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COPPER COPPER CONTENT IN FOOD - (Milligrams) Best Wishes,Chris Copper and Hyperthyroidism Thyroid and immune system health are crucially dependent upon copper. As far as I can see now, copper deficiency is the most important factor in the development of hyperthyroidism. Virtually all hypers in the hyperthyroidism group have found that copper supplementation reduced their symptoms, usually within hours or a few days at most. Most have reported that within three to six months of beginning copper supplementation, they have been able to significantly reduce their intake of antithyroid drugs.While copper is the big story in hyperthyroidism, it is not the whole story. If it were, it would have been discovered years ago. Proper copper metabolism interrelates with and depends upon many other nutrients. Copper, Zinc, and Sex One unique thing about copper is that women need more of it than men. This seems to be primarily because copper is required for the production of the enzymes which convert progesterone into estrogen. Men, however, require more zinc, which seems to be the mineral necessary to form the enzymes which convert progesterone into testosterone. Studies show that copper intake in America is borderline or inadequate. Foods that contain copper, such as nuts and seeds, beans and other legumes, lobster, and crab, are not eaten, especially by women who need more copper, because of beliefs that these foods are fattening or contain toxic substances (shellfish). Other foods like beer and chocolate are good sources of copper but because of the other ingredients, alcohol in beer, and caffeine and sugar in chocolate, they are not consumed in amounts sufficient for women. Because copper content of the average diet is marginal, men are generally able to get enough copper for two reasons: first, their requirement for copper is slightly less; second, most men drink beer. Beer contains reasonably high levels of two critical minerals: copper and selenium. Probably men have a drive to drink beer for its selenium content which is necessary for testosterone production, and as a by-product consume a lot of copper. Because copper slows down the thyroid, this is the probable reason that drinkers of beer put on weight and get a "beer-belly." Women, on the other hand, driven by a desire to stay thin, generally avoid the high copper foods because of the perception (which is correct) that the high copper foods can cause weight gain. Tobacco smoking Other women start smoking tobacco for a similar reason: because of the perception that smoking makes you stay thin. I believe that there is truth to this perception, because it appears that the cadmium in tobacco smoke is a copper antagonist. This results in low copper levels, and when combined with a high-zinc, meat-based diet, results in higher thyroid output, a higher rate of metabolism, and staying thinner. Unfortunately, for women there seems to be an interaction between estrogen and cadmium which results in high cadmium levels which not only depress copper, but depress zinc. Once zinc is depressed, the metabolic rate decreases and obesity sets in. Depending upon dietary intake of copper and zinc, cadmium can either push the woman to hypothyroidism (low zinc) or hyperthyroidism (low copper). The combination of estrogen and cadmium acts as an accelerator which pushes women one way or the other and makes the happy medium difficult to accomplish. Copper and vitamins I believe that many people probably consume a nutritionally adequate amount of copper in their diets. However, because copper absorption and utilization depend upon the presence of many other nutrients including many of the B complex vitamins, many people do not get an adequate amount of copper into their cells. Many of the B Complex vitamins are essential for copper utilization and deficiencies of these vitamins are similar to copper deficiencies. Vitamins B-1 (thiamine), B-2 (riboflavin), B-3 (niacin), B-5 (pantothenic acid), biotin, and PABA all seem to work with copper and information about these can be found in separate pages on them. Of all these B vitamins, I believe that biotin and PABA are the most important because they are usually the most neglected and probably under-represented in most B Complex and multiple vitamin supplements. Books on vitamins typically describe biotin as a vitamin which doesn't get deficient unless raw eggs are eaten and rarely even mention PABA as a possible deficiency. There are some sources which indicate that PABA is beneficial in hyperthyroidism which adds support to my belief that PABA is an important nutrient to assist copper metabolism. Often it seems that deficiencies of other nutrients, which are needed for copper metabolism, are the problem in hyperthyroidism. However, even when these other nutrients are inadequate, increasing copper intake seems to help. The other side of the situation is that excessive amounts of the vitamins which facilitate copper metabolism may deplete copper further if copper is deficient. Vitamin C is essential for copper metabolism, but excess vitamin C, such as 5000-10000 mgs per day seems to deplete copper. It's important to have all the nutrients balanced and not to take an excessive amount of any one nutrient. How does copper work in the body and what are the documented effects of copper deficiency in humans? Copper is essential for maintaining the strength of the skin, blood vessels, and epithelial and connective tissue throughout the body. Deficiencies of copper can result in hernias, aneurysms, and blood vessel breakage manifesting as bruising or nosebleeds. If copper is important in cellular membrane structure, then a copper deficiency could seriously alter the movement of nutrients through cell walls. Copper and Autoimmune Disease Grave’s disease is characterized as an autoimmune disease. This means that the immune system is not operating properly. Immune bodies known as immunoglobulins (IGs) are stimulating the thyrotropin receptors in the thyroid gland and this stimulation causes the thyroid to increase hormone output. I think that it’s obvious that healthy immune system function, like any biological function, is dependent upon an adequate supply of essential nutrients. It is not a great leap of faith to see that a deficiency of an essential nutrient could cause the immune system to malfunction. There is very little scientific evidence that copper is involved in immune system function, but it is my belief that copper deficiency is the principal nutritional deficiency involved in autoimmune diseases. Approximately 80% of the people who suffer from autoimmune diseases are women. The most important nutrient that women need more of than men is copper. Any nutritional detective who is trying to find the culprit in autoimmune diseases should first suspect copper. Women need more copper and get autoimmune diseases more frequently. Men need less copper and generally don’t get autoimmune disease. Copper deficiency is the obvious suspect. What’s the evidence? First of all, the main copper antagonist, zinc, is known to be involved in immune system function. Zinc and zinc containing herbs like ginseng are listed in many health books as immune system boosters. I believe that many health practitioners and autoimmune disease sufferers alike interpret this information incorrectly. They are recommending and using zinc supplements for the treatment of autoimmune dysfunction. I believe that this is completely incorrect and the last thing you would want to do in the case of an autoimmune disease is to stimulate the immune system by supplementing zinc. Autoimmune diseases are characterized by an out-of-control immune system. To use a car analogy, the immune system, which is the system to maintain the proper functioning of the auto, could be represented by the mechanic. In the case of autoimmune diseases, the mechanic is out-of-control and ruining things rather than fixing them. Supplementing with zinc and stimulating the immune system would be like giving coffee to the out-of-control mechanic so that he works twice as fast and destroys twice as many things in the car. If the immune system were under performing, then zinc would be a proper supplement to increase its functioning. But when the immune system is so overactive that it is causing damage to the body, then it’s completely inappropriate. The proper nutrient to supplement would be zinc’s antagonist, copper. Copper will decrease the stimulation to the immune system that zinc causes and enable the immune system function to slow down and perform normally. Is there any evidence that copper is involved in the functioning of the immune system? Yes. There is a disease called Wilson’s disease, which is characterized by the body’s inability to properly metabolize copper and the copper accumulates in the liver, brain, and other organs to the point where it causes damage. One of the main medical treatments of Wilson’s disease is the use of d-penicillamine, which is a drug which chelates (or grabs) metals, especially copper, and removes them from the body. Many Wilson’s patients who are treated with penicillamine develop autoimmune diseases like lupus. Penicillamine chelates both copper and zinc and many patients also need to supplement zinc and B-6 (the B vitamin that helps zinc metabolism) to stay healthy. Penicillamine has also been shown to induce autoimmune disease in rats (study). Another study shows that copper deficiency in mice impairs immune system function. "Dietary copper (Cu) was restricted in Swiss albino mice during five discrete intervals over a 9-wk period of perinatal development: gestation only (G), lactation only (L), 3 wk postlactation (PL), 1 wk after birth through postlactation (2/3L + PL), and lactation plus postlactation (L + PL). Biochemical and immunological status of mice in copper-deficient (-Cu) treatment groups in models G and L did not differ from that of copper-adequate (+Cu) controls. Signs of severe copper deficiency, such as low liver copper levels, and significant reductions in activity of plasma ceruloplasmin and splenocyte Cu-Zn superoxide dismutase were most evident in 6-wk-old mice from two groups, -Cu 2/3L + PL and -Cu L + PL. Mice in these groups were anemic and had small thymuses and enlarged spleens compared to controls receiving +Cu treatment. The -Cu mice demonstrated impaired antibody (plaque-forming cells, PFC) response to sheep erythrocytes, and the attenuation was proportional to copper deficiency, as judged by liver copper levels. Total plasma IgM levels were not greatly altered by -Cu treatment except in model L + PL. Total IgG levels were markedly reduced in this group and in the -Cu 2/3L + PL group. The PFC response of mice in the -Cu PL group was normal even though signs of copper deficiency were evident; however, the PFC response was reduced when -Cu treatment was extended to 5 wk and was reversible by switching to +Cu treatment. Splenocyte reactivity to B- and T-cell mitogens was not greatly different between groups. Incorporation of thymidine into DNA in the absence of mitogen was higher in -Cu mice. It is evident that severity of copper deficiency is related to degree of impaired immunity. Furthermore, severity of copper deficiency is dependent on duration and time of initiation of dietary copper restriction." (Copper deficiency during prenatal development: effects on the immune response of mice.) In an experiment on calves, "in vitro Cu supplementation decreased (P < .01) lymphocyte blastogenic response." One form of hypothyroidism is called Hashimoto’s Disease. This is a form of hypothyroidism characterized by immune system dysfunction and is the hypothyroid version of Grave’s Disease. Some people in the health field consider Grave’s and Hashimoto’s the same disease. While the actual thyroid function is different in the two diseases, one high and the other low, other characteristics of the diseases are very similar. For example in both diseases, patients might have thyroid eye disease (TED, ophthalmopathy, orbitopathy) or pretibial myxedema (swelling of the tissue at the front of the shin). At this point in my research it looks like TED and pretibial myxedema are more the result of zinc deficiency than copper deficiency, but taking zinc without copper does not seem to be a wise decision in light of the fact that Hashimoto’s and Grave’s are both autoimmune diseases. Copper is necessary for the control of the immune system dysfunction, before zinc can be supplemented to control the fibroblast growth which is seen in TED and myxedema. Copper and Hypothyroidism Is copper deficiency involved in hypothyroidism? In one study it was found that copper deficiency enhances the effects of PTU-induced hypothyroidism. "Thus, copper-deficient and hypothyroid states were considerably enhanced when the 2 existed concurrently, giving added meaning and necessity to close surveillance of trace mineral concentrations and thyroid gland status."
