Absorption from the Gastrointestinal Tract

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The mechanisms by which iron crosses the membrane of the enterocyte and is then transferred to the circulation have become much more clearly understood in the last few years. A number of new proteins have been identified which are involved in mucosal iron absorption (Figure 2). Heme iron is the most effective source of dietary iron in man, and after its uptake across the apical (brush-border) membrane of the intestine, probably via a specific receptor, its iron is released by the action of heme oxygenase as Fe2+, with concomitant production of CO and the bile pigment, biliverdin [1].

Mineral Absorption Intestine

Figure 2. Schematic representation of iron absorption in normal subjects. Iron is taken up from the gastrointestinal tract either as heme or nonheme iron. The former is degraded to release Fe(II) by heme oxygenase, whereas the latter is reduced by DcytB and transported across the apical membrane by DMT1. Within the enterocyte the iron pool can equilibrate with the intracellular storage protein ferritin. At the basolateral membrane, iron is transported out of the cell by IREG1: its incorporation into apotransferrin may be aided by the ferroxidase activity of hephaestin. DcytB, duodenal cytochrome b; DMT1, divalent cation transporter protein 1; IREG 1, iron-regulated gene; Haem Ox, heme oxygenase; Cp, ceruloplasmin; Tf, transferrin; NTBI, non-transferrin-bound iron. (Reproduced with permission from [1]).

Figure 2. Schematic representation of iron absorption in normal subjects. Iron is taken up from the gastrointestinal tract either as heme or nonheme iron. The former is degraded to release Fe(II) by heme oxygenase, whereas the latter is reduced by DcytB and transported across the apical membrane by DMT1. Within the enterocyte the iron pool can equilibrate with the intracellular storage protein ferritin. At the basolateral membrane, iron is transported out of the cell by IREG1: its incorporation into apotransferrin may be aided by the ferroxidase activity of hephaestin. DcytB, duodenal cytochrome b; DMT1, divalent cation transporter protein 1; IREG 1, iron-regulated gene; Haem Ox, heme oxygenase; Cp, ceruloplasmin; Tf, transferrin; NTBI, non-transferrin-bound iron. (Reproduced with permission from [1]).

Nonheme dietary iron seems to cross the brush border membrane of the enterocyte, after reduction by a duodenal ferric reductase, Dcytb (for duodenal cytochrome b), a plasma membrane di-heme protein [5]. The amino acid sequence of Dcytb has around 50% similarity to the cytochrome b561 family of plasma membrane reductases, and it is highly expressed in the brush border membrane of duodenal enterocytes. The ferrous iron is then transported into the intestinal cell by the divalent metal transporter 1 (DMT-1). (DMT-1 is also involved, as mentioned below, in the transport of Fe2+ in the transferrin to cell iron cycle). DMT-1 is not specific for Fe2+ and transports other divalent metal ions, including cobalt, copper, manganese, nickel, and zinc [6]. The metal ion transport is coupled to co-transport of a proton and depends on the cell membrane potential. The DMT1 protein has 12 putative membrane-spanning domains, is expressed at the highest levels in the proximal duodenum, and is up-regulated by dietary iron deficiency [6].

Within the intestinal cell, Fe2+ derived from both heme and nonheme Fe2+ enters a low molecular weight pool. This iron can either be stored in ferritin within the mucosal cell (and lost from the body when the mucosal cell exfoliates), or it can be transported across to the basolateral membrane. There, the trans-membrane transporter protein IREG 1 can allow the Fe2+ to reach the interstitial fluid/plasma. This basolateral iron transporter, also known as ferroportin or MTP1 was found almost simultaneously by three groups [7-9]. It was isolated from duodenal mucosa of homozygous atransferrinemic mice, which have high levels of iron absorption [7]. IREG-1 is a transmembrane protein, with 10 potential membrane spanning regions, that localizes to the basolateral membrane of polarized epithelial cells. The incorporation of iron into the apotransferrin of plasma may be facilitated by the oxidation of Fe2+ to Fe3+, either by hephaestin, a transmembrane-bound multicopper ferroxidase, which is highly expressed in intestine [10], or by ceruloplasmin, the principal copper-containing protein of serum.

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