Iron - Toxicology of Metals - page 565

5 BIOLOGICAL FUNCTION
AND METABOLISM

reversibly. The turnover of transferrin iron is approxi-
mately 30 mg/24 hours and, normally, approximately
80% of this iron is transported to the bone marrow for
hemoglobin synthesis in developing erythroid cells.
Senescent erythrocytes are phagocytosed by macro-
phages of the reticuloendothelial system, where the
heme moiety is split from hemoglobin and catabolized
enzymatically by means of heme oxygenase-1 (HO-1).
Iron, which is liberated from its confi nement within
the tetrapyrrole ring inside macrophages, is returned
almost quantitatively to the circulation. The remaining
5 mg of the daily plasma iron turnover is exchanged
with nonerythroid tissues, primarily the liver. Approxi-
mately 1 mg of dietary iron is absorbed per 24 hours,
and the total iron balance is maintained by a daily loss of
1 mg by means of nonspecifi c mechanisms (mostly cell
desquamation) (Andrews, 2005; Ponka, 2003; Ponka et
al ., 1998). This process is an extraordinarily delicate bal-
ancing act, given that iron amounts to approximately
1/100,000,000th part (w/w) of the human body.

5.1 Overview of Iron Metabolism
Iron is a precious metal for the organism because of
its unsurpassed versatility as a biological catalyst. It is
involved in a broad spectrum of essential biological
functions such as oxygen transport, electron transfer,
and DNA synthesis. Hence, iron is an essential element
required for growth and survival. However, the very
chemical properties of iron that allow this versatility
also create a paradoxical situation, making acquisition
by the organism of the fourth most abundant element
in the earth's crust exceedingly diffi cult. At pH 7.4 and
physiological oxygen tension, the relatively soluble fer-
rous ion is readily oxidized to the ferric ion, which on
hydrolysis forms virtually insoluble ferric hydroxides.
The concentration of aquatic Fe(III) in aqueous solutions
(pH 7.4) cannot exceed 10 −17 mol/L. Moreover, unless
appropriately “shielded,” iron promotes the formation
of harmful oxygen radicals, which ultimately cause
peroxidative damage to vital cell structures. Because of
this virtual insolubility and potential toxicity, iron must
constantly be chaperoned; specialized mechanisms
and molecules for the acquisition, transport, and stor-
age of iron in a soluble, nontoxic form have evolved to
meet the cell's and the organism's iron requirements.
Moreover, organisms are equipped with sophisticated
mechanisms that prevent the accumulation of a cata-
lytically active intracellular iron pool, while maintain-
ing suffi cient concentrations of the metal for metabolic
use (Aisen et al ., 2002; Andrews, 2005; Eaton and Qian,
2002; Harrison and Arosio, 1996; Hentze et al ., 2004;
Ponka et al ., 1998; Richardson and Ponka, 1997).
Iron, both in its heme and nonheme forms, is present
in every cell in the body, and most cells, except for
mature red cells and terminally differentiated lens epi-
thelium, have the capacity to acquire iron. However,
cellular iron acquisition and its proper intracellular tar-
geting into functional iron proteins depend on an array
of other proteins. “Traditional” proteins involved in
iron metabolism include transferrin, transferrin recep-
tor, and ferritin, but a remarkable fl urry of activity in
the past several years has identifi ed a large number
of novel genes whose products emerge as important
players in iron metabolism (Table 1).
The bodies of adult men and women contain
55 mg and 45 mg of iron per kilogram of body weight,
respectively. Normally, 60-70% of total body iron is
present in hemoglobin in circulating erythrocytes. In
vertebrates, iron is transported within the body between
sites of absorption, storage, and use by the plasma glyc-
oprotein transferrin that binds iron (III) very tightly but

5.2 Cellular Iron Acquisition from Transferrin
With some notable exceptions (e.g., enterocytes), vir-
tually all the cells in the organism take up iron from
transferrin. Delivery of iron to cells occurs after the
binding of transferrin to its cognate receptors on the cell
membrane (Hentze et al ., 2004; Ponka and Lok, 1999;
Richardson and Ponka, 2003). The transferrin-receptor
complexes are then internalized by endocytosis, and
iron is released from transferrin by a process involving
endosomal acidifi cation (Figure 1). It has been shown
that the transporter, DMT1 (also known as Nramp2 or
DCT1), is likely responsible for the egress of iron from
the endosome (Canonne-Hergaux et al ., 2001; Fleming
et al ., 1997; Gunshin et al ., 1997). The protein is encoded
by a gene that belongs to the Nramp (Natural resist-
ance-associated macrophage protein) family of genes
identifi ed by Gros and coworkers (Cellier et al ., 1995).
Mutations of one form of Nramp were found to predis-
pose organisms to diseases (such as leprosy and tuber-
culosis) caused by intracellular pathogens. Interestingly,
Nramp2 generates two alternatively spliced mRNAs
that differ at their 3' untranslated regions (UTR) by
the presence or absence of the iron- responsive element
(IRE, discussed later) and that encode two proteins
with distinct carboxy termini (Canonne-Hergaux et al .,
1999; 2001). In collaboration with Dr. Philippe Gros, we
have recently found it is isoform II (derived from non-
IRE containing mRNA) that is the major DMT1 protein
isoform expressed in the developing erythroid cells
(Cannone-Hergaux et al ., 2001). One of us (Ponka) was
a member of the team who identifi ed the fi rst human