Possible interrelationships of copper-deficient (copper-deficient ration) and hypothyroid (thiouracil treatment) states in rats were examined. Clinical signs, necropsy changes, and thyroxine concentrations were determined in 6 groups of rats treated as follows: group A--nontreated control; group B--thiouracil treated; group C--fed copper-deficient ration; group D--thiouracil treated and fed copper-deficient ration; group E--thyroid-stimulating hormone (TSH) treated; and group F--TSH treated and fed copper-deficient ration. Clinical signs occurred first and were most severe in the thiouracil-treated rats fed copper-deficient ration and included conformational changes and slower maturation, weakening of ear cartilage, middle ear changes (reflected by tilting of heads), and alopecia. Fatty infiltration of hepatic tissue was found in all rats fed copper-deficient rations, and considerable fluid retention occurred in rats fed copper-deficient ration and subjected to daily TSH treatment. Adrenal gland weights were 81% of control values (adjusted for body weight) in thiouracil-treated rats fed copper-deficient ration, and hypophysis weights were 114 and 154% of control values in thiouracil-treated rats and thiouracil-treated rats fed copper-deficient ration, respectively. Thyroid gland weights were 281% of control values in both thiouracil-treated rats and thiouracil-treated rats fed copper-deficient ration. Plasma thyroxine concentrations were markedly reduced (9% of control value) in thiouracil-treated rats fed copper-deficient ration. Thus, copper-deficient and hypothyroid states were considerably enhanced when the 2 existed concurrently, giving added meaning and necessity to close surveillance of trace mineral concentrations and thyroid gland status. Some women with hypothyroidism also have galactorrhea, which is a condition of excessive production of prolactin, the hormone which causes breast milk secretion. The result is spontaneous release of breast milk and body weight gain which is the apparent result of the body being in a pregnancy-like state due to hormonal imbalance. There is a study suggesting that copper may be involved in the production of prolactin. There is a case of a woman who developed galactorrhea from a copper IUD. This association of galactorrhea with hypothyroidism could be evidence of a disturbance of copper metabolism in hypothyroidism.
We report a case of galactorrhea in a normoprolactinemic fertile woman (30 years old) wearing a copper intra-uterine device (Gravigard). The Gravigard was first inserted in July 1977. In February 1979 our patient noted spontaneous galactorrhea, mainly on the left, but it was also present on the right, after breast pressure. X-ray film of the sella turcica, visual-field examination, thyroid function and basal prolactin levels were all within normal limits. In May 1979 the Gravigard was withdrawn and milk loss stopped finally in December 1979. In March 1980 the IUD was replaced; after only 3 days, mild spontaneous lactation again ensued, on the right side. The patient never took drugs which might have occasioned a prolactin rise. Possible explanations for this unusual phenomenon are discussed. In a study on rats there is evidence that copper is necessary for proper iodine metabolism and consequently of proper thyroid hormone synthesis. Title [The effect of copper on the metabolism of iodine, carbohydrates and proteins in rats]
Experiments on 156 rats maintained at ration with copper deficiency have demonstrated a decrease in the values of iodine metabolism in organs and tissues excluding the liver where a sharp increase in the concentration and content of inorganic iodine was observed. A disturbance in indices of carbohydrate and proteins metabolism in the organism of animals is marked. A direct relationship with a correlation coefficient equaling 0.87-1.00 is determined between changes in the concentration of protein-bound iodine in blood and concentration of glycogen in the liver, skeletal muscles, albumins, alpha 1-, alpha 2-globulins, urea concentration; an inverse relationship with glucose, activity of blood lipo-dehydrogenase and liver mitochondria, aldolase, concentration of pyruvic and lactic acids is established as well. It is concluded that copper deficiency can exert both a direct effect on metabolic processes (as data from literature testify) and an indirect one disturbing iodine metabolism, i. e. sharply decreasing protein-bound iodine production by the thyroid gland. COPPER Copper is essential for maintaining the strength of the skin, blood vessels, and epithelial and connective tissue throughout the body. Deficiencies of copper can result in hernias, aneurysms, and blood vessel breakage manifesting as bruising or nosebleeds. If copper is important in cellular membrane structure, then a copper deficiency could seriously alter the movement of nutrients through cell walls. JJ
[D-penicillamine: mechanism of cellular action and induced autoimmune diseases]. [Article in French] Meyer O The fall in the IgM rheumatoid factors under treatment is not sufficient to explain the effectiveness of D-penicillamine in rheumatoid arthritis. The mechanism of action of D-penicillamine is still poorly elucidated. In vitro, in the presence of copper ions, D-penicillamine inhibits the lymphoblastic transformation induced by polyclonal mitogens; it decreases the production of immunoglobulins by lymphocytes stimulated by the Pokeweed mitogen. This inhibitory action is exerced on the helper T lymphocytes via the production of hydrogen peroxide (H2O2). Monocytes are capable of blocking the inhibitory action of D-penicillamine. The mechanism of the auto-immune complications induced by D-penicillamine is controversial. Two theories have been proposed:--a modification of the auto-antigens due to the presence of the highly reactive thiol group;--an interference with the lymphoid cells involved in suppressor or effector lymphocyte cellular co-operation. These auto-immune complications can be classified into two groups: organ-specific diseases such as myasthenia, polymyositis, thyroiditis, and non organ-specific diseases such as Sjogren's syndrome and lupus. The suspension of D-penicillamine generally leads to the resolution of the symptoms, but corticosteroid and immunosuppressant treatment is sometimes required. The following study shows that beer mitigates some of the effects of copper deficiency. Copper deficient rats given beer lived six times as long as copper deficient rats given water. Interestingly, the effects were found to be unrelated to the copper, chromium, and alcohol in the beer. My guess is that the effect is due to the yeast which other studies show increases copper uptake in the cells.
Copper deficiency in rats causes increased serum levels of T3:
The aim of the present study was to investigate the effect of copper deficiency on thyroid hormone metabolism in rats. Therefore, an experiment with growing male Sprague-Dawley rats was carried out, consisting of two groups of rats fed either a copper-deficient (0.06 mg Cu/kg) or a copper-adequate diet (16 mg Cu/kg). Both groups of rats were fed identical quantities of diet by pair-feeding. Copper deficiency decreased the final body weight of the rats by 5% compared to copper-adequate control rats. A severe copper-deficient state in the rats fed the copper-deficient diet was proved by a large decrease of ceruloplasmin activity in serum (by 97%) and hematological changes. For estimation of thyroid hormone metabolism, the concentrations of total and free thyroxine (T4) and triiodothyronine (T3) in serum and the activity of hepatic 5'monodeiodinase (5'D) were determined. Copper-deficient rats had an increased concentration of T3 in serum, whereas the concentrations of total and free T4 as well as the activity of hepatic 5'D were not different compared with copper-adequate control rats. Therefore, the study shows that copper deficiency has only slight effects on thyroid hormone metabolism in growing rats. Copper deficiency enhances the effects of PTU-induced hypothyroidism.
