Iron and erythrocytes: physiological and pathophysiological aspects

It is generally accepted that iron when released from the macromolecular complexes (ferritin, transferrin, heme proteins, etc.) normally sequestering it, represents a source of oxidative stress. The reductive release of iron from ferritin has received extensive consideration, while the release of iron in an oxidative manner from heme proteins has been relatively little studied. We have shown that iron is released from hemoglobin or heme in a non protein-bound desferrioxamine-chelatable form (DCI) in a number of conditions in which the erythrocytes are subjected to oxidative stress. Such conditions can be related to toxicological events (haemolytic drugs) or to physiological situations (erythrocyte ageing, reproduced in a model of prolonged aerobic incubation) or pathological conditions (thalassemia, diabetes mellitus), but can also result from more subtle circumstances in which a state of ischemia-reperfusion is imposed on erythrocytes (e.g. childbirth). The released iron could play a central role in oxidation of membrane proteins, in particular band 3 protein, and in autologous IgG binding, one of the major pathways for erythrocyte removal. Iron chelators able to enter cells (such as ferrozine, quercetin, and fluorbenzoil-pyridoxalhydrazone) prevent both membrane protein oxidation and IgG binding. The increased release of iron observed in -thalassemia patients and newborns (particularly premature babies) suggests that fetal hemoglobin is more prone to release iron than adult hemoglobin. In newborns the release of iron in erythrocytes is correlated with plasma non-protein-bound iron and may contribute to its appearance. Since disulfide-cross-linked band 3 dimers are the minimal aggregates with enhanced affinity for autologous IgG, we have observed that such oxidatively modified band 3 is present in a much higher percentage of newborns (especially premature) than of adults and that a correlation between free iron level and IgG binding is evident in erythrocytes. The IgG binding is present also in a much higher percentage of diabetic subjects than of controls. Iron release is higher in diabetic erythrocytes showing IgG binding and a significant correlation between iron release and IgG binding is also evident. Therefore a large part of newborn (and possibly thalassemic) and diabetic erythrocytes are ready to be eliminated. Thus the iron appears an element of conflicting effect, it can be either beneficial or detrimental to the red cells, depending on whether it serves as a micronutrient or as a catalyst of free radical reactions, with consequent decrease of their life-span. © 2008 Springer Netherlands.