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Title
Neutropenia caused by copper deficiency: possible mechanisms
of action.
Author
Percival SS
Address
Department of Food Science and Human Nutrition' University of
Florida' Gainesville 32611' USA.
Source
Nutr Rev, 53(3):59-66 1995 Mar
Abstract
Although copper is an essential nutrient in the human diet' overt
or severe copper deficiency is not a maJor public health concern
in the United States. A marginal or borderline deficiency has
been suggested by researchers' although the widespread nature
of copper deficiency has yet to be established. Reports indicate
that copper deficiency occurs secondary to gastric resection'
unsupplemented total parenteral nutrition' high levels of zinc
intake' or general malnutrition. An early clinical sign of copper
deficiency is a reduction in the number of circulating neutrophils.
Although copper is known to play a wide variety of roles in the
organism and in the immune system' the molecular mechanism for
copper-deficient neutropenia is not known. Very little data exist
with which to examine this question. This paper will summarize
our existing knowledge of the mechanism by which copper deficiency
results in neutropenia. Although the data are scarce' analysis
of this question will allow us to better understand additional
molecular roles of this trace element' and' in turn' to promote
an improved knowledge of immune cell functions and cellular differentiation.
Title
Antioxidant defense mechanisms in the female rat: interactions
with alcohol' copper' and type of dietary carbohydrate.
Author
Fields M; Lewis CG
Address
Beltsville Human Nutrition Research Center' USDA' MD 20705' USA.
Source
Alcohol, 12(3):227-31 1995 May-Jun
Abstract
The purpose of this study was to examine the effects of ethanol'
type of dietary carbohydrate (fructose vs. starch)' and levels
of dietary copper (deficient vs. adequate) on antioxidant defense
mechanism in the female rat. The consumption of 20% ethanol in
the drinking water depressed growth rate due to a reduction of
feed efficiency. Ethanol also lowered hepatic copper concentration'
but had no effect on hepatic iron. Among the three antioxidant
enzymes studied [i.e.' superoxide dismutase (SOD)' glutathione
peroxidase (GSH-Px)' and catalase ' only catalase activity was
increased by ethanol. This effect was independent of copper or
the type of dietary carbohydrate. As expected' copper deficiency
dramatically reduced SOD. copper deficiency also reduced GSH-Px
activity; however' the combination of fructose feeding with copper
deficiency caused a further reduction in GSH-Px. The data show
that copper deficiency' per se' and the combination of copper
deficiency with fructose feeding lower the antioxidant defense
system in female rats.
Title
A review of evidence for a role of magnesium and possibly copper
deficiency in necrotizing enterocolitis.
Author
Caddell JL
Address
Thomas Jefferson University Department of Pediatrics' Philadelphia'
PA 19107-6799' USA.
Source
Magnes Res, 9(1):55-66 1996 Mar
Abstract
Necrotizing enterocolitis (NEC) is a neonatal disorder of unknown
cause characterized by rapid necrosis of the bowel' primarily
the ileum and colon. It is a worldwide problem. NEC is the most
common gastrointestinal emergency in the neonatal intensive care
unit' and ranks second as a cause of neonatal death. The incidence
of NEC is inversely proportional to the birth weight and the
degree of maturity. Infants born at or before 28 weeks gestational
age have not received 80 per cent of the magnesium and 67 per
cent of the copper found at term. Congenital deficiencies of
these essential minerals may be compounded by high renal or gastrointestinal
losses and high metabolic demand during the preterm infant`s
accelerated growth. Platelet thrombi appear early in the intestinal
microvasculature in NEC. Platelet thrombosis and release of vasoconstrictor'
platelet aggregating thromboxane A2 (TXA2) in human NEC appears
to potentiate the intestinal ischaemia and necrosis in neonates
who develop NEC. Magnesium and copper deficiency each enhance
the synthesis of TXA2. Plasma levels of the inflammatory cytokines
tumour necrosis factor (TNF) and interleukin-6 (IL-6) are increased
in NEC and in magnesium deficiency; these experimentally produce
shock and tissue inJury' especially of the intestine. The synthesis
of the potent vasoconstrictor endothelin is increased in magnesium
deficiency. NEC has been regarded as a luminal insult that causes
local generation of destructive oxygen free radicals. Tissues
from animals deficient in magnesium are more susceptible to oxidative
inJury and lipid peroxidation than tissues from normal animals.