Possible interrelationships of copper-deficient (copper-deficient ration) and hypothyroid (thiouracil treatment) states in rats were examined. Clinical signs, necropsy changes, and thyroxine concentrations were determined in 6 groups of rats treated as follows: group A--nontreated control; group B--thiouracil treated; group C--fed copper-deficient ration; group D--thiouracil treated and fed copper-deficient ration; group E--thyroid-stimulating hormone (TSH) treated; and group F--TSH treated and fed copper-deficient ration. Clinical signs occurred first and were most severe in the thiouracil-treated rats fed copper-deficient ration and included conformational changes and slower maturation, weakening of ear cartilage, middle ear changes (reflected by tilting of heads), and alopecia. Fatty infiltration of hepatic tissue was found in all rats fed copper-deficient rations, and considerable fluid retention occurred in rats fed copper-deficient ration and subjected to daily TSH treatment. Adrenal gland weights were 81% of control values (adjusted for body weight) in thiouracil-treated rats fed copper-deficient ration, and hypophysis weights were 114 and 154% of control values in thiouracil-treated rats and thiouracil-treated rats fed copper-deficient ration, respectively. Thyroid gland weights were 281% of control values in both thiouracil-treated rats and thiouracil-treated rats fed copper-deficient ration. Plasma thyroxine concentrations were markedly reduced (9% of control value) in thiouracil-treated rats fed copper-deficient ration. Thus, copper-deficient and hypothyroid states were considerably enhanced when the 2 existed concurrently, giving added meaning and necessity to close surveillance of trace mineral concentrations and thyroid gland status. Copper controls the DNA encoding of the thyroid hormone receptor.
To study thyroid hormone receptor (TR), we developed an in vivo expression system in yeast by using a copper-responsive yeast metallothionein promoter and ubiquitin-fusion protein technology. The cDNA encoding full-length rat liver TR beta was expressed under the control of copper. The [125I]T3 binding activities to yeast extracts were significantly correlated with the added copper sulfate into the medium. Partially purified TR from the transformed yeast had a high hormone binding affinity (Kd = 0.34) for T3 and could bind thyroid hormone response element in gel retardation analysis. Copper-zinc superoxide dismutase (cu,zn-SOD)
The intracellular localization of Cu/Zn- and Mn-superoxide dismutase (SOD), which catalyze the dismutation of superoxide radicals (O2-) to O2 and H2O2, was studied in the thyroid tissue of various thyroid disorders by an immunohistochemical technique. The concentrations of both SODs in those tissues were measured also by a sandwich enzyme immunoassay technique. Copper/zinc-SOD in thyroid tissues were identified by immunocytochemical staining in most cases of papillary carcinoma and in some cases of other thyroid disorders. In normal follicular cells this enzyme is localized in the perinuclear cytoplasm, whereas in thyroid tumor or hyperplastic follicular cells it exists homogeneously in cytoplasm. Manganese-SOD stained strongly in papillary carcinoma and papillary-growing cells in the thyroid tissue of adenoma and Graves' disease. The concentrations of Cu/Zn-and Mn-SOD in thyroid tumor tissues and hyperplastic follicular disorders were significantly higher than those in normal thyroid tissue when they were compared as a function of protein or deoxyribonucleic acid contents. The ratio of Mn-SOD to Cu/Zn-SOD was significantly higher only in papillary carcinoma, except for other thyroid disorders as compared with that in the normal thyroid. In conclusion, SOD seems to be related to cell proliferation and differentiation in the thyroid follicular cell because Cu/Zn-SOD changes its localization in tumor and hyperplastic follicular cells and because the Mn-SOD concentration is increased in papillary carcinoma or papillary-growing cells. Diamine oxidase (and monamine oxidase) are copper containing enzymes which deaminate (break down) chemicals in the body.
The catabolism of 14C-putrescine (1,4-tetramethylene-diamine) to labeled CO2 in small laboratory animals has been studied extensively in order to establish the influence of nutritional, endocrine and other factors on this process. Special attention has been paid to treatments that are known to affect the activity of diamine oxidase (DAO, histaminase, EC, 1.4.3.6), a copper-containing enzyme characteristically inhibited by semicarbazide. Thus, copper-deficient rats metabolize putrescine more slowly than their controls. Antimalarial drugs that inhibit histamine N-methyltransferase also inhibit putrescine catabolism in vivo and DAO activity in vitro. Adrenalectomized rats metabolize the diamine at a reduced rate, a result consistent with the previously demonstrated decrease of DAO in the tissues of several species of animal. There is no effect on the rate of catabolism of putrescine when thyroid state is altered. Heparin (up to 15,000 U/kg), which releases DAO from the small (0.1 mg/kg), intestine, and aminoguanidine (0.1 mg/kg), which inhibits the enzyme powerfully, both cause decreased rates of catabolism of the diamine in rats. The putrescine-catabolizing ability returns with a half-time of recovery of 15-18 h, corresponding to the estimates of SHAFF and BEAVEN [36] for recovery of intestinal DAO activity following administration of heparin or cycloheximide. Together with out other results this suggests that what is being measured by putrescine catabolism depends to a significant extent on the activity of DAO in vitro. Copper catalyzes LDL oxidation.
Oxidation of low density lipoproteins (LDL) results in increased macrophage uptake of LDL which may contribute to the formation of macrophage-derived foam cells in the early atherosclerotic lesion. In this study we show that thyroxine (T4), its optical antipodes, certain desiodo analogs and probucol inhibited cupric sulfate-catalyzed oxidation of human LDL in a concentration-dependent manner as assessed by measuring the electrophoretic mobility, thiobarbituric acid reactive substances (TBARS) and LDL degradation in mouse macrophages. In Cu(2+)-catalyzed LDL oxidation at 24 hr, the TBARS level was 80 nmol/mg LDL protein/24-hr incubation. The concentrations (microM) of each agent producing 50% inhibition in the formation of oxidized LDL (IC50) for TBARS, electrophoretic mobility and macrophage degradation, respectively, were 1.13, 1.27 and 1.30 for reversed triiodothyronine; 1.33, 1.80 and 1.27 for triiodothyronine; 1.33, 1.37 and 1.37 for racemic thyroxine, DL-T4; 1.10, 1.40 and 1.50 for L-T4; 1.13, 1.33 and 1.23 for D-T4; and 1.47, 1.63 and 1.37 for probucol. No differences in inhibitory potency were observed when rT3, T3, the optical antipodes of T4 and the hydrophobic antioxidant drug probucol were compared. In air-induced LDL oxidation, TBARS was 16.1 nmol/mg LDL protein/6-hr incubation. The IC50 concentrations (microM) for TBARS and diene conjugation, respectively, were 0.187 and 0.336 for D-T4; 0.205 and 0.243 for L-T4 and 1.30 and 3.02 for probucol. With air-induced LDL oxidation conditions, the L-T4 concentrations included the physiological range, and thyroid-binding globulin did not modify the inhibitory effect of the endogenous enantiomer, L-T4. Putative uptake of this stereoisomer into LDL inhibited oxidation of these lipoproteins. Since concentrations of these thyronines which blocked air-induced LDL oxidation were in the physiological range, we conclude that thyronines, like the pharmacological agent probucol, limit the oxidative modification of LDL and thus may serve as natural inhibitors of atherogenesis. Copper protects against osteoporosis.
Trace Elements are essential for normal growth and development of skeletons in humans and animals. Although they are minor building components in teeth and bone, they play important functional roles in bone metabolism and bone turnover. Fluoride accumulates in new bone formation sites and results in a net gain in bone mass. Aluminum induces impairment of bone formation by the inhibition of osteoblastic function. Magnesium enhances bone turnover by through the stimulation of osteoclastic function. Zinc regulates secretion of calcitonin from thyroid grand and influences on bone turnover. Gallium suppresses bone turnover in humoral hypercalcemia of malignancy in a similar mechanism as aluminum and cadmium. Copper induces low bone turnover by both suppressions of osteoblastic and osteoclastic functions. Iodine as the hormonal forms of thyroxine and triiodothyronine enhances bone turnover. Among the trace elements in bone and hair, significant differences were found in the contents of zinc, copper and manganese between normal subjects and osteoporotic patients. However, exact involvements of the trace elements in osteoporosis have not yet been clarified. Copper requirement is higher with dietary fructose than with dietary starch. Copper deficiency reduces immune system function. Immune system dysfunction created by excess dietary copper is restored by dietary zinc. Vitamin A increases serum copper levels.
The effect of hypervitaminosis A on the content of sodium, potassium, magnesium, iron, zinc and copper in rat serum was studied. Results were compared to findings in non-treated animals. The serum content of potassium, magnesium and copper increased significantly, while the content of sodium, zinc and iron decreased significantly in the treated animals, when compared to the values obtained with untreated animals. Possible mechanisms for these changes are discussed, and we conclude that high doses of vitamin A cause a marked change in the serum content on the measured cations.
