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

1078 (IRP1 and IRP2). Double knockout of the genes encoding these proteins
is embryonic lethal, and conditional double knockout of these
genes in the intestine results in cellular iron depletion and death of
intestinal epithelial cells (Galy et al., 2008). These IRPs are cytosolic
RNA-binding proteins that bind to iron regulating elements
(IREs) present in the 5′ or 3′ untranslated regions of mRNA encoding
apoferritin or the transferrin receptors, respectively. Binding of
these IRPs to the 5′ IRE of apoferritin mRNA represses translation,
whereas binding to the 3′ IRE of mRNA encoding the transferrin
receptors enhances transcript stability, thereby increasing protein
production. When iron is abundant, IRP2 undergoes rapid proteolysis
and IRP1 is converted from a RNA-binding protein into aconitase,
an enzyme that catalyzes the interconversion of citrate and
isocitrate. This results in increased production of apoferritin and
reduced production of transferrin receptors. Conversely, when iron
is in short supply, these IRPs accumulate, thereby repressing
translation of apoferritin while enhancing production of transferrin
receptors.
SECTION IV
INFLAMMATION. IMMUNOMODULATION, AND HEMATOPOIESIS
The flow of iron through the plasma amounts to
a total of 30-40 mg per day in the adult (~0.46 mg/kg
of body weight) (Finch and Huebers, 1982). The major
internal circulation of iron involves the erythron and
reticuloendothelial cells (Figure 37–3). About 80% of
the iron in plasma goes to the erythroid marrow to be
packaged into new erythrocytes; these normally circulate
for ~120 days before being catabolized by the reticuloendothelial
system. At that time, a portion of the iron
is immediately returned to the plasma bound to transferrin
while another portion is incorporated into the ferritin
stores of reticuloendothelial cells and returned to
the circulation more gradually. Isotopic studies indicate
some degree of iron wastage in this process, in which
defective cells or unused portions of their iron are transferred
to the reticuloendothelial cell during maturation,
bypassing the circulating blood. With abnormalities in
erythrocyte maturation, the predominant portion of iron
assimilated by the erythroid marrow may be rapidly
localized in the reticuloendothelial cells as defective
red-cell precursors are broken down; this is termed ineffective
erythropoiesis. The rate of iron turnover in
plasma may be reduced by half or more with red-cell
aplasia, with all the iron directed to the hepatocytes for
storage.
The most remarkable feature of iron metabolism
is the degree to which body stores are conserved. Only
10% of the total is lost per year by normal men (i.e.,
~1 mg/day). Two-thirds of this iron is excreted from the
gastrointestinal (GI) tract as extravasated red cells, iron
in bile, and iron in exfoliated mucosal cells. The other
third is accounted for by small amounts of iron in
desquamated skin and in the urine. Physiological losses
of iron in men vary over a narrow range, from 0.5 mg
ERYTHROID MARROW
uptake about 25 mg/day
CIRCULATING
ERYTHROCYTES
pool about 2,100 mg;
daily turnover 18 mg
DIETARY IRON
14.4 mg/day;
about 6 mg/1,000 kcal
INTESTINAL MUCOSA
absorption about 1 mg/day
PLASMA IRON
pool about 3 mg;
turnover about 10X/day
INTERSTITIAL
FLUID
PARENCHYMAL
EXCHANGE-
ESPECIALLY LIVER
about 6 mg/day
FERRITIN STORES
RETICULOENDOTHELIUM
25 mg/day from erythron
Figure 37–3. Pathways of iron metabolism in humans (excretion
omitted).
in the iron-deficient individual to 1.5-2 mg per day
when excessive iron is consumed. Additional losses of
iron occur in women due to menstruation. Although the
average loss in menstruating women is ~0.5 mg per day,
10% of menstruating women lose >2 mg per day.
Pregnancy and lactation impose an even greater requirement
for iron (Table 37–3). Other causes of iron loss
include blood donation, the use of anti-inflammatory
drugs that cause bleeding from the gastric mucosa, and
GI disease with associated bleeding. Two much rarer
causes are the hemosiderinuria that follows intravascular
hemolysis, and pulmonary siderosis, where iron
deposited in the lungs becomes unavailable to the rest
of the body.
The limited physiological losses of iron point to
the primary importance of absorption in determining the
body’s iron content (Garrick and Garrick, 2009). After
acidification and partial digestion of food in the stomach,
iron is presented to the intestinal mucosa as either