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

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Chapter | 22 Trace Minerals
2 . Systemic Regulation of Cu
From the intestine, a case can be made for the transport of
Cu on albumin and in the form of low-molecular-weight
complexes (e.g., histidine) to target tissues, particularly
the liver. From the liver, ceruloplasmin seems to aid in
the transport of Cu to other tissues. Ceruloplasmin is the
predominant Cu-containing protein in mammalian serum,
a glycosylated multi-Cu ferroxidase that carries 95% of
total serum Cu. Surprisingly, whereas ceruloplasmin can
function in Cu transport, the absence of ceruloplasmin has
not been shown to alter Cu levels in the peripheral tissues.
Such observations come from what is known about individuals
and animal models that have aceruloplasminemia,
a genetic disorder of ceruloplasmin deficiency. Moreover,
analbunemic rats do not have significantly impaired Cu
metabolism. Apparently Cu movement from serum proteins
to the cell surface reductase-Ctr transporters is not highly
specific ( Hellman and Gitlin, 2002 ).
3 . Disorders of Cu Metabolism-Cu Defi ciency
A number of pathologies are associated with Cu deficiency
that represent perturbations in the functions of Cu outlined
earlier. For example, anemia (microcytic hypochromic or
normocytic hypochromic) is probably the most frequent
sign associated with chronic Cu deficiency. Cu deficiency
results in impaired normal iron absorption ( O’Dell and
Sunde, 1997 ), mobilization, and utilization, partly because
of Cu’s role as a redox cofactor in various membrane associated
ferrioxidases that oxidize Fe 2 and Fe 3 , thereby
promoting the transfer of iron to transferrin. Reduced
aminolevulinic acid dehydrase, important to the first step
in heme synthesis, is also decreased in Cu deficiency.
Heinz body anemia caused by ROS can also develop with
a significant depression of CuZnSOD activity ( O’Dell and
Sunde, 1997 ).
Cardiovascular defects have been associated with Cu
deficiency since the 1950s. In cattle, Cu deficiency can
result in severe degeneration of the myocardium with
fibrosis ( “ falling disease ” ). Sudden death is a frequent
observation and is thought to be due to acute heart failure.
Cardiac failure associated with cardiac hypertrophy
has also been reported in Cu-deficient rats. A number of
biochemical lesions can underlie the changes in the heart
observed with Cu deficiency (e.g., decreased cytochrome
oxidase activity, abnormalities in cardiac and vessel wall
elastin and collagen structure because of lysyl oxidase, and
low cardiac norepinephrine levels, which can decrease coronary
resistance and reduce systolic pressure) ( Tinker and
Rucker, 1985 ). In experimental Cu deficiency in young
animals, such as turkey poults, aortic aneurysms can occur
( Savage et al. , 1966 ). This is the result of poor biomechanical
properties of elastic fibers (constitutes as much as 50%
of the total protein in aorta) that are weakened as a result
of defective and reduced cross-linking. Such elastin is also
susceptible to degradation and lost. Contrast this condition
with normal elastin that normally has a biological halflife
best measured in months to years (Tinker and Rucker,
1985) .
In addition, skeletal defects have been reported in
Cu-deficient dogs, sheep, chicks, cattle, foals, and humans.
The primary biochemical lesion underlying development
of bony lesions in Cu-deficient animals is again a reduction
in the activity of lysyl oxidase leading to a reduction in the
cross-linking of bone collagen, thus reducing bone stability
and strength analogous to the situation with elastin ( Tinker
and Rucker, 1985 ).
An increased rate of tissue lipid peroxidation is another
mechanism by which Cu deficiency can contribute to a
wide variety of lesions. In addition to the depression in
CuZnSOD activity, Cu deficiency can reduce the activity
of selenium(Se)-dependent glutathione peroxidase (GPx).
Thus, two major components of the cells ’ antioxidant
defense system can be affected by Cu deficiency. Another
lipid alteration is hypercholesterolemia (Engel et al. , 2000;
Gooneratne et al. , 1989 ; Keen et al. , 2003 ; Mills, 1987 ;
Schuscha, 1997 ) . In Cu-deficient animals, total cholesterol
and free cholesterol levels are elevated and are associated
with high concentrations of high- and low-density lipoproteins
(HDL and LDL). The lipid composition of HDL
isolated from Cu-deficient animals has been reported to
be similar to that of Cu-supplemented animals, but the
HDL has been shown to be enriched in apo F. A primary
biochemical lesion underlying the hypercholesterolemia is
a reduction in hepatic HDL binding that results in a slower
turnover of HDL and leads to an accumulation of apo
E-rich HDL. Both of these phenomena, lipid peroxidation
and abnormal lipid transport, are important features that
underlie abnormal membrane function.
Important to Cu’s role in oxidative defense are observations
that link Cu status to NO metabolism, an important
mediator of cellular regulation. NO can be synthesized
in both the cytosol and mitochondria ( Wu and Meininger,
2002 ). Among its major functions as a signaling molecule,
NO modulates oxidative phosphorylation and protects
mitochondria from oxygen radicals. This process, however,
depends on optimal cytochrome oxidase and CuZnSOD
activities. Cu deficiency limits NO availability, because in
the presence of ROS, NO is converted to products, such as
peroxynitrite, thus altering NO-dependent signaling and
contributing to processes that can range from abnormal
development to aging to neurological and cardiovascular
disorders. Indeed, many neurological signs can be associated
with Cu deficiency, owing to Cu’s role as a cofactor in
dopamine β -monooxygenase and in influencing NO metabolism
( Wu and Meininger, 2002 ). A classical example
of a neurological disorder is neonatal ataxia.
Neonatal ataxia has been shown to be a consequence
of perinatal Cu deficiency in lambs, goats, swine, guinea