Magnesium and copper deficiency impair antioxidant defence through
decreased synthesis of glutathione and reduced activity of Cu/Zn
superoxide dismutase' respectively. Although the aetiology of
NEC is unknown' there appears to be sufficient data to implicate
magnesium and possibly copper deficiencies in the pathogenesis.
Consequences of deficiency of one or both minerals may include
increased synthesis or activity of inJurious mediators: IL-1'
IL-6' TNF' TXA2' endothelin' and oxygen free radicals. A prospective
trial of magnesium supplementation' but not copper supplementation'
in very premature neonates can be recommended' with NEC as one
of the outcome measures.
Title
Cardiac nuclear encoded cytochrome c oxidase subunits are decreased
with copper restriction but not iron restriction: gene expression'
protein synthesis and heat shock protein aspects.
Author
Medeiros DM; Shiry L; Samelman T
Address
Department of Human Nutrition and Food Management' Ohio State
University' Columbus 43210-1295' USA.
Source
Comp Biochem Physiol A Physiol, 117(1):77-87 1997 May
Abstract
Hearts from rats fed a copper-deficient (Cu-) diet have decreased
levels of nuclear-encoded peptides of cytochrome c oxidase (CCO).
Studies were conducted to determine whether iron deficiency would
lead to a similar finding' whether mRNA transcripts and the chaperonin
heat shock proteins (HSP) 60 and 70 from hearts of Cu- rats were
decreased as compared with copper-adequate controls and whether
synthesis of mitochondrial and nuclear encoded peptides differed
as affected by diet copper. In study 1' weanling rats were assigned
to one of three groups (n = 6 in each group): (1) control copper
and iron adequate fed rats; (2) Cu- rats and (3) iron-deficient
(Fe-) rats. Western blotting of nonmyofibrillar cardiac proteins
revealed that the nuclear encoded peptides of CCO from the Cu-
rats were markedly decreased as compared with control and Fe-
rats. Mitochondrial encoded subunits did not appear to differ
by treatment groups. Iron-deficient rats had similar nuclear
encoded peptide levels as those of controls. In study 2' mRNA
transcripts from Cu- (n = 4) and control copper adequate (n =
4) rats did not appear to differ for subunits II and IV' which
correspond to mitochondrial and nuclear encoded subunits' respectively.
In study 3' levels of HSP 60 and 70 from hearts of Cu- rats (n
= 3) did not differ from Cu+ rats (n = 3). In study 4' infusion
of 3H-(4'5)-leucine into the hearts of Cu+ and Cu- rats suggested
there was no difference in synthesis of the nuclear encoded peptides
by copper status and some indication there was enhanced breakdown
of the nuclear encoded peptides among the Cu- rats. As expected'
more isotope was incorporated into the mitochondria of Cu- rats
than Cu+ rats. These results demonstrate an independent effect
of copper upon the apparent decrease in the nuclear encoded subunits
of CCO' the effect of copper upon the CCO subunits is probably
post-transcriptional and that translocation of the nuclear encoded
subunits from the ribosomes to the mitochondria via the chaperonin
proteins is not a primary defect in explaining these observations
in hearts from Cu- rats and synthesis of the nuclear encoded
subunits of CCO in not impaired in copper deficiency.
Title
Impaired endocrine and exocrine pancreatic functions in copper-deficient
rats: the effect of gender.
Author
Fields M; Lewis CG
Address
United States Department of Agriculture' ARS Beltsville Human
Nutrition Research Center' Metabolism and Nutrient Interactions
Laboratory' Beltsville' MD 20705' USA.
