Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 9 Iron Metabolism and Its Disorders
Transferrin
Apotransferrin
Monoferric
transferrin
Diferric
transferrin
Fe + 3
FIGURE 9-3 Apotransferrin is a bilobar protein with two binding
sites for Fe 3 ions. When one or two Fe 3 ions are bound, the protein
is referred to as monoferric or diferric transferrin, respectively. There is
a random distribution of iron on binding sites, with apotransferrin predominant
at low plasma iron concentrations and diferric transferrin predominant
at high plasma iron concentrations. Monoferric transferrin
is predominant at 50% saturation of transferrin with iron, with lesser
amounts of apotransferrin and diferric transferrin present.
with iron, with lesser amounts of monoferric and diferric
iron present. Transferrin is primarily responsible for iron
transport throughout the body.
Ferritin is another iron-binding protein that can be
measured in plasma. Although ferritin is released in small
amounts from the liver and macrophages and can be
taken up by cells (especially hepatocytes), it is of little or
no importance in iron transport under normal conditions.
Ferritin is normally present in very low concentrations in
plasma and has low iron content; consequently, it contributes
little to the plasma iron pool ( Ponka et al ., 1998 ).
Nontransferrin bound iron (NTBI) has been measured
in people with severe iron overload, when transferrin is
fully saturated, and in mice with hereditary hypotransferrinemia.
The nature of NTBI is unclear, but it may be
complexed with low-molecular-weight molecules such as
citrate, sugars, and amino acids or nonspecifically bound
to albumin and other plasma proteins. NTBI has the potential
to promote the formation of oxygen-free radicals and
cause tissue injury ( Ponka et al ., 1998 ).
III. IRON ABSORPTION
Iron is not actively excreted from the body and minimal
iron loss normally occurs, except in menstruating primates
and egg-laying birds ( Finch et al ., 1978 ; Kolb, 1963 );
consequently, the amount within the body must be controlled
at the point of absorption. Iron absorption from
the diet depends on age, species of the animal, iron stores,
changes in rate of erythropoiesis, hypoxia, inflammation,
and pregnancy, as well as the amount and chemical form
of iron ingested ( Frazer and Anderson, 2005 ; Mackenzie
and Garrick, 2005 ; Stewart et al ., 1953 ). A low percentage
(0.2% to 4.5%) of dietary iron is generally absorbed in
normal adult animals ( Finch et al ., 1978 ; Nathanson et al .,
1985 ). Iron absorption occurs through mature villus enterocytes
of the duodenum and proximal jejunum. Absorption
FIGURE 9-4 Mechanisms of iron absorption. Ferrous iron (Fe 2 ) ions
are transported into enterocytes in the duodenum by the divalent metal
transporter-1 (DMT1) after reduction of ferric iron (Fe 3 ) ions using a
duodenal cytochrome b (DctyB). Heme is transported into enterocytes
using heme carrier protein-1 (HCP1). Once inside, inorganic iron is
released from heme by the action of the heme oxygenase (HO) reaction.
Fe 2 ions are exported from enterocytes using ferroportin, oxidized to
Fe 3 using hephaestin, and bound by apotransferrin (aTf) to form monoferric
transferrin (mTf) and diferric transferrin (not shown). Hepcidin in
plasma inhibits iron export to plasma by interacting directly with ferroportin,
leading to ferroportin’s internalization and lysosomal degradation.
Fe 2 not transported to plasma is stored as ferritin following oxidation to
Fe 3 . Iron stored as ferritin is returned to the small intestine lumen when
enterocytes are sloughed at the tip of the villus.
includes iron uptake at the apical membrane of the enterocyte,
translocation within the cytoplasm, and transfer to
plasma at the basolateral membrane of the enterocyte. Iron
can be taken in by enterocytes as free ions or as heme by
different pathways ( Fig. 9-4 ). The relative importance of
these pathways varies depending on animal species and
diet ( Steele et al ., 2005 ).
Compounds in the diet such as phytates, tannins, and
phosphates bind iron in insoluble complexes that cannot
be absorbed. Most nonheme iron in the diet is in the Fe 3
state. Dietary Fe 3 is solubilized from food by hydrochloric
acid in the stomach and binds to mucins and various small
molecules, which keep the iron soluble and available for
absorption in the more alkaline environment of the small
intestine ( Mackenzie and Garrick, 2005 ). Unbound Fe 3
is prone to hydrolysis, forming essentially insoluble ferric
hydroxide and oxohyroxide polymers ( Ponka et al ., 1998 ).
The most important pathway for nonheme iron uptake utilizes
the divalent metal transporter-1 (DMT1). A protoncoupled
process facilitates this uptake. Although DMT1 has
the highest affinity for iron, it can also transport manganese
and potentially other divalent metal ions. Fe 3 ions must be
reduced to Fe 2 ions before they can be transported into the
enterocyte via the DMT1. Ascorbic acid in the diet or from
gastric or biliary secretions promotes the reduction of Fe 3
ions. Although some Fe 3 ion reduction may occur by direct
interaction with ascorbic acid, most reduction appears to
rely on the presence of one or more brush border ferrireductase
enzymes. A duodenal cytochrome b (DcytB) is believed
to be important in this regard, but other intestinal ferrireductases
may also exist ( Mackenzie and Garrick, 2005 ).
Although the dominant role of DMT1 is acknowledged,
debate continues as to whether important alternative