The deposition of copper on Descemet's membrane and the anterior and posterior lens capsule with extreme hypercupremia and IgG hypergammaglobulinemia has been previously described with multiple myeloma and pulmonary carcinoma. A 66-year-old man presenting with blurred vision was found to have bilateral golden-brown metallic dust-like deposits on the central region of Descemet's membrane and the anterior and posterior lens capsule. Laboratory investigations revealed an elevated serum copper level 10 times the normal level associated with a monoclonal gammopathy and a normal ceruloplasmin
The effects of severe, moderate, and mild copper deficiencies on cellular and humoral immunity were studied. Fifty male Sprague-Dawley rats, 5 wk of age, were fed diets containing 0.5, 2.0, 3.5, or 5.0 micrograms Cu/g for either 4 or 8 wk. Ten of the rats were fed the control diet, but were pair-fed with the 0.5-micrograms/g treatment group. All rats were immunized once with sheep red blood cells. Mean plasma-copper concentration reflected the dietary levels of copper, and ceruloplasmin activity correlated highly to plasma copper. Rats consuming suboptimal levels of copper responded differently to the deficiencies, so copper status varied among those animals. After 8 wk, cell proliferation, when stimulated by phytohemagglutinin, was dependent on the copper status of the animal. Severely deficient rats had consistently lower lymphocyte stimulation indexes for phytohemagglutinin and concanavalin A, but specific antibody response was not reduced. Immunoglobulin G (IgG) concentrations were variable for all rats, and immunoglobulin M (IgM) concentrations were lower for the severely deficient rats.
The hinge region of a recombinant-DNA-produced human IgG1 (Campath 1H) is specifically cleavable at a single copper-sensitive peptide bond, yielding a distinct fragment resolved by size-exclusion high-performance liquid chromatography. This novel metal ion-catalysed cleavage at slightly alkaline pH is inhibited by EDTA and its rate is reduced at slightly acidic conditions (pH 5-6) and accelerated by increasing concentrations of cupric ion and higher temperature. Complete cleavage was observed after incubation at pH 8 for 24 h with 1 mM CuCl2. Sequence analysis determined the cleavage site to be the Lys226-Thr227 bond in the hinge-region sequence DKTHT. Cleavage of other IgGs was observed to varying degrees, and specific cleavage of synthetic peptides containing this pentapeptide sequence was also observed.
Dietary copper (Cu) was restricted in Swiss albino mice during five discrete intervals over a 9-wk period of perinatal development: gestation only (G), lactation only (L), 3 wk postlactation (PL), 1 wk after birth through postlactation (2/3L + PL), and lactation plus postlactation (L + PL). Biochemical and immunological status of mice in copper-deficient (-Cu) treatment groups in models G and L did not differ from that of copper-adequate (+Cu) controls. Signs of severe copper deficiency, such as low liver copper levels, and significant reductions in activity of plasma ceruloplasmin and splenocyte Cu-Zn superoxide dismutase were most evident in 6-wk-old mice from two groups, -Cu 2/3L + PL and -Cu L + PL. Mice in these groups were anemic and had small thymuses and enlarged spleens compared to controls receiving +Cu treatment. The -Cu mice demonstrated impaired antibody (plaque-forming cells, PFC) response to sheep erythrocytes, and the attenuation was proportional to copper deficiency, as judged by liver copper levels. Total plasma IgM levels were not greatly altered by -Cu treatment except in model L + PL. Total IgG levels were markedly reduced in this group and in the -Cu 2/3L + PL group. The PFC response of mice in the -Cu PL group was normal even though signs of copper deficiency were evident; however, the PFC response was reduced when -Cu treatment was extended to 5 wk and was reversible by switching to +Cu treatment. Splenocyte reactivity to B- and T-cell mitogens was not greatly different between groups. Incorporation of thymidine into DNA in the absence of mitogen was higher in -Cu mice. It is evident that severity of copper deficiency is related to degree of impaired immunity. Furthermore, severity of copper deficiency is dependent on duration and time of initiation of dietary copper restriction.
Title The effects of copper deficiency with or without high dietary iron or molybdenum on immune function of cattle.
Two experiments were conducted to determine the effects of Cu deficiency with or without high dietary Mo or Fe on the specific immunity of calves. In Exp. 1, calves from 38 bred heifers, fed corn silage-based experimental diets from the last third of gestation until the calves were weaned, were used. Dietary treatments were control (no supplemental Fe, Mo, or Cu), 600 mg of supplemental Fe/kg of DM, 5 mg of supplemental Mo/kg of DM, and 10 mg of supplemental Cu/kg of DM. In Exp. 2, 18 Holstein bull calves were fed commercial milk replacer low in Cu for 49 d and then fed semipurified diets containing approximately 1.1 mg of Cu/kg of DM or diets supplemented with 5 mg of Mo or 10 mg of Cu per kilogram of DM for 126 d. Feeding diets not supplemented with Cu resulted in severe Cu deficiency in both experiments. During Exp. 1, control calves had higher (P < .10) secondary antibody response to pig erythrocytes than Cu-, Mo-, and Fe-supplemented calves. During Exp. 2, in vitro Cu supplementation decreased (P < .01) lymphocyte blastogenic response. In vivo cell-mediated response to phytohemagglutinin was decreased (P < .10) by Cu supplementation during Exp. 1 but was increased (P < .10) by Cu and Mo supplementation during Exp. 2. Copper deficiency and Cu deficiency coupled with high dietary Mo or Fe produced inconsistent immune function responses, indicating that Cu deficiency may not affect specific immune function of calves. Title: Specific cleavage of histidine-containing peptides by copper(II), including tyrosine and IgG.
Copper(II) cleaves with moderate specificity peptides containing Ser-His or Thr-His sequences, at the N-terminal side of the hydroxyaminoacyl residue. The reaction is slow, and is first-order in peptide: CuII complex, with a half-life of several hours at 62 degrees C in sodium bicarbonate buffer, pH 8. Cleavage of other histidine-containing peptides also occurs, at a rate around 10-100-fold less. EDTA completely quenches the cleavage. The reaction is stoichiometric in CuII and is inhibited by amine-containing buffer components; Tris at 19 mM inhibits cleavage by 50%. The reaction has a complex pH-dependence, being very slow below pH 5, and with rates increasing with pH from pH 7 to pH 9.5. Slower degradative side reactions do occur, with destruction of tyrosine residues, particularly in the presence of high concentrations of chloride ion, but the specific cleavage appears to be a hydrolysis, as determined by amino-acid analysis and mass spectrometry of the products. The cleavage is clearly different from the previously described oxidative degradation of proteins catalysed by copper ions. Cleavage of denatured IgG protein occurs with sufficient specificity to reveal distinct bands on SDS-polyacrylamide gel electrophoresis under reducing conditions. Copper deficiency contributes to osteoporosis.
Ascorbic acid has been found to interact with several elements in such a manner as to render them less available for animals. This property of the vitamin has a negative effect on the animals fed a copper-deficient diet, but a positive effect on those fed toxic levels of copper, selenium, vanadium, and cobalt. The effect of ascorbic acid in alleviating cadmium toxicity has been attributed to the effect of the vitamin on iron metabolism, since ferrous iron will also alleviate cadmium toxicity in the Japanese quail. The results of studies reported here indicate that iron will alleviate lead toxicity but ascorbic acid is ineffective. Ascorbic acid will alleviate mercury toxicity, but iron exacerbates this condition. For these two elements, the effects of iron and ascorbic acid are independent of each other.
Liver and lung activities of the antioxidant enzymes glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were determined in control and copper-deficient rats. Decreased activity of SOD was found in liver and decreased activity of the selenoenzyme GSH-Px was found in liver and lung in the copper-deficient animals. The decreased liver activity of GSH-Px could be partially corrected by daily supplementation of the basal diet with sodium selenite. Urinary, fecal and biliary excretion of 75SeO3(2-) were determined in controls and copper-deficient rats in order to assess selenium losses. Urinary excretion of 75Se was not different in the two groups. Fecal loss of 75Se was increased in the copper-deficient animals when compared to controls and biliary excretion was decreased. Tissue retention of 75Se was also determined in both groups. Retention of 75Se in the copper-deficient rats was increased in brain and lung and decreased in liver. This pattern of tissue retention of 75Se is similar to that which occurs in selenium-deficient rats. Copper deficiency in rats results in decreased liver activity of both the copper-containing enzyme SOD and the selenoenzyme GSH-Px. The mechanism of decreased GSH-Px activity is unknown.
Copper deficiency was induced in weanling rats fed diets whose sole source of carbohydrates was starch or fructose for 7 weeks. Conventional parameters of copper status, plasma copper concentrations, ceruloplasmin activity, and erythrocyte superoxide dismutase (SOD) activity were longitudinally monitored weekly to follow the development of the deficiency and to correlate these indices with the degree of severity of the deficiency. Although 30% of the rats fed a copper-deficient fructose diet died and no deaths occurred in rats fed the copper-deficient starch diet, plasma copper, ceruloplasmin, and SOD activities were reduced to a similar extent in all rats fed copper-deficient diets regardless of the type of dietary carbohydrate. Thus, none of the indices used accurately reflected the greater degree of deficiency or mortality in rats fed the fructose diet deficient in copper. The results of the present study underscore the need for more sensitive tests or alternative parameters to assess copper status in living animals.
