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

IV. Plasma Iron Transport
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pathways of nonheme iron uptake exist. The role of the
protein mobilferrin needs further evaluation. It might be
part of a separate uptake pathway for Fe 3 ions, or it might
interact with DMT1 in Fe 2 ion uptake ( Conrad et al .,
2000 ; Mackenzie and Garrick, 2005 ). Although humans
absorb Fe 2 salts more readily from the intestine than the
Fe 3 salts, dogs are reported to absorb both valence forms
equally well ( Moore et al ., 1944 ). The reason for this difference
is not known, but it could be related to a greater
ability to reduce Fe 3 in the dog intestine, the presence of
an important pathway for Fe 3 absorption in the dog intestine,
or a greater ability to prevent the formation of insoluble
Fe 3 complexes in the gastrointestinal tract of dogs.
Heme is released from dietary myoglobin and hemoglobin
by the action of digestive enzymes. Dietary heme
iron is generally more bioavailable than is nonheme iron
and is an important nutritional source of iron in carnivores
and omnivores. Heme enters duodenal enterocytes as an
intact metalloporphyrin using a membrane protein named
heme carrier protein 1 (HCP1) that has homology to bacterial
metal-tetracycline transporters ( Shayeghi et al ., 2005 ).
The expression of HCP1 is regulated pre- and posttranslationally
in hypoxic and iron-deficient mice, respectively
( Latunde-Dada et al ., 2006b ). Once inside the enterocyte,
inorganic iron is apparently released from heme by the
action of the heme oxygenase reaction, and this hemesplitting
reaction appears to be the rate-limiting step in the
absorption of iron contained within hemoglobin and myoglobin
( Wheby and Spyker, 1981 ).
The intracellular transport of iron within the enterocyte
is poorly understood. Iron ions in this labile iron pool
(LIP) are presumably bound to chaperone molecules to
keep them soluble. The nature of these chaperone molecules
is yet to be defined. Iron ions can catalyze oxidative reactions
that would injure the cell. The enterocyte protects itself
against the toxic effects of excess iron by increasing apoferritin
synthesis and incorporating the excess iron into ferritin.
Consequently, iron uptake into enterocytes in excess of
that needed for metabolic purposes or transferred to plasma
is stored as ferritin. Iron stored as ferritin is returned to the
small intestine when enterocytes are sloughed at the tip of
the villus after 1 to 2 days ( Steele et al ., 2005 ).
The transfer of iron atoms from enterocytes to transferrin
in plasma is mediated by ferroportin (also known as
Ireg1), an iron transport protein located on the basolateral
surface of mature enterocytes. In addition to ferroportin, the
efflux of iron from enterocytes requires a copper-containing
protein called hephaestin that is also located on the basolateral
membranes of mature enterocytes. Hephaestin is a
membrane-bound ferroxidase that has significant homology
to the plasma protein ceruloplasmin. Hephaestin’s function
may relate to its ability to oxidize Fe 2 ions to Fe 3 ions
for binding to transferrin in plasma ( Steele et al ., 2005 ).
Sex-linked anemia (sla) mice have a block in mucosal iron
transfer to plasma, with resultant microcytic hypochromic
anemia because these animals have an inherited hephaestin
defect ( Wessling-Resnick, 2006 ).
Components of brush border iron uptake, including DMT1
and DcytB, are strongly influenced by the iron concentration
within enterocytes, with increased components expressed when
intracellular iron content is low and decreased components
expressed when iron content is high ( Frazer and Anderson,
2005 ). These locally responsive changes in brush border transport
components help buffer the body against the absorption
of excessive iron, but it is the control of the basolateral transport
of iron from enterocytes to plasma that represents the
primary site at which iron absorption is controlled ( Steele
et al ., 2005 ). Hepcidin, a peptide produced by hepatocytes
and secreted into plasma, inhibits iron transfer from enterocytes
to plasma by interacting directly with ferroportin,
leading to the internalization and lysosomal degradation of
this iron export protein. Hepcidin production is increased in
disorders such as iron overload and inflammation that result
in decreased intestinal iron absorption. Hepcidin production
is decreased in iron deficiency and disorders with increased
erythropoiesis that result in increased iron absorption by
enterocytes. Hephaestin expression is minimally affected by
iron status ( Vokurka et al ., 2006 ).
IV. PLASMA IRON TRANSPORT
At physiological pH and oxygen tension, Fe 2 in solution
is readily oxidized to Fe 3 , which is prone to hydrolysis
and precipitation. In addition, unless appropriately
chelated, iron in plasma can promote harmful oxygen
radical formation and peroxidative tissue damage because
of its catalytic action in one-electron redox reactions
( Ponka et al ., 1998 ). Fortunately, most iron in plasma is
bound to the protein apotransferrin to form transferrin.
The binding of iron to apotransferrin keeps iron molecules
soluble and prevents iron catalyzed oxidative reactions.
In addition, the vast majority of iron is transported to
cells within the body following binding to apotransferrin
in plasma ( Ponka et al ., 1998 ). At normal iron saturation
levels, apotransferrin is most abundant in plasma, followed
by monoferric transferrin and diferric transferrin ( Ponka
et al ., 1998 ). Although diferric transferrin is normally
much lower in concentration (about 10% of total transferrin)
than monoferric transferrin, it accounts for most of
the iron delivery to cells because diferric transferrin binds
with 8- to 10-fold higher affinity to transferrin receptor-1
(TfR1) receptors on cells than does monoferric transferrin
( Anderson and Frazer, 2005 ; Huebers et al ., 1985 ).
Apotransferrin has very low affinity for TfR1 receptors on
cells ( Ponka et al ., 1998 ).
Iron turns over in 3 h or less in plasma ( Smith, 1997 ).
Nearly all of the iron in plasma under normal conditions
comes from the release of iron by macrophages that
have phagocytized and degraded erythrocytes ( Fig. 9-1 ).