Source
J Am Coll Nutr, 16(4):346-51 1997 Aug
Abstract
OBJECTIVE: To examine the effect of gender on endocrine and exocrine
pancreatic function in female and male rats fed from weaning
a copper-deficient diet. METHODS: Weanling male and female rats
were fed a copper-deficient or adequate diet for 4 weeks. Rats
were sacrificed after an overnight fast. Livers and pancreata
were removed' weighed and the concentrations of copper and iron
were determined. In addition' insulin was measured in pancreatic
tissue and plasma. Lipase and amylase activities were measured
in pancreas. Lipid peroxidation was assessed in liver. RESULTS:
copper deficiency in the male resulted in a profound reduced
glandular mass of the pancreas. The pancreas continued low activities
of lipase and amylase but excessive levels of insulin. Iron retention
in the pancreas of the copper-deficient male rat was greater
than in the female counterpart. Effects of copper deficiency
in female rats on pancreas mass and endocrine pancreas were of
lesser magnitude compared with males. Plasma insulin in the female
rat was much higher than in the male rat. Hepatic lipid peroxidation
was increased by copper deficiency in the male rat but was unaffected
in the female. CONCLUSIONS: Data show that pancreatic atrophy
is more pronounced in males compared with females' and the endocrine
pancreas of the male is more susceptible to dietary copper deprivation
than the female rat. The greater degree of pancreatic atrophy
and associated abnormalities in males compared with females may
be related to the greater retention of pancreatic iron and subsequent
peroxidative damage.
Title
In vivo oxidative modification of erythrocyte membrane proteins
in copper deficiency.
Author
Sukalski KA; LaBerge TP; Johnson WT
Address
Department of Biochemistry and Molecular Biology' University
of North Dakota School of Medicine' Grand Forks 58202-9037' USA.
Source
Free Radic Biol Med, 22(5):835-42 1997
Abstract
Oxidative stress has been postulated to contribute to the pathology
associated with dietary copper deficiency. In vivo' erythrocytes
are probable targets of oxidative damage because they are exposed
to high concentrations of oxygen and contain heme iron that can
autoxidize' which results in the formation of superoxide anions.
Activity of the important antioxidant enzyme' copper' zinc superoxide
dismutase' decreases markedly in erythrocytes during copper deficiency.
The effect of dietary copper deficiency on indicators of oxidative
stress was examined in erythrocyte membranes of rats maintained
on a purified copper-deficient diet for 35 days after weaning.
Erythrocytes were separated into young and old populations on
a Percoll gradient prior to membrane isolation and quantification
of lipid peroxides and protein carbonyls. Protein carbonyls'
determined by Western blot immunoassay' were detected predominantly
in both the alpha and beta chains of spectrin. Alpha and beta
subunits of spectrin in erythrocyte membranes from copper-deficient
rats contained higher amounts of carbonyls than controls' regardless
of the population of erythrocytes studied. This study suggests
that spectrin may be a specific target for oxidative damage when
erythrocyte copper' zinc superoxide dismutase activity is reduced
by copper deficiency.
Title
copper deficiency increases hepatic apolipoprotein B secretion
and mRNA editing in rats.
Author
Reaves SK; Hoogeveen RC; Wang YR; Wu JY; Lei KY
Address
Department of Nutritional Sciences' University of Arizona' Tucson
85721' USA.
Source
Am J Physiol, 271(2 Pt 1):C595-604 1996 Aug
Abstract
Male weanling Sprague-Dawley rats were assigned to copper-deficient
(9.0 mumol Cu/kg diet) or copper-adequate (102 mumol Cu/kg diet)
dietary treatments for 6 wk. Pulse-chase studies using freshly
isolated rat liver parenchymal cells demonstrated that apolipoprotein
B (apoB)-48 and apoB-100 syntheses were not altered' but secretion
was increased twofold in hepatocytes derived from copper-deficient
rats. Both plasma apoB-48 and apoB-100 levels were increased
by copper deficiency' but only the apoB-48 increase was significant.
Hepatic apoB mRNA editing' expressed as a ratio of apoB-48 mRNA
to apoB-48 plus apoB-100 mRNA' was significantly increased from
60.8% in copper-adequate to 70.2% in copper-deficient rats. Moreover'
hepatic apoB mRNA abundance was not significantly altered by
copper deficiency. Thus the increased amount of nascent apoB-48
secreted into the medium as well as the enhanced apoB mRNA editing
may have contributed to the differential increase in plasma apoB-48
over apoB-100 level in copper-deficient rats.
Title
Dietary copper in the physiology of the microcirculation.
Author
Schuschke DA
Address
Center for Applied Microcirculatory Research, University of Louisville,
Louisville, KY 40292, USA.
