Iron - Toxicology of Metals - page 569

FIGURE 2 Scheme of possible iron pathways in reticuloendothelial macrophages involved in the recycling
of hemoglobin iron. After phagocytosis of senescent red blood cells (RBC), the erythrocyte membrane is lysed,
and heme is transported to the endoplasmic reticulum (ER) to be degraded by heme oxygenase-1 (HO-1).
Most of the iron derived from hemoglobin catabolism is promptly returned to the circulation, likely being
transported across the plasma membrane by ferroprotein 1. In Kupffer cells, ferroprotein 1 (MTP1, Ireg1) is
present not only at the plasma membrane but also in the cytoplasm (Abboud and Hailey, 2000).

on ligands and reducing agents present in the diet.
Ascorbic acid is the most powerful promoter of non-
heme iron absorption, which is also enhanced by the
organic acids (e.g., citric acid and amino acids). On the
other hand, compounds that form insoluble complexes
with iron (e.g., phosphates, phytates, and tannin) pre-
vent absorption. Similarly, conditions in which there is
a failure of gastric acid secretion (e.g., atrophic gastri-
tis) may signifi cantly reduce the availability of iron for
absorption (Miret et al ., 2003).
The process of inorganic iron absorption is not fully
understood, but a compelling candidate for iron trans-
porter has recently been identifi ed. DMT1, which is
involved in iron transport across the endosomal mem-
brane (see previously), is also a principal transporter
of iron in the intestine (Canonne-Hergaux et al ., 1999;
Gunshin et al ., 1997). DMT1 transports only the ferrous
(reduced) form of iron, and this explains why reduc-
ing agents enhance iron absorption. Moreover, the duo-
denal brush border contains a ferric reductase, Dcytb
(McKie et al., 2001), which has been proposed to play a
role in the formation of Fe(II) before its transport into the
enterocyte. However, recently, Andrews and coworkers
inactivated the murine Dcytb gene and showed that
Dcytb defi ciency did not impair intestinal iron absorp-

tion when mice were fed normal chow (Gunshin et al .,
2005). Hence, Dcytb does not seem to be an essential
component of the intestinal iron absorption system in
mice. The chemical nature of iron in the labile inter-
mediate pool in enterocytes is unknown, but recently
a protein necessary for iron egress from enterocytes
was identifi ed. This protein, ferroportin 1 (Abboud and
Hailey, 2000; Dononvan et al ., 2000; McKiet et al ., 2000),
is identical to the Fe(II) exporter involved in iron egress
from macrophages (see Figure 2). The ferroxidase activ-
ity of hephaestin (Anderson et al ., 2002; Vulpe et al .,
2001), a membrane-bound ceruloplasmin homolog,
also plays an important role in iron export from intesti-
nal epithelial cells to the circulation (Hellman and Git-
lin, 2002). Hephaestin is not an iron transporter itself
but likely interacts with the ferroportin1 to facilitate
the movement of iron across the membrane (Figure 3).
Hephaestin is mutated in sex-linked anemia ( sla/sla )
mice that take up iron from the intestinal lumen into
the epithelial cells normally, but the subsequent exit
of iron into the circulation is diminished (Vulpe et al .,
2001). It is of interest that during the process of absorp-
tion, iron undergoes at least two changes in its oxida-
tion status: reduction at the brush border and oxidation
at the basolateral membrane.