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chapter 29
Metabolism of Iron and Heme
TABLE 29-1
Distribution o f Iron in a 70-kg Adult
1
Circulating erythrocytes
1800 mg
2
Bone marrow (erythroid)
300 mg
Muscle myoglobin
300 mg
Heme and non-heme enzymes
180 mg
Liver parenchyma
3
1 0 0 0
mg
Reticuloendothelial macrophages
4
600 mg
Plasma transferrin
5
3 mg
1
These are approximate values. Premenopausal women have lower
iron stores due to periodic blood loss through menstruation. Iron bal-
ance in the body is maintained by intestinal absorption of
1 - 2
mg/day
and by loss of
1 - 2
mg/day.
2
1
mg = 17.9/rmol
3
Primarily storage forms of iron.
4
Senescent red blood cells are catabolized by the macrophages, the
salvaged iron is temporarily stored, and made available via transferrin
for erythron and for hemoglobin synthesis.
5
Transportable form of iron.
Iron in food exists mainly in the ferric (Fe3+) state, com-
plexed to proteins, amino acids, organic acids, or heme.
It is absorbed in the ferrous state, reduction being accom-
plished in the gastrointestinal tract by ascorbate, succinate,
and amino acids. Gastric acid potentiates iron absorption
by aiding in formation of soluble and absorbable ferrous
chelates. In achlorhydria or after partial gastrectomy, ab-
sorption is subnormal but is increased by administration
of hydrochloric acid. Carbonates, tannates, phosphates,
phytates, and oxalates may decrease iron absorption by
formation of insoluble complexes, but their effect can be
prevented by adequate dietary calcium, which complexes
with them and makes them unavailable for reaction with
iron. Absorption of heme iron is not affected by these
agents. Heme is absorbed intact from food and more ef-
fectively than inorganic iron. Antacids, such as aluminum
hydroxide and magnesium hydroxide, also decrease iron
absorption.
In general, foods of animal origin provide more assimil-
able iron than foods of vegetable origin, since on a weight
basis, vegetables contain less iron and more substances
(e.g., phytates) that inhibit iron absorption. Foods that
contain more than 5 mg of iron per 100 g include organ
meats (liver, heart), wheat germ, brewer’s yeast, oysters,
and certain dried beans. Foods that contain 1-5 mg of iron
per
1 0 0
g include muscle meats, fish, fowl, some fruits
(prunes, raisins), most green vegetables, and most cereals.
Foods that contain less than 1 mg of iron per 100 g include
milk and milk products and most nongreen vegetables.
Ferrous iron is absorbed principally from the mature
enterocytes lining the absorptive villi of the duodenum.
The amount of iron absorption by these enterocytes is
determined by the prior programming of the duodenal
crypt cells based on iron requirements of the body as they
undergo maturation. The regulation of intestinal iron ab-
sorption is critical because iron excretion from the body
is a limiting physiological process (discussed later). The
small intestine is also an excretory organ for iron, since
that stored as ferritin in the epithelial cells is lost when they
are shed and replaced every 3-5 days. Heme iron is trans-
ported intact into the mucosal cells and the iron removed
for further processing.
The mechanism of entry of ferrous iron from the intesti-
nal lumen into the enterocytes and its eventual transport
into the portal blood is beginning to be understood. The
first step is the programming of the duodenal undiffer-
entiated deep-crypt cells with regard to sensing the iron
requirements of the body. The programming of the crypt
cells for capacity to absorb iron is thought to occur as fol-
lows. A protein (HFE) that spans the cell membrane like an
HLA molecule associates with /32-microglobulin like an
HLA protein. The HFE protein is coded for by a gene
(HFE)
located on the short arm of chromosome
6
near
the
MHC
gene loci. Mutations in the
HFE
gene are
associated with an inherited disorder of excessive dietary
iron absorption that is known as
hereditary hemochro-
matosis
(discussed later). HFE protein spans the cell mem-
brane of the crypt enterocytes with its N-terminal domain
projecting outside. Near the cell membrane a segment
of HFE protein, like an HLA protein, associates with
/32-microglobulin (Figure 29-1) and stabilizes the HFE
protein.
Plasma transferrin transports iron in the ferric state and
is an indicator of iron stores in the body. Each molecule
of transferrin binds with two ferric ions (diferric transfer-
rin) and undergoes receptor-mediated endocytosis when
bound to transferrin receptors (discussed later) with the
aid of HFE protein /l2-microglobulin complex. In the cy-
tosol, iron is released from the endosomes. The level of
cytoplasmic iron regulates the translation of mRNA of a
protein known as divalent metal transporter-1
(DMT1),
which participates in iron entry into the enterocytes lo-
cated on the villus tip (Figure 29-2). Regulation of DMT1
synthesis is coupled to cytoplasmic iron levels and in-
volves the presence of a stem-loop hairpin structure in the
3'-untranslated region that resembles an iron regulatory
element (IRE) and its interaction with an iron regulatory
protein (IRP1). In the iron-deficient state, IRP binds to
IRE and stabilizes the mRNA of DMT1. This stabiliza-
tion of mRNA leads to increased production of DMT1 and
its eventual localization on the cell surface. The transport
of ferrous iron across the apical membrane of the villus
enterocyte that is mediated by DMT1 occurs through a
proton-coupled process. DMT1 also transports a number
