Page 467 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

434 SECTION | V Metals and Micronutrients

VetBooks.ir loss. Under normal conditions, iron is poorly absorbed from hemoglobin to cells in the peripheral tissues; myocytes bind
O 2 for intracellular utilization; mitochondrial proteins of the
most diets with approximately 5% 15% absorbed from the
electron transport chain bind O 2 for energy production; and
gastrointestinal (GI) tract. This uptake can double in iron
deficiency. The body has a very limited ability to excrete P450 enzymes bind O 2 for its use in phase I metabolism of
iron; therefore, iron homeostasis is maintained by adjusting endogenous and xenobiotic chemicals. However, because of
iron absorption to the body’s needs. The amount of dietary its reactivity, iron in its ferrous state must be carefully
iron that is absorbed through the GI tract is determined by sequesteredawaytoprevent theformationofhighlyROS
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the needs of the individual animal and is inversely related to which can elicit severe cellular damage. Ferrous iron (Fe )
1
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serum ferritin concentrations (Bothwell et al., 1979). There and other transition metal ions, Cu ,Cr ,Ni 21 or Mn ,
2
are four main factors influencingironabsorption inthe GI can catalyze the formation of hydroxyl ion (HO )and the
tract: (1) individual factors including the animal’s age, iron extremely reactive and dangerous hydroxyl radical (HO )
d
status, and health; (2) conditions in the GI tract; (3) the from the reduction of endogenous hydrogen peroxide
chemical form and amount of iron ingested; and (4) other (HOOH) via the Fenton reaction:
components of the diet which can enhance or reduce intesti- 21 31 2
HOOH 1 Fe -Fe 1 HO 1 HO (28.1)
nal absorption. Iron is absorbed by enterocytes of the small
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intestine in ferrous (Fe ) form and transferred to the serum The Fenton reaction causes site-specific accumulation
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where it is converted to the ferric (Fe ) form and bound to of free radicals and initiates biomolecular damage. Free
transferrin (Goyer and Clarkson, 2001). In normal animals, radicals are molecules or molecular fragments that contain
most of fecal iron comes from ingested iron, which is not one or more unpaired electrons in their outer orbital shell.
absorbed. Once absorbed, the body vigorously retains If produced in great enough quantities to overwhelm the
ingested iron unless bleeding occurs with daily iron loss lim- cellular antioxidant and radical-quenching protective
ited to about 0.01% (of the body total) per day (Goyer and mechanisms, hydroxyl radicals promote the formation of
Clarkson, 2001). It has been found that even in the face of more hydroxyl radicals and other ROS such as superoxide.
hemolytic anemia with destruction of erythrocytes, less than Superoxide combines with nitric oxide and forms peroxyni-
1% of the iron is excreted in the urine and feces trite, which is as detrimental as hydroxyl radical. These
(Underwood, 1977). ROS and reactive nitrogen species (RNS) damage and
In the bloodstream, serum iron is primarily bound to destroy proteins and DNA by causing cross-linking, which
transferrin with lesser amounts bound to ferritin. Iron in inhibits their normal functions, or by initiating extensive
the serum forms a pool from which it enters, is transported, damage and spontaneous degeneration of molecules such
leaves and reenters at a variable rate for the synthesis of as lipids (Avery, 2011). ROS/RNS not only cause DNA
hemoglobin, ferritin, cytochromes, and other iron- damage but also inhibit repair activities. ROS induce lipid
containing proteins. Of the total iron in the body, approxi- peroxidation, which if not quenched, can initiate a chain
mately two-thirds is bound to hemoglobin and 10% to reaction of lipid destruction and ROS formation destroying
myoglobin and iron-containing enzymes, with the remain- vital cell membranes in mitochondria, nuclei and the cell
der bound to the storage proteins ferritin and hemosiderin periphery. Together, these effects can be of great enough
(Goyer and Clarkson, 2001). Ferritin and hemosiderin are magnitude to cause cell death, organ dysfunction, and
found throughout the body with the main concentrations death. However, it is also of interest to note that iron is
being in the liver, spleen, and bone marrow. They are pro- necessary for the normal functioning of macrophages and
tective in that they keep cellular iron in a bound form. other leukocytes during the respiratory burst in inflamma-
Ferritin contains up to 20% iron, while hemosiderin is up tion to catalyze the formation of bactericidal hydroxyl radi-
to 35% iron. In the normal animal, nonviable RBCs are cal (Gregus and Klaassen, 2001).
removed from the circulation by cells of the reticuloendo-
thelial system in the liver, spleen, and bone marrow. There,
heme is broken down, and the iron recycled for further use. TOXICITY
In aged animals, when large amounts of iron are injected General
and rapidly cleared from the serum, or during chronic iron
storage disease, the iron is preferentially deposited as Iron poisoning is not common in animals, although poten-
hemosiderin, thereby increasing intracellular concentrations tially it could occur in any species. Clinical cases of acute
and giving rise to the hemosiderosis that can be seen histo- iron toxicosis have been reported in dogs, pigs, horses,
logically (Underwood, 1977; Goyer and Clarkson, 2001). cattle and goats (Greentree and Hall, 1983; Ruhr et al.,
1983; Osweiler et al., 1985; Holter et al., 1990). Toxicity
can occur through ingestion or parenteral administration.
MECHANISM OF ACTION
Because of their indiscriminate eating habits and close
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For many functions, the body utilizes ferrous (Fe )ironto proximity to people and their nutritional supplements,
bind molecular O 2 .In thisway, O 2 is transported by dogs are the species most likely to ingest large quantities