Faculty of Medicine, Jerusalem, Israel.
Konijn
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AM
Hershko
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D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D002478:Cells, Cultured; D000077543:Deferiprone; D003676:Deferoxamine / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D051381:Rats; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology