Link G, Konijn A M, Hershko C
Department of Human Nutrition and Metabolism, Hebrew University, Faculty of Medicine, Jerusalem, Israel.
J Lab Clin Med. 1999 Feb;133(2):179-88. doi: 10.1016/s0022-2143(99)90011-2.
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.
由于线粒体内膜呼吸复合物是铁毒性的重要靶点，我们利用培养的铁负荷大鼠心脏细胞来研究铁螯合剂去铁胺（DFO）和去铁酮（L1）以及抗氧化剂和还原剂（抗坏血酸和α-生育酚）对线粒体酶的有益作用。还原型烟酰胺腺嘌呤二核苷酸-细胞色素c氧化还原酶（复合物I-III）和琥珀酸脱氢酶是铁毒性和心脏保护作用最敏感的指标。尽管在浓度低于0.3 mmol/L时，L1的铁动员作用小于DFO，但二者在保护或恢复线粒体呼吸酶活性方面同样有效。在1.0 mmol/L时，L1的毒性表现为呼吸酶抑制，而DFO没有这种作用。抗坏血酸（0.057至5.7 mmol/L）仅在最高浓度时具有轻微的心脏保护作用，同时细胞铁摄取减少。相比之下，α-生育酚（0.023 mmol/L）完全抑制线粒体铁毒性，而不影响铁的摄取或释放，且无论其在体外铁负荷之前、期间或之后使用均有效。这些观察结果说明了铁螯合剂和其他用于预防心脏及其他重要器官铁毒性的药物的有效性和局限性，并强调了在临床环境中更详细地探索这些药物作用的必要性。