Rat embryos (gestation days 9.0 and 10.0) obtained from dams that were fed a Cu-adequate (8 micrograms Cu/g) or Cu-deficient (< 0.5 micrograms Cu/g diet were cultured for 48 hr in Cu-adequate (16.2 microM) or Cu-deficient (1.0 microM) rat serum. Control embryos cultured in control serum were morphologically normal. Embryos from Cu-deficient dams developed abnormally when cultured in Cu-deficient serum; the abnormalities included distended hindbrains, blisters, blood pooling, and cardiac defects. Control embryos cultured in Cu-deficient serum and Cu-deficient embryos cultured in control serum also showed abnormal development, but to a lesser degree than that of the Cu-deficient embryos cultured in Cu-deficient serum. To test the idea that the above abnormalities were due in part to free radical induced damage occurring secondary to an impaired oxidant defense system, a chemiluminescence assay was used to detect superoxide dismutase (SOD) activity in the cultured embryos. SOD activity was lowest in embryos cultured in Cu-deficient serum. When the Cu-deficient serum was supplemented with antioxidants (CuZnSOD or glutathione peroxidase), its teratogenicity was reduced. These data support the idea that an impaired oxidant defense system contributes to the dysmorphology associated with Cu deficiency. However, the Cu-deficient embryos also had low cytochrome c oxidase activity compared to control embryos--thus, multiple factors are likely contributing to Cu deficiency-induced abnormalities.
Copper may be involved in migraine headaches.
Some foods in our diet can spark off migraine attacks in susceptible individuals. Some foods can bring an attack on through an allergic reaction. A certain number such as citrus fruits, tea, coffee, pork, chocolate, milk, nuts, vegetables and cola drinks have been cited as possible allergens associated with migraine. This mechanism has however been criticized: an improvement in symptoms by eliminating some food(s) from our diet does not necessarily mean an immunologically based allergic reaction. The high IgE incidence rate is not greater in such patients than in the population at large. Other allergic reactions unrelated to diet may also be associated with migraine attacks. On the other hand substances in food may be the cause of modifications in vascular tone and bring migraine on in those so prone. Among such substances are tyramine, phenylalanine, phenolic flavonoids, alcohol, food additives (sodium nitrate, monosodium glutamate, aspartame) and caffeine. Another recognized trigger for migraine is hypoglycemia. Such foods as chocolate, cheese, citrus fruits, bananas, nuts, 'cured' meats, dairy products, cereals, beans, hot dogs, pizza, food additives (sodium nitrate, monosodium glutamate in Chinese restaurant food, aspartame as a sweetener), coffee, tea, cola drinks, alcoholic drinks such as red wine, beer or whisky distilled in copper stills, all may bring on a migraine attack. For every patient we have to assess which foodstuffs are involved in the attack (not necessarily produced by consuming the product concerned) in order to try to avoid their consumptions as a means of prophylaxis for migraine.
OBJECTIVE: To test the hypothesis that copper deficiency in rats may be hyperlipidemic only when the diets consumed contain nutrients which contribute to blood lipids such as fructose and high fat. METHODS: Weanling male Sprague Dawley rats were fed diets which contained either starch or fructose as their sole carbohydrate source. The diets were either inadequate (0.6 microg Cu/g) or adequate (6.0 microg Cu/g) in copper and contained either high (300 g/kg) or low (60 g/kg) fat. At the end of the 4th week the rats were killed. Livers were analyzed for copper content. Plasma was analyzed for cholesterol and triglyceride concentrations. RESULTS: High-fat diet did not increase blood lipids in rats fed a copper-deficient diet containing starch. In contrast, the combination of high-fat diet with fructose increased blood triglycerides and fructose with copper deficiency resulted in a significant increases in blood cholesterol. CONCLUSIONS: Hyperlipidemia of copper deficiency in rats is dependent on synergistic effects between dietary fructose and copper deficiency and fructose and amount of dietary fat. Hyperlipidemia does not develop if starch is the main source of dietary carbohydrate in a copper-deficient diet even if a high-fat diet is fed.
Title
Copper deficiency has been reported to be associated with decreased cytochrome c oxidase activity, which in turn may be responsible for the observed mitochondrial impairment and cardiac failure. We isolated mitochondria from hearts of copper-deficient rats: cytochrome c oxidase activity was found to be lower than in copper-adequate mitochondria. The residual activity paralleled copper content of mitochondria and also corresponded with the heme amount associated with cytochrome aa3. In fact, lower absorption in the alpha-band region of cytochrome aa3 was found for copper-deficient rat heart mitochondria. Gel electrophoresis of protein extracted from mitochondrial membranes allowed measurements of protein content of the complexes of oxidative phosphorylation, revealing a lower content of complex IV protein in copper-deficient rat heart mitochondria. The alterations caused by copper deficiency appear to be specific for cytochrome c oxidase. Changes were not observed for F0F1ATP synthase activity, for heme contents of cytochrome c and b, and for protein contents of complexes I, III and V. The present study demonstrates that the alteration of cytochrome c oxidase activity observed in copper deficiency is due to a diminished content of assembled protein and that shortness of copper impairs heme insertion into cytochrome c oxidase.
BACKGROUND/AIMS: Copper overload leads to liver injury in humans with Wilson's disease and in Bedlington terriers with copper toxicosis; however, the mechanisms of liver injury are poorly understood. This study was undertaken to determine if oxidant (free radical) damage to hepatic mitochondria is involved in naturally occurring copper toxicosis. METHODS: Fresh liver samples were obtained at the time of liver transplantation from 3 patients with Wilson's disease, 8 with cholestatic liver disease, and 5 with noncholestatic liver disease and from 8 control livers. Fresh liver was also obtained by open liver biopsy from 4 copper-overloaded and 4 normal Bedlington terriers and from 8 control dogs. Hepatic mitochondria and microsomes (humans only) were isolated, and lipid peroxidation was measured by lipid-conjugated dienes and thiobarbituric acid-reacting substances. In humans, liver alpha-tocopherol content was measured. RESULTS: Lipid peroxidation and copper content were significantly increased (P < 0.05) in mitochondria from patients with Wilson's disease and copper-overloaded Bedlington terriers. More modest increases in lipid peroxidation were present in microsomes from patients with Wilson's disease. Mitochondrial copper concentrations correlated strongly with the severity of mitochondrial lipid peroxidation. Hepatic alpha-tocopherol content was decreased significantly in Wilson's disease liver. CONCLUSIONS: These data suggest that the hepatic mitochondrion is an important target in hepatic copper toxicity and that oxidant damage to the liver may be involved in the pathogenesis of copper-induced injury.
Wilson's disease results in excess tissue accumulation of copper and is often complicated by skeletal and mineral abnormalities. We investigated vitamin D metabolism in rats fed a copper-laden diet rendering hepatic copper content comparable with that found in Wilson's disease. Injection of 25-hydroxyvitamin D3 [25(OH)D3] resulted in reduced 1,25-dihydroxyvitamin D [1,25(OH)2D] levels in copper-intoxicated rats. In vitro 25(OH)D-1 alpha-hydroxylase activity was impaired in renal mitochondria from copper-intoxicated animals. Activity was also inhibited in mitochondria from controls when copper was added to incubation media. Impaired conversion of 25(OH)D to 1,25(OH)2D occurs in copper intoxication and suggests that altered vitamin D metabolism is a potential factor in the development of bone and mineral abnormalities in Wilson's disease.
Antioxidant enzymes, Cu/Zn- and Mn-superoxide dismutase, catalase, and glutathione peroxidase, constitute an important defense mechanism against cytotoxicity of reactive oxygen species. Copper is essential for the activity of Cu/Zn-superoxide dismutase. Oxidative stress, therefore, is expected in organs of rats fed copper-deficient diet due to reduced Cu/Zn-superoxide dismutase activity. Our previous studies have shown that the expression of antioxidant enzymes was altered in copper-deficient rat liver. The present report was undertaken to study further the transcription of these enzymes in liver nuclei of rats made copper-deficient for 4 weeks. While copper deficiency decreased the copper in liver by about 80%, it did not alter the copper content in liver nuclei. In spite of a 100% elevation in nuclear iron concentration, liver nuclei from copper-deficient rats showed normal appearance. The transcriptional rates for Cu/Zn-superoxide dismutase, glutathione peroxidase, and glyceraldehyde-3-phosphate dehydrogenase were not altered by dietary copper deprivation. In contrast, transcriptional rates for Mn-superoxide dismutase and beta-actin were increased but that for catalase was reduced in the nuclei isolated from the copper-deficient rat liver. These results suggest that oxidative stress, resulting from copper deficiency, differentially modulates the gene transcription for the antioxidant enzymes in rat liver.