Source
J Nutr, 127(12):2274-81 1997 Dec
Abstract
Dietary copper has long been known to be essential for cardiovascular
homeostasis. However, the role of copper and cuproenzymes in
the normal control of vascular physiology is not well understood.
Most studies in the cardiovascular system have focused on copper
deficiency-induced defects in the heart or large vessels. Recently,
attention has also focused on the effects of copper deficiency
in the microcirculation or the small blood vessels that control
blood flow, nutrient and waste exchange, and peripheral vascular
resistance. Studies in the microcirculation demonstrate that
copper is important in mechanisms of macromolecular leakage,
platelet-endothelial interactions and vascular smooth muscle
reactivity. There is a significantly greater leakage of proteins
from postcapillary venules in copper-deficient rats in response
to mast cell-released histamine. This response appears to be
the result of increased numbers of mast cells and thereby increased
available histamine. copper deficiency also causes an inhibition
of in vivo thrombogenesis, which appears to be related to an
inhibition of platelet adhesion. Subsequent studies have demonstrated
that this is probably caused by a diminished concentration of
the adhesion molecule von Willebrand factor. Nitric oxide (NO)-mediated
arteriole vasodilation is also compromised in copper-deficient
rats. This functional deficit to NO can be reversed by the addition
of Cu, Zn-superoxide dismutase (SOD), suggesting that degradation
of NO by superoxide anion occurs during copper deprivation. These
observations demonstrate that dietary copper is necessary for
several microvascular control mechanisms affecting inflammation,
microhemostasis and regulation of peripheral blood flow.
Title
The relationship of nutritional copper to the development of
postmenopausal osteoporosis in rats.
Author
Yee CD; Kubena KS; Walker M; Champney TH; Sampson HW
Address
Department of Animal Science' College of Veterinary Medicine'
Texas A&M University' College Station 77843' USA.
Source
Biol Trace Elem Res, 48(1):1-11 1995 Apr
Abstract
Factors that influence tissue copper concentration include age'
diet' hormones' and pregnancy. In this study we altered diet
independently' hormone (estrogen) independently' and various
combinations of diet and hormone in animals of the same age to
study the effects of ovariectomy complicated with dietary copper
deficiency; a deficiency that has been demonstrated to cause
bone defects. Sprague-Dawley rats were placed on various combinations
of copper deficient or enriched diets before and/or after ovariectomy
to determine if copper deficiency aggravated osteoporosis and
if return to a copper-adequate diet alleviated it. In this study'
ovariectomy did induce an osteopenia that was characterized by
decreased trabecular bone. This osteopenia was slightly more
severe with copper deficiency' but was not necessarily alleviated
by the return of normal copper levels to the diet.
Title
Gender' dietary copper and carbohydrate Source influence
cardiac collagen and lysyl oxidase in weanling rats.
Author
Werman MJ; Barat E; Bhathena SJ
Address
Metabolism and Nutrient Interactions Laboratory' U.S. Department
of Agriculture' Beltsville Human Nutrition Research Center' MD
20705' USA.
Source
J Nutr, 125(4):857-63 1995 Apr
Abstract
The present investigation was conducted to determine the effects
of consumption of diets containing fructose or cornstarch on
cardiac collagen metabolism in weanling male and female rats
fed copper-deficient or copper-adequate diets for 5 wk. Although
both male and female rats that consumed the copper-deficient
diet containing fructose were similarly copper deficient' only
the males showed severe cardiac pathologies and two died prematurely
due to heart-related abnormalities. These pathologies were accompanied
by a significant reduction of cardiac lysyl oxidase activity
and elevated soluble and total cardiac collagen concentrations
compared with rats fed copper-adequate diets. These abnormalities
were less severe in copper-deficient rats fed cornstarch. The
data show that the activity of the copper-containing enzyme lysyl
oxidase is affected by both dietary carbohydrate and gender.
The pathologies of heart tissue could be the result of abnormal
crosslinking of collagen induced by the combination of copper
deficiency' fructose feeding and the sex of the rats.
Title
Serum concentrations of zinc and copper in bull terriers with
lethal acrodermatitis and tail-chasing behavior.
Author
Uchida Y; Moon-Fanelli AA; Dodman NH; Clegg MS; Keen CL
Address
Department of Surgery' School of Veterinary Medicine' Tufts University'
North Grafton' MA 01536' USA.
