DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

intake, malabsorption, blood loss, or an increased
requirement, as with pregnancy. When severe, it results
in a characteristic microcytic, hypochromic anemia.
However, the impact of iron deficiency is not limited to
the erythron (Dallman, 1982). Iron also is an essential
component of myoglobin; heme enzymes such as the
cytochromes, catalase, and peroxidase; and the metalloflavoprotein
enzymes, including xanthine oxidase
and the mitochondrial enzyme α-glycerophosphate oxidase.
Iron deficiency can affect metabolism in muscle
independently of the effect of anemia on oxygen delivery.
This may reflect a reduction in the activity of irondependent
mitochondrial enzymes. Iron deficiency also
has been associated with behavioral and learning problems
in children, abnormalities in catecholamine
metabolism, and possibly, impaired heat production.
Awareness of the ubiquitous role of iron has stimulated
considerable interest in the early and accurate detection
of iron deficiency and in its prevention.
History. The modern understanding of iron metabolism began in
1937 with the work of McCance and Widdowson on iron absorption
and excretion and Heilmeyer and Plotner’s measurement of iron in
plasma (Beutler, 2002). In 1947, Laurell described a plasma iron
transport protein that he called transferrin (Laurell, 1951). Hahn and
coworkers first used radioactive isotopes to measure iron absorption
and define the role of the intestinal mucosa to regulate this function
(Hahn, 1948). In the next decade, Huff and associates initiated isotopic
studies of internal iron metabolism. The subsequent development
of practical clinical measurements of serum iron, transferrin
saturation, plasma ferritin, and red-cell protoporphyrin permitted the
definition and detection of the body’s iron store status and irondeficient
erythropoiesis. In 1994, Feder and colleagues identified the
HFE gene, which is mutated in type 1 hemochromatosis, on the
short arm of chromosome 6 at 6p21.3 (Feder et al., 1996). In 2000,
Ganz and colleagues discovered a peptide produced by the liver,
which was termed hepcidin (Park et al., 2001). Soon thereafter hepcidin
was found to be the master regulator of iron homeostasis and
to play a role in anemia of chronic disease (Ganz, 2003; Ganz and
Nemeth, 2009).
Iron and the Environment. Iron exists in the environment largely as
ferric oxide or hydroxide or as polymers. In this state, its biological
availability is limited unless solubilized by acid or chelating agents.
For example, bacteria and some plants produce high-affinity chelating
agents that extract iron from the surrounding environment. Most
mammals have little difficulty in acquiring iron; this is explained by
an ample iron intake and perhaps also by a greater efficiency in
absorbing iron. Humans, however, appear to be an exception.
Although total dietary intake of elemental iron in humans usually
exceeds requirements, the bioavailability of the iron in the diet is
limited.
Metabolism of Iron. The body store of iron is divided
between essential iron-containing compounds and
excess iron, which is held in storage. Quantitatively,
Table 37–2
The Body Content of Iron
MG/KG OF BODY WEIGHT
MALE FEMALE
Essential iron
Hemoglobin 31 28
Myoglobin and enzymes 6 5
Storage iron 13 4
Total 50 37
hemoglobin dominates the essential fraction (Table 37–2).
This protein, with a molecular weight of 64,500 Da,
contains four atoms of iron per molecule, amounting to
1.1 mg (20 μmol) of iron per milliliter of red blood
cells. Other forms of essential iron include myoglobin
and a variety of heme and nonheme iron-dependent
enzymes. Ferritin is a protein-iron storage complex that
exists as individual molecules or as aggregates. Apoferritin
has a molecular weight of ~450,000 and is composed of
24 polypeptide subunits that form an outer shell, within
which resides a storage cavity for polynuclear hydrous
ferric oxide phosphate. More than 30% of the weight
of ferritin may be iron (4000 atoms of iron per ferritin
molecule). Ferritin aggregates, referred to as hemosiderin
and visible by light microscopy, constitute about
one-third of normal stores, a fraction that increases as
stores enlarge. The two predominant sites of iron storage
are the reticuloendothelial system and the hepatocytes,
although some storage also occurs in muscle.
Internal exchange of iron is accomplished by the
plasma protein transferrin (Garrick and Garrick, 2009).
This 76-kDa β 1
-glycoprotein has two binding sites for
ferric iron. Iron is delivered from transferrin to intracellular
sites by means of specific transferrin receptors
in the plasma membrane. The iron-transferrin complex
binds to the receptor, and the ternary complex is internalized
through clathrin-coated pits by receptormediated
endocytosis. A proton-pumping ATPase
lowers the pH of the intracellular vesicular compartment
(the endosomes) to ~5.5. Iron subsequently dissociates
and the receptor returns the apotransferrin to the
cell surface, where it is released into the extracellular
environment.
Cells regulate their expression of transferrin receptors and
intracellular ferritin in response to the iron supply (De Domenico et al.,
2008). The synthesis of apoferritin and transferrin receptors is regulated
post-transcriptionally by two iron-regulatory proteins 1 and 2
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CHAPTER 37
HEMATOPOIETIC AGENTS