The transport, storage and metabolism of iron in the body are depicted in Figure 1.1. When iron is absorbed from the duodenum and upper jejunum of the gastrointestinal tract (GIT), it is either transferred to the liver or to the blood-iron transport-protein, apotransferrin, via the venous portal drainage. Apotransferrin is a globular glycoprotein (MW of 76,000 Dalton) which possesses two binding sites each with high but unequal affinity (K=1020M-1) for iron(III) (Aisen et al., 1978). The binding affinity of the C-terminal site for iron(III) is around twenty times that of the N-terminal site (Aisen et al., 1978; Evans and Williams, 1978).
Figure 1.1: The turnover of iron pools in normal adult. RES (reticuloendothelial System). Adapted from Guyton, 1991.
The concentration of free iron(III) in blood in the presence of apotransferrin is less than 10-12 M and at this concentration iron is not able to trigger damage via hydroxyl radical production. The normal plasma concentration of transferrin is 30mM, although it is only one-third saturated with iron (i.e. 60 mM total iron binding capacity (TIBC)). Transferrin experiences a tenfold turnover each day. There is, thus, sufficient binding capacity to ensure that transferrin is never fully saturated, except in chronic iron overload disorders. Transferrin also contributes to defence system against infection by micro-organisms. In normal individuals, the level of potentially toxic non-transferrin bound iron (NTBI) is exceedingly low. Cells which require iron for maturation or division express high densities of transferrin receptors on the surface of their plasma membrane (Huebers and Finch, 1987). The transferrin-receptor complex is internalised by endocytosis and the iron released by protonation in the relatively acidic endosome (May and Cuatrecasas, 1985). As a consequence, iron is specifically directed from the blood to tissue where it is required. Once iron has been released from transferrin, apotransferrin is secreted back into the extracellular space (Harding et al., 1983) where it is reloaded with iron originating either from liver, reticuloendothelial cells or GIT. A reductive process, a membrane bound NADH dehydrogenase (Thorstensen and Ramslo, 1988), is involved in releasing iron from transferrin, therefore, delivering iron in the ferrous state to the cytosol. On average, each molecule of transferrin is estimated to undertake over 200 such cycles before being catabolised in lysozymes. The half-life of the bound metal is of the order of 1-2 hours whilst that of the protein is around 7-8 days. A large proportion of this transit complex is directed towards furnishing bone marrow with iron for erythropoiesis.
Excess iron is stored intracellularly in two forms, either as soluble ferritin or as insoluble haemosiderin deposits (Munro and Linder, 1978). These iron stores can be found almost in all cells but are present in large amounts in organs such as liver, heart, and spleen. Ferritin, which has a molecular weight of approximately 450,000, acts as a long-term mobilisable reservoir. Apoferritin consists of 24 equivalent subunits which provide a hollow centre where up to 4,000 iron(III) atoms can be stored in the form of a regular lattice of ferric-hydroxide-phosphate (Ford et al., 1984). In this form, the potential to interact with oxygen and to form oxygen radicals is minimal. Haemosiderin is believed to be the product of lysosomal degradation of ferritin and forms insoluble deposits within the cell. In normal healthy individuals, the amount of haemosiderin is negligible in comparison with ferritin, however, haemosiderin in certain conditions such as iron overload disease, contains between 20-40% of the total body iron storage content.
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