Iron - Toxicology of Metals - page 563

CHAPTER
30

Iron

PREM PONKA, MILTON TENENBEIN, AND JOHN W. EATON

ABSTRACT

ment of iron across the membranes of enterocytes and
macrophages, respectively. Cells are also equipped with
a regulatory system that controls iron levels in the la-
bile pool. Levels of iron modulate the capacity of iron
regulatory proteins (IRPs) to bind to the iron-responsive
elements (IREs) present in the untranslated regions of
mRNAs for several proteins involved in iron metabo-
lism (e.g., ferritin, transferrin receptor, DMT1); these as-
sociations, or lack of them, in turn control the expression
of these proteins. In fact, important information about
the regulation of iron metabolism came from studies of
proteins (e.g., HFE, ferroportin, and hepcidin) coded by
genes, mutations of which cause different types of he-
reditary hemochromatoses. Despite these homeostatic
mechanisms, organisms can face the threat of either iron
defi ciency or iron overload.
Acute iron overload resulting from unintentional
or intentional overdose is potentially life threaten-
ing. Chronic iron overload leads to slowly developing
(and, in extremis , lethal) damage to organs such as the
heart and liver. However, the nature of the accumu-
lated damage that eventuates in such organ failure is
not yet fully known. In addition, occupational inha-
lation exposures to iron may give rise to siderosis, a
benign condition easily diagnosed by chest X-ray. Our
developing knowledge of iron metabolism increasingly
emphasizes the simultaneously vital and threatening
nature of this most important and abundant metal.

Iron is the fourth most abundant metal in the earth's
crust and the most abundant transition metal. Iron can
easily change valence and form complexes with oxygen,
and iron-mediated reactions support the respiration of
nearly all aerobic organisms. However, unless appropri-
ately shielded, iron catalyzes the formation of radicals
that can damage biological molecules, cells, tissues, and
entire organisms. Exposure to excess iron—typically
from multiple blood transfusions over many years—can
lead to numerous pathological consequences. By con-
trast, severe iron defi ciency may also have serious health
consequences. Because of the inherent danger of iron,
specialized molecules for the acquisition, transport, and
storage (ferritin) of iron in a soluble nontoxic form have
evolved. Delivery of iron to most cells occurs after the
binding of transferrin to transferrin receptors on the cell
membrane. The transferrin-receptor complexes are then
internalized by endocytosis, and iron is released from
transferrin by a process involving endosomal acidifi ca-
tion and reduction. Iron is then transported through the
endosomal membrane by the Fe(II) transporter DMT1/
Nramp2. Importantly, this identical transporter is in-
volved in the absorption of inorganic iron in the duode-
num, a process facilitated by the ferric reductase Dcytb,
which presumably provides Fe(II) for DMT1/Nramp2.
Organisms and cells possess limited ability to excrete
excess iron, and only some specialized cells have active
mechanisms to export iron. Iron release from these “do-
nor cells” (primarily enterocytes and macrophages that
recycle hemoglobin iron) is mediated by ferroportin 1.
The ferroxidase activity of copper-containing proteins,
hephaestin and ceruloplasmin, facilitates the move-

1 PHYSICAL AND CHEMICAL PROPERTIES

Iron (Fe): atomic weight, 55.8; atomic number, 26,
density, 7.9; melting point, 1535°C; boiling point, 2750°C;