Understanding of the absorption pathway for dietary iron has recently expanded greatly with the discovery of key proteins involved in transport of the metal. These proteins are highly but not exclusively expressed in the duodenal mucosa, the principal site of iron absorption. Iron cannot be readily excreted by the body so duodenal iron transport must be tightly regulated and respond rapidly to changes in the body’s requirements for iron. Potent regulators of intestinal iron transport include body iron stores, erythropoesis and hypoxia. These conditions also regulate the duodenal expression of many of the proteins involved. By using mutant hypo-transferrinaemic mice that exhibit a particularly high rate of iron absorption, we identified two of the genes involved. Ireg1 encodes a highly hydrophobic membrane protein highly expressed in the basolateral membrane of intestinal cells, placenta and macrophages, where it is thought to be involved, respectively, in iron transfer to the circulation and recycling of iron resulting from the breakdown of haem. The regulation of Ireg1 is unusual in that it contains an iron response element (IRE) within the 5Ì end of the mRNA, yet both mRNA and protein are up-regulated by iron deficiency in the intestine (McKie et al. 2000). Interestingly the regulation of Ireg1 appears to be different in other cell types. Dcytb (for duodenal cytochrome b) on the other hand encodes a putative di-haem protein, which is highly expressed in the brush-border membrane of duodenal enterocytes (McKie et al. 2001). Dcytb is similar to the cytochrome b561 family plasma membrane reductase’s and when expressed in cultured cells is capable of reducing ferric iron complexes. Antibodies raised against Dcytb block the endogenous ferric reductase of the intestinal mucosa, supporting the notion that Dcytb is responsible for the physiological ferric reductase previously described in the duodenum (Raja et al. 1992). As with Ireg1, Dcytb mRNA and protein levels are upregulated by stimulators of iron absorption such as iron deficiency, hypoxia and hypo-transferrinaemia. The identification of Ireg1 and an intestinal ferric reductase (Dcytb) are important steps forward in our understanding of how dietary iron is absorbed and are likely to have implications for iron trafficking in other cell types.

This work is supported by The Wellcome Trust, MRC, NIH, EU and the Human Frontier Science Program.