Source
Am J Vet Res, 58(8):808-10 1997 Aug
Abstract
OBJECTIVE: To establish similarities or differences in tissue
concentrations of zinc' copper' and iron in Bull Terriers with
lethal acrodermatitis (LAD) and tail-chasing behavior (TCB) and
to confirm the suspicion that copper is involved in the etiopathogenesis
of LAD. SAMPLES: Serum samples from 29 Bull Terriers (9 control
dogs' 6 dogs with LAD' 14 dogs with TCB)' and liver and kidney
specimens from 2 dogs and 1 and 4 dogs with LAD or TCB' respectively.
PROCEDURE: Serum' liver' and kidney mineral (zinc' copper' and
iron) concentrations in Bull Terriers with LAD or TCB and in
a group of control dogs were analyzed' using flame atomic absorption
after wet ashing technique. RESULTS: Serum zinc and copper concentrations
were lower (P < 0.05) in dogs with LAD' compared with values
for control dogs and dogs with TCB. Liver zinc and copper concentrations
were similar to serum values. Kidney zinc and copper concentrations
were similar among the 3 groups. Serum' liver' and kidney iron
concentrations had a wide range of variability within all 3 groups.
CONCLUSION: copper deficiency is associated with LAD. The primary
cause of LAD may be copper deficiency' with zinc involved secondarily'
or combined zinc and copper deficiencies. The role of ion deficiency
in TCB was not clarified. CLINICAL RELEVANCE: Serum zinc and
copper concentrations should be determined when LAD is suspected.
Title
Dietary ferric vs. ferrous iron in copper-deficient rats fed
fructose-based diets.
Author
Fields M; Lewis CG; Lure MD; Burns WA
Address
Metabolism and Nutrient Interactions Laboratory' Beltsville Human
Nutrition Research Center' Maryland 20705' USA.
Source
J Am Coll Nutr, 14(4):399-403 1995 Aug
Abstract
OBJECTIVE: This preliminary study was undertaken to determine
whether the valence state of dietary iron affects signs associated
with copper deficiency in rats fed fructose. METHODS: Rats were
fed either copper-deficient or adequate diets containing 62%
fructose as the sole dietary carbohydrate for 5 weeks. The mineral
mixture contained equal concentration of either ferric or ferrous
iron. RESULTS: copper deficiency resulted in growth retardation'
anemia' heart hypertrophy but pancreatic atrophy. The consumption
of ferrous iron resulted in increased hematocrit and pancreas
size. The combination of ferrous iron with copper deficiency
reduced heart size. CONCLUSIONS: copper deficiency had a maJor
impact on each parameter measured. Although the valence state
of iron did not protect the rats against the pathological consequence
of copper deficiency it did have some positive effects. It may
be that ferrous iron is a more available form than ferric iron.
Title
Effect of copper deficiency on the activity levels of ceruloplasmin
and superoxide dismutase in tissues of young and old rats.
Author
Gomi F; Matsuo M
Address
Tokyo Metropolitan Institute of Gerontology' Japan.
Source
Aging (Milano), 7(1):61-6 1995 Feb
Abstract
Six- and 24-month-old rats were fed a copper deficient diet for
10 weeks; the copper content of the diet was one fourteenth that
of a control diet. After the 10-week feeding period' the copper
contents of the cerebrums' livers' lungs' and serum were decreased
by 20-17' 49-47' 48-37' and 84-83%' respectively' while those
of hearts and muscles were unchanged or only slightly decreased.
There was no difference in the decreases in copper content of
tissues between young and old rats. copper deficiency decreased
the activity level of ceruloplasmin in the serum of young and
old rats by 95%' and the copper/zinc superoxide dismutase (CuZn-SOD)
activity levels of cerebrums' lungs' and livers of young rats
by 16' 36' and 34%' respectively' but did not change the CuZn-SOD
activity levels of tissues of old rats. Although copper deficiency
affected catalase activity' vitamin E concentration' and reduced
glutathione concentration in several tissues' no consistent trends
were observed. On the basis of the survival time of rats exposed
to more than 96% oxygen' it is suggested that a decrease in CuZn-SOD
activity due to copper deficiency increases oxygen susceptibility. |
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