Male and female rats were used to investigate the effects of type of dietary carbohydrate (CHO), copper, and ethanol consumption on lung antioxidant enzyme activities and levels of phosphorylated compounds in whole blood. Copper-deficient female rats exhibited a greater degree of copper deficiency than males, as assessed by hepatic copper concentration and hepatic copper superoxide dismutase (CuSOD) activity. However, copper-deficient male rats fed fructose-containing diets exhibited greater growth retardation, anemia, and heart hypertrophy than females consuming the same diets and males fed starch. In addition, one of 10 copper-deficient male rats that ate a fructose-based diet and drank water and one of 10 copper-deficient male rats that ate a starch-based diet and drank ethanol died. Copper-deficient, starch-fed males exhibited the highest activities of glutathione peroxidase (GSH-Px) and catalase as compared with fructose-fed rats. Ethanol consumption elevated the activities of GSH-Px and catalase. Copper-deficient female rats exhibited higher catalase but lower GSH-Px activities than males. It is suggested that in copper deficiency, the ability to increase antioxidant enzyme activities in rats consuming starch is greater than in rats consuming fructose. Rats fed starch are provided with a greater degree of protection against oxidative damage than rats fed fructose. In addition, polyphosphorylated compounds in blood were reduced in copper-deficient male rats that consumed fructose-based diets. This may impair supply of oxygen to tissues.
Copper deficiency causes more salient pathologic changes in the heart than in the liver of rats. Although oxidative stress has been implicated in copper deficiency-induced pathogenesis, little is known about the selective toxicity to the heart. Therefore, we examined the relationship between the severity of copper deficiency-induced oxidative damage and the capacity of antioxidant defense in heart and liver to investigate a possible mechanism for the selective cardiotoxicity. Weanling rats were fed a purified diet deficient in copper (0.4 microgram/g diet) or one containing adequate copper (6.0 microgram/g diet) for 4 weeks. Copper deficiency induced a 2-fold increase in lipid peroxidation in the heart (thiobarbituric assay) but did not alter peroxidation in the liver. The antioxidant enzymatic activities of superoxide dismutase, catalase, and glutathione peroxidase were, respectively, 3-, 50- and 1.5-fold lower in the heart than in the liver, although these enzymatic activities were depressed in both organs by copper deficiency. In addition, the activity of glutathione reductase was 4 times lower in the heart than in the liver. The data suggest that a weak antioxidant defense system in the heart is responsible for the relatively high degree of oxidative damage in copper-deficient hearts.
The livers of 13 Sika deer (Cervus nippon Temminck) aged 4 to 9 years and suffering from copper deficiency (enzootic ataxia) were examined histologically, histochemically and by electron microscopy. In addition, the serum and liver copper concentrations, measured in three animals, were found to be low. Histologically, the hepatocytes exhibited cloudy swelling, and numerous haemosiderin deposits were seen in the hepatocytes and Kupffer cells. Staining with p-dimethyl amino-benzylidene-rhodamine revealed distinctly fewer copper granules than normal. Histochemically, 3,3'-diaminobenzidine-H2O2 staining revealed increased numbers of catalase-positive granules around nuclei. Electron microscopically, "giant" and bizarre-shaped mitochondria, irregular depression of the mitochondrial membrane, and fusion of cristae were noted. Disorders of copper-containing enzymes, including cytochrome oxidase, caeruloplasmin and monoamine oxidase, may have been responsible for the mitochondrial abnormalities. Copper deficiency can cause a magnesium deficiency. Title
Copper is a trace element known to be critical for normal brain function, and abnormal copper metabolism has been associated with some disorders involving the auditory system. We examined effects of copper deficiency on metabolism in major structures of the auditory system. Homogenates of cochlea, cochlear nucleus and inferior colliculus of rats, as well as whole brain, were assayed for activities of enzymes of oxidative and glycolytic energy metabolism--malate and lactate dehydrogenase, enzymes of acetylcholine metabolism--choline acetyltransferase and acetylcholinesterase, and concentrations of amino acids. Whole brain was also assayed for activity of superoxide dismutase, a copper-containing enzyme, and concentrations of minerals. For these chemicals and tissues, the only significant differences between copper-deficient and copper-adequate rats were: (1) decreased copper and magnesium and increased potassium concentrations in whole brain of copper-deficient rats and (2) an elevation of glutamine concentration in inferior colliculus and whole brain of copper-deficient rats. The elevated glutamine could not be related to any change in activity of glutamine synthetase or glutaminase, major enzymes of glutamine metabolism. It is speculated that the increase in glutamine might result from a net increase in ammonia accumulation in the brains of copper-deficient rats.
The physiologically important copper complexes of oxidized glutathione have been examined by electron spin resonance (ESR) spectroscopy in aqueous solution at neutral pH. Low temperature measurements show that the Cu(II) binding site in oxidized glutathione has the same ligand arrangement as in copper complexes of S-methylglutathione, glutamine, glutamate and glycine. The site is composed of the amino nitrogens and the carboxyl oxygens of two gamma-glutamyl residues; there is no interaction with amide nitrogens, the sulphur bond or the glycyl carboxyl groups. At high metal to ligand ratios a binuclear species exists, in which each Cu(II) binds only to one gamma-glutamyl residue. The previously reported forbidden transition detected at g = 4 is due to non-specific aggregation and not to spin coupling of intramolecular sites. Liquid solution ESR spectra show the Cu(II)-glutathione complex has a lower mobility than the corresponding Cu(II)-S-methylglutathione species. From the degree of spectral anisotropy the complex with glutathione is calculated to exist as a dimer. These results demonstrate that the physiologically relevant complex between copper and oxidized glutathione in solution is completely different from the known solid state structure determined by crystallography.
Cellular copper metabolism and the mechanism of resistance to copper toxicity were investigated using a wild type hepatoma cell line (HAC) and a copper-resistant cell line (HAC600) that accumulates copper and has a highly elevated level of metallothionein (MT). Of the enzymes involved in reactive oxygen metabolism, only glutathionine peroxidase was elevated (3-4-fold) in resistant cells, suggestive of an increase in the cellular flux of hydrogen peroxide. A majority of the cytoplasmic copper (greater than 60%) was isolated from both cell lines as a GSH complex. Kinetic studies of 67Cu uptake showed that GSH bound 67Cu before the metal was complexed by MT. Depletion of cellular GSH with buthionine sulfoximine inhibited the incorporation of 67Cu into MT by greater than 50%. These results support a model of copper metabolism in which the metal is complexed by GSH soon after entering the cell. The complexed metal is then transferred to MT where it is stored. This study also indicates that resistance to metal toxicity in copper-resistant hepatoma cells is due to increases in both cellular GSH and MT. Furthermore, it is suggested that elevated levels of GSH peroxidase allows cells to more efficiently accommodate an increased cellular hydrogen peroxide flux that may occur as a consequence of elevated levels of cytoplasmic copper.
Dietary copper deficiency has been shown to reduce copper-dependent superoxide dismutase (SOD) activity and to increase lipid peroxidation in rats. Circulating reduced glutathione (GSH) concentrations are elevated in copper-deficient (CuD) rats, which suggests an increased GSH synthesis or decreased degradation, perhaps as an adaptation to the oxidative stress of copper deficiency. GSH synthesis was examined in isolated hepatocytes from CuD rats. Isolated hepatocytes were prepared by collagenase perfusion and incubated in Krebs-Henseleit bicarbonate buffer, pH 7.4, 10 mM glucose, 2.5 mM Ca2+ in the presence and absence of 1.0 mM buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis. Cell viability was assessed by trypan blue exclusion. GSH and oxidized glutathione (GSSG) were measured by the glutathione reductase recycling assay. Copper deficiency depressed hepatocyte Cu by greater than 90% and increased intracellular GSH by 41-117% over the 3-h incubation, with a two- to threefold increase in the rate of intracellular GSH synthesis. Intracellular GSSG values were minimally influenced by CuD, with a constant mol% GSSG. Extracellular total glutathione (GSH + 2GSSG) synthesis was increased by approximately 33%. Both intracellular GSH and extracellular total glutathione synthesis were inhibited by BSO. The pattern of food consumption in CuD rats, meal fed versus ad libitum fed, had no effect on glutathione synthesis. The results indicate an increased hepatic GSH synthesis as a response to dietary copper deficiency and suggest an interrelationship between the essential nutrients involved in oxyradical metabolism.
