Iron is an essential element that functions as a component of oxygen-carrying proteins ( hemoglobin, myoglobin ) and of numerous redox enzymes in cellular metabolism [E Nemeth, T Ganz, 2006]. However, under physiological conditions, the free form of iron is practically insoluble and potentially toxic. Thus, iron is always found bound to specific ligands in such a way as to render it both soluble and non-toxic.
The toxicity of iron stems from its ability to redox cycle . The release of an electron from ferrous iron, if uncontrolled, may result in the formation of highly reactive oxygen species capable of oxidising lipids, proteins and DNA causing damage to the structures and processes in which they are involved. However, many catalytic and other biological processes rely on the redox properties of iron; hence, iron must be available in a form which allows it to donate and accept electrons without causing non-specific damage [RM Graham, 2007].
IRON HOMEOSTASIS
The average adult human contains 2–4 g of iron.
In normal healthy adults, some 0.5-2 mg of iron is lost each day due to blood loss and the constant exfoliation of iron-containing epithelial cells that line the gastrointestinal and urinary tracts, skin and hair.
Therefore, the same amount of iron from dietary sources is required each day to replace the lost iron and maintain body iron homeostasis.
Even though iron is an essential metal in human metabolism, it is highly toxic to cells and tissues if present in elevated levels. Perversely, humans do not possess the necessary machinery to rid the body of excess iron and, therefore, the absorptive process must be tightly regulated within defined physiological limits to avoid pathologies associated with both iron deficiency and overload [P Sharp, SK Srai, 2007].
The tissues and cells that generate major iron flows into the plasma compartment include:
These different cell types use several distinct pathways for iron input, but a single pathway for iron export into plasma.
REGULATION OF CELLULAR AND EXTRACELLULAR IRON CONCENTRATIONS
Iron concentrations and fluxes are regulated on both the cellular and the systemic level.
Intracellularly, iron concentrations are sensed by two iron regulatory proteins (IRP1 and IRP2). When cytoplasmic iron is low, IRPs bind to iron regulatory element (IRE) sequences in mRNAs of iron-regulated proteins. Depending on the position of IRE (5' or 3' untranslated region), IRP binding has opposite effects on the synthesis of iron-regulated proteins: binding of IRPs to 3' IREs stabilizes mRNA , resulting in increased protein synthesis, whereas binding to 5' IREs prevents the translation of mRNA , resulting in decreased protein synthesis. The IRE/IRP-regulated mRNAs include transferrin receptor, ferritin, one isoform of DMT-1, and ferroportin.
Ferroportin , the sole membrane iron exporter, is post-translationally regulated by hepcidin, the principal regulator of extracellular iron concentration ( Regulation of iron by hepcidin).