Dietary copper deficiency causes hypercholesterolemia and increased hepatic 3-hydroxy-3-methyl-glutaryl coenzyme A (MHG-CoA) reductase activity and increased hepatic glutathione (GSH) in rats. We hypothesized that inhibition of GSH production by L-buthionine sulfoximine (BSO), a specific GSH synthesis inhibitor, would abolish the cholesterolemia and increased HMG-CoA reductase activity of copper deficiency. In two experiments, two groups of 20 weanling male rats were fed diets providing 0.4 and 5.8 micrograms Cu/g, copper-deficient (Cu-D) and copper-adequate (Cu-A), respectively. At 35 days plasma cholesterol was significantly elevated by 30 to 43% in Cu-D and 10 animals in each of the Cu-D and Cu-A groups were randomly assigned to receive 10 mM BSO solution in place of drinking water and continued on the same diets for another 2 wk. At necropsy Cu-D animals had a significant 52 to 58% increase in plasma cholesterol. BSO administration abolished the cholesterolemia in Cu-D rats, but had no influence on plasma cholesterol of Cu-A rats. Hepatic GSH was increased 39 to 82% in Cu-D rats and BSO abolished this increase. BSO was without effect on cardiac hypertrophy, plasma and liver copper, and hematocrit indices of copper status. Liver microsome HMG-CoA reductase activity was significantly increased 85 to 288% in Cu-D rats and BSO administration abolished this increase in activity in Cu-D rats. The results suggest that copper deficiency cholesterolemia and elevated HMG-CoA reductase activity are a consequence of elevated hepatic GSH, and provide evidence for GSH regulation of cholesterol metabolism in intact animals.
Selenium (Se) deficiency in rats produced significant increases in the activity of hepatic glutathione S-transferase (GST) with 1-chloro-2,4-dinitrobenzene as substrate and in various GST isoenzymes when determined by radioimmunoassay. These changes is GST activity and concentration were associated with Se deficiency that was severe enough to provoke decreases of over 98% in hepatic Se-containing glutathione peroxidase activity (Se-GSHpx). However, decreases in hepatic Se-GSHpx of 60% induced by copper (Cu) deficiency had no effect on GST activity or concentration. Increased GST activity in Se deficiency has previously been postulated to be a compensatory response to loss of Se-GSHpx, since some GSTs have a non-Se-glutathione peroxidase (non-Se-GSHpx) activity. However, the GST isoenzymes determined in this study, GST Yb1Yb1, GST YcYc and GST YaYa, are known to have up to 30-fold differences in non-Se-GSHpx activity, but they were all significantly increased to a similar extent in the Se-deficient rats.
Effects of metallothionein (MT) synthesis inhibiting compounds (actinomycin D, cycloheximide), MT synthesis stimulating compounds (dexamethasone, dibu-cAMP) and interfering metals (Cd, Zn) on copper accumulation were investigated in rat hepatoma tissue culture cells. Copper-metallothionein (Cu-MT) and MT-associated copper levels were determined to find a possible correlation between cytosolic copper concentrations and MT as a Cu-detoxifying protein. Further, intracellular non-MT associated copper levels and levels of GSH and SOD were determined. Cell viability was tested under all experimental conditions by measuring LDH-release, K+ uptake and total cell protein. Administration of dexamethasone and dibu-cAMP showed no effect on MT levels (compared with controls), and only a marginal effect on 64Cu and total Cu accumulation. Administration of actinomycin D resulted in increased copper accumulation in the particulate fraction, possibly due to inhibition of copper secretion processes and/or protein synthesis. Presence of zinc had no effect on MT levels nor on total Cu and 64Cu levels, in contrast with cadmium which drastically enhanced copper accumulation and MT levels in the cells. Cu/MT ratios varied from 1.0 +/- 0.3 to 3.3 +/- 1.2, which is far below the assumed maximum molar ratio of 8-12 mol Cu per mol MT. SOD levels appeared to be enhanced up to 2- or 3-fold in the presence of Cd2+, relative to control values. The role of GSH as Cu-intermediate in intracellular Cu distribution plus its role in copper defence mechanism(s) was tested by application of BSO, an inhibitor of GSH synthesis. It was found that BSO had no effect on intracellular MT level; it was found however that MT-bound copper levels were markedly decreased. The results presented support a model for copper metabolism in hepatoma tissue culture (HTC) cells, where Cu(I) is complexed by GSH immediately after entering the cell. GSH is capable of transferring copper to MT where it is stored. Depletion of GSH (by administration of Cd2+, actinomycin D, cycloheximide) almost instantaneously results in enhanced cellular toxicity. When also MT is depleted (by actinomycin D) non-MT associated, 'free' cytosolic Cu2+ is elevated, and HTC cells rapidly loose their resistance to copper toxicity, as also reflected in loss of cell viability (LDH, K+ and total cell protein).
Mast cell-released histamine has been implicated in the enhanced acute inflammatory response of copper-deficient rats. The present study examined possible changes in the copper-deficient mast cell which may account for increased macromolecular leakage and edema formation. Mast cell populations were determined in the cremaster muscle of copper-adequate and copper-deficient rats. Total histamine content, unstimulated histamine release and concentration-dependent histamine release with the mast cell secretagogue compound 48/80 were also determined in isolated peritoneal mast cells. A significantly higher number of mast cells were found in the cremaster muscle of the copper-deficient rats (78 +/- 7 cells/5 microns section) than in the copper-adequate controls (51 +/- 4). Total histamine content per cell as well as unstimulated and stimulated release of the inflammatory mediator per cell were not different between the groups. The results suggest that dietary copper deficiency increases the mast cell population but does not alter the mast cell histamine content or sensitivity to degranulation in the rat. This increase in the number of mast cells may be a mechanism by which acute inflammation is enhanced in copper deficiency.
A posterior ataxia or paralysis in goats and sheep is a syndrome known as Shalal within the Sultanate of Oman. An investigation was carried out into the etiology of the syndrome. Samples of blood and tissues were obtained from normal and Shalal-affected goats and sheep. Samples of feed were collected from the affected areas of the Sultanate. Chemical analyses of samples showed that affected animals suffered from severe copper deficiency in spite of sufficient copper contents in feed. However, concentrations of sulphur and iron in the feed were high. It was concluded that the Shalal syndrome in Oman is the condition generally known as swayback or enzootic ataxia caused by conditioned copper deficiency. The deficiency is probably due to copper-sulphur and copper-iron interactions in the rumen, enhanced by feeding of fresh roughage containing rumen degradable proteins.
Molybdenum does not exist naturally in the pure metallic form and of the 5 oxidation states (2-6) the predominant species are Mo(IV) and Mo(VI). Molybdenum rapidly polymerizes to a wide variety of complex polymolybdate compounds in solution. The vast majority of molybdenum is used in metallurgical applications (stainless steel, cast-iron alloys). Ammonium tetrathiomolybdate is an experimental chelating agent for Wilson's disease. For the general population, the diet is the most important source of molybdenum and concentrations in water and air usually are negligible. The average daily dietary intake is about 0.1-0.5 mg m.o. Molybdenum is an essential element with relatively low toxicity. Enzymes containing molybdenum catalyze basic metabolic reactions in the carbon, sulfur, and nitrogen cycles. Elimination of molybdenum occurs via the kidney and usually is complete within several weeks. Molybdenosis (teart) is a form of molybdenum toxicity that produces a disease in ruminants similar to copper-deficiency. Little data are available on the human toxicity of molybdenum. A gout-like syndrome and pneumoconiosis have been associated with excessive concentrations of molybdenum, but the inadequate design of the studies prevents an adequate determination of the etiology of these effects.
The liver is the main storage site of vitamin A and copper. Inverse relationships between copper and vitamin A liver concentrations have been suggested. We have investigated the consequences of a copper-deficient diet on liver and blood vitamin A storage in Wistar rats. Animals were fed either a copper-deficient diet for 45 days from weaning, or an identical diet containing adequate amounts of copper. Concentrations of vitamin A were determined by isocratic high performance liquid chromatography using UV detection. We have observed in the liver of the rats fed a copper-deficient diet a significantly higher mean level of retinyl esters (148 +/- 37 micrograms/g of liver) and retinol (3.3 +/- 1.4 micrograms/g of liver) compared to the mean concentration of the retinyl esters (53 +/- 8.5 micrograms/g of liver) (p less than 0.01) and retinol (1.4 +/- 0.5 micrograms/g of liver) (p less than 0.01) in controls. Opposite results were observed in the serum of the group fed a copper-deficient diet as these rats had a significantly lower level of retinol (22 +/- 4 micrograms/100 ml) compared to the mean concentration in the controls (64 +/- 20 micrograms/100 ml) (p less than 0.01). These findings suggest that a copper-deficient diet may cause defective transport of vitamin A from liver to blood. This experimental model may be useful to further investigate unusual liver vitamin A and copper concentrations observed in children during various hepatobiliary diseases.
In Vivo 1989 Jul-Aug;3(4):285-93Rhodium, iridium, copper and gold antitumor organometallic compounds (review).Haiduc I, Silvestru CBabes-Bolyai University, Chemistry Department, Cluj-Napoca, Romania. Recent results on the antitumor activity of organometallic compounds of rhodium, iridium, copper and gold are reviewed. Coordination compounds of some organic ligands are also briefly mentioned. The most promising seem to be copper and gold complexes which exhibited remarkable activity against several tumor system. J Med Invest 1999 Feb;46(1-2):29-33Effects of vitamin E and vitamin C supplementation on plasma lipid peroxidation and on oxidation of apolipoprotein B-containing lipoproteins in experimental hyperthyroidism.Dirican M, Tas SDepartment of Biochemistry, Uludag University Medical School, Turkey. Increasing numbers of experimental and epidemiological studies suggest the involvement of free radicals in the pathogenesis of various disease entities. Similarly, oxidative processes have been implicated as playing roles in the genesis of hyperthyroidism-induced damage. In this study, we investigated the effects of vitamin E and vitamin C on plasma lipid peroxidation and the susceptibility of apolipoprotein B (apo B)-containing lipoproteins to oxidation in experimental hyperthyroidism. The study animals were initially divided into a control group (Group C) and a hyperthyroid group. The latter was further re-grouped later according to their vitamin supplementation status: Hyperthyroid group without vitamin supplementation (Group H), hyperthyroid group with vitamin E supplementation (Group H+E) and hyperthyroid group with vitamin C supplementation (Group H+C). Malondialdehyde (MDA) level was measured as an indicator of plasma lipid peroxidation. The apo B-containing lipoproteins were separated by precipitation and incubated with copper sulphate. The MDA levels of this non-HDL fraction were measured prior to and after 1, 2 and 3 hours of incubation. Plasma MDA levels showed no significant differences among groups. Whereas MDA levels measured in non-HDL fraction were significantly higher in Group H than Group C. Group H+E and Group H+C had significantly lower MDA levels than Group H in all these measurements. This finding strongly indicates an increased susceptibility of apo B-containing lipoproteins to oxidation in hyperthyroidism, and that vitamin E as well as vitamin C supplementation protect these lipoproteins from copper-induced oxidation. PMID: 10408154, UI: 99336497 Agents Actions 1981 Apr;11(1-2):20-7Putrescine metabolism and the study of diamine oxidase activity in vivo.Sourkes TL, Missala KThe catabolism of 14C-putrescine (1,4-tetramethylene-diamine) to labeled CO2 in small laboratory animals has been studied extensively in order to establish the influence of nutritional, endocrine and other factors on this process. Special attention has been paid to treatments that are known to affect the activity of diamine oxidase (DAO, histaminase, EC, 1.4.3.6), a copper-containing enzyme characteristically inhibited by semicarbazide. Thus, copper-deficient rats metabolize putrescine more slowly than their controls. Antimalarial drugs that inhibit histamine N-methyltransferase also inhibit putrescine catabolism in vivo and DAO activity in vitro. Adrenalectomized rats metabolize the diamine at a reduced rate, a result consistent with the previously demonstrated decrease of DAO in the tissues of several species of animal. There is no effect on the rate of catabolism of putrescine when thyroid state is altered. Heparin (up to 15,000 U/kg), which releases DAO from the small (0.1 mg/kg), intestine, and aminoguanidine (0.1 mg/kg), which inhibits the enzyme powerfully, both cause decreased rates of catabolism of the diamine in rats. The putrescine-catabolizing ability returns with a half-time of recovery of 15-18 h, corresponding to the estimates of SHAFF and BEAVEN [36] for recovery of intestinal DAO activity following administration of heparin or cycloheximide. Together with out other results this suggests that what is being measured by putrescine catabolism depends to a significant extent on the activity of DAO in vitro. Nahrung 1988;32(8):755-65The physiological role of copper and the problems of copper nutritional deficiency.Wachnik ANational Institute of Food-Hygiene and Nutrition, Budapest, Hungary. The paper deals with recent achievements concerning the physiological role of copper in the human organism. The problem of copper supplementation of the human diet is discussed. An outlook is given on the contemporary theories referring to the role of copper in nutrition. Special attention has been paid to the copper-containing enzymes and copper-dependent enzymes as well as to the problem of nutritional copper deficiencies. This paper shows the necessity of copper for: --"cleaning" of the organism from the excesses of free radicals, biogenic amines and cholesterol --the proper synthesis of hemoglobin, elastin, collagen and probably thyroid hormones --providing the energy formed in the respiratory chain and needed for biochemical syntheses and proper physical activity. J Biol Inorg Chem 1999 Apr;4(2):145-53Copper chaperones: function, structure and copper-binding properties.Harrison MD, Jones CE, Dameron CTNational Research Centre for Environmental Toxicology, University of Queensland, Australia. Copper is an absolute requirement for living systems and the intracellular trafficking of this metal to copper-dependent proteins is fundamental to normal cellular metabolism. The copper chaperones perform the dual functions of trafficking and the prevention of cytoplasmic exposure to copper ions in transit. Only a small number of copper chaperones have been identified at this time but their conservation across plant, bacterial and animal species suggests that the majority of living systems utilise these proteins for copper routing. The available data suggest that each copper-dependent protein in the cell is served by a specific copper chaperone. Although copper chaperones cannot be substituted for one another in a given cell type, copper chaperones that deliver to the same protein in different cell types appear to be functionally equivalent. The majority of the copper chaperones identified thus far have an "open-faced beta-sandwich" global fold with a conserved MXCXXC metal-binding motif. Specificity for a given copper-dependent protein appears to be mediated by the residues surrounding the copper-binding motif. Copper binds to such proteins as Cu(I) in a trigonal complex with three sulfur ligands. Only the copper chaperone specific for cytochrome-c-oxidase, Cox17, deviates from this design. Biofactors 1999;10(1):53-9Copper and signal transduction: platelets as a model to determine the role of copper in stimulus-response coupling.Johnson WTUnited States Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, ND 58202-9034, USA. tjohnson@gfhnrc.ars.usda.gov Platelets from copper-deficient rats have been used as a model to investigate the role of copper in receptor-mediated cellular responses. Copper deficiency doubles the rate of dense granule secretion and increases myosin association with the platelet cytoskeleton following thrombin stimulation. Mechanisms underlying the effects of copper deficiency on thrombin-induced signals that elicit dense granule secretion involve suppression of protein kinase C activity and impairment of Ca2+ release from intracellular stores. Copper deficiency also reduces the cellular GTP content of platelets. This may limit receptor effector coupling through GTP-dependent regulatory proteins leading to protein kinase C activation and the release of Ca2+ from intracellular stores. The reduction in GTP content during copper deficiency results from its utilization to maintain cellular ATP levels in response to severely inhibited cytochrome c oxidase activity in platelet mitochondria. Thus, the role of copper in maintaining normal signal transduction may be indirectly related to its biological function in mitochondria.
Ann Nutr Metab 1986;30(5):335-44
Carl C. Pfeiffer, Ph.D., M.D. UNSUSPECTED COPPER AND/OR ALUMINUM POISONING IN PATIENTS AND THE TREATMENT Many patients have a low blood histamine (histapenia) & high serum copper level. Low histamine patients are typically overstimulated with thoughts racing through their minds making normal ideation difficult. Low histamine children are hyperactive while often healthy in other respects. Serum Cu levels in these patients are abnormally high. The normal level of serum Cu is about 100 mcg%. Since Cu is a brain stimulant and destroys histamine, the elevated serum (and presumably brain Cu) level probably accounts for many symptoms, including the low blood histamine level. The treatment Rx consists of the administration of zinc, manganese, vit. C, niacin, vit. B-12, and folic acid. Folic acid in conjunction with B-12 injections raises blood histamine while lowering the degree of symptomatology. Zn allows for the normal storage of histamine in both the blood cells and the brain. Zn and manganese increase the urinary excretion of copper. Patients with loss of memory frequently have high blood AL levels above 20 ppb. As magnesium, zn and vit C. are given the high blood AL level decreases to normal (less than 10 ppb) and memory improves. Accumulation of AL occurs in various human tissues including blood, brain, liver & bone. Several independent research reports now indicate that a high AL intake may have an adverse effect on memory in the adult (Alzheimer's D.), & may be a factor in learning disabilities & behavioral problems in younger people. Humans do not need AL for any purpose. Individuals with elevated blood AL levels, memory loss & those frequently exposed to AL compounds will find it beneficial to minimize or eliminate all AL sources.
Grand Forks Human Nutrition Research Center Leslie M. Klevay M.D., S.D. in Hyg. Recent Research Accomplishments Clofibrate, a lipid-lowering drug, improves copper nutriture. Clofibrate will
lessen the hypercholesterolemia of copper deficiency. The effect is mediated by
an increase in liver copper. This observation led to the concept of
cholesterotropic and cuprotropic chemicals. Some of these--for example, aspirin,
clofibrate and sodium phytate--lower plasma cholesterol and enhance copper
metabolism. Others--for example, ascorbic acid, cholesterol plus cholic acid and
zinc--raise plasma cholesterol and inhibit copper metabolism. Extra dietary
copper can abolish the hypercholesterolemia caused by feeding cholesterol plus
cholic acid. Since 1924, cholesterol plus cholic acid have been fed to animals
to induce atherosclerosis. This procedure induces copper deficiency in rats.
Cholesterol fed to rabbits without cholic acid lowers liver copper and may
induce copper deficiency. This method has been used since 1913 in the induction
of atherosclerosis.
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