Copper (Cu) - Scientific Paper Abstracts

Am J Clin Nutr 1998 May;67(5 Suppl):1041S-1045S

Copper intake and assessment of copper status.
Milne DB

US Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202-9034, USA.

dmilne@gfhnrc.ars.usda.gov

The diagnosis of marginal copper deficiency has not been perfected despite an increased understanding of the physiologic roles of copper. The use of nonstandardized procedures and the effects of factors other than copper nutriture have impeded identification of an ideal indicator of copper nutritional status in humans. A review of studies of experimental copper deprivation conducted in adult humans over the past 12 y indicated that between 1.0 and 1.25 mg Cu/d is needed by adults for copper maintenance for periods of up to 6 mo. and that < or = 2.6 mg Cu/d for periods of up to 42 d is not sufficient for recovery from copper deprivation. Copper-containing enzymes in blood cells, such as erythrocyte superoxide dismutase and platelet cytochrome-c oxidase, may be better indicators of metabolically active copper and copper stores than plasma concentrations of copper or ceruloplasmin because the enzyme activities are sensitive to changes in copper stores and are not as sensitive to factors not related to copper nutriture.

Adv Exp Med Biol 1989;258:1-20

Food sources of dietary copper.
Kies C

Dept. of Human Nutrition and Food Service Management, University of Nebraska, Lincoln 68583.

Large scale surveys of nutrient intakes of human populations groups generally have not included estimations of dietary copper intakes. Because of a lack of accurate tables of copper contents of foods, until recently, this could not be accomplished. Copper intakes of Americans are thought to be lower than in the past because of a rise in popularity of consumption of highly processed foods but this conclusion may be the result of over-estimation due to less sensitive methods of copper analyses which were used in the past.

Br J Surg 1985 May;72(5):352-353

Is tissue copper deficiency associated with aortic aneurysms?
Senapati A, Carlsson LK, Fletcher CD, Browse NL, Thompson RP

It has been suggested that patients with abdominal aortic aneurysms are deficient in tissue copper. Levels of copper and zinc in liver and aortic wall were therefore measured in 11 patients with aortic aneurysms and 11 fresh cadavers with normal aortas. The concentrations of copper were similar in both groups. Zinc concentration was higher in the normal aortic wall, probably because of the greater thickness of the media in the normal aorta. We found no evidence that aortic aneurysms are associated with reduced tissue copper concentrations.

Arch Surg 1982 Sep;117(9):1212-1213

Decreased hepatic copper levels. A possible chemical marker for the pathogenesis of aortic aneurysms in man.
Tilson MD

The spontaneously aneurysm-prone Blotchy mouse has a mutation on the X chromosome resulting in low hepatic copper levels; and copper is an essential cofactor for lysyl oxidase, which catalyzes reactions leading to the cross-linking of collagen and elastin. Population characteristics and family histories of patients with aneurysms suggest that aneurysmal disease may also be sex linked in man. Hepatic copper levels were determined in 13 patients who died with abdominal aortic aneurysms and in 13 control patients selected on the criterion of severe atherosclerotic occlusive disease of the abdominal aorta. Excluding two patients with severe liver disease, the tissue copper level in the patients with aneurysms was only 26% of the control level. The results suggest that additional studies of the biologic markers for aneurysm formation in the Blotchy mouse should be carried out prospectively in human subjects.

Biol Trace Elem Res 1996 Oct;55(1-2):55-70

Aspects of cardiomyopathy in copper-deficient pigs. Electrocardiography, echocardiography, and ultrastructural findings.
Wildman RE, Medeiros DM, Hamlin RL, Stills H, Jones DA, Bonagura JD

Department of Human Nutrition and Food Management, Ohio State University, Columbus 43210-1295, USA.

Pigs were made copper (Cu)-deficient to evaluate cardiac function and pathology, and electrocardiography. Fifteen-day-old pigs were fed a Cu-restricted diet over an 8 wk period and compared to Cu-adequate diet-fed pigs. Cardiac effects were examined concerning gross morphometry and ultrastructure, echocardiography, and electrocardiography, as well as serum cholesterol levels. The Cu-restricted diet-fed pigs exhibited a marked deceleration of growth and lower hematocrit, hemoglobin, and liver and serum Cu concentrations compared to the Cu-adequate diet-fed pigs. The Cu-restricted diet-fed pigs developed a significantly greater heart weight:body weight ratio, along with greater diastolic measures of ventricular wall and internal dimension relative to body weight. Electrocardiography in the Cu-restricted diet-fed pigs revealed one instance of electrical alternans and an intraventricular conduction disturbance and several instances of T-wave inversion. The Cu-restricted pigs also displayed a prolonged QT interval at the closure of study. Increased mitochondrial volume density and mitochondria:myofibril volume density ratio were observed in the Cu-restricted pig electron micrographs along with excessive lipid and glycogen inclusion and focal degradation of Z-lines, intercalated disk, and sarcomeres. Copper-restriction in young pigs results in cardiac pathology and electrical disturbances. These alterations are similar to those reported for young Cu-restricted rodents. Given then that many cardiac manifestations of developed Cu-deficiency appear conserved across specie lines, the potential for human disturbances in response to severe Cu-deficiency may be plausible.

Biol Trace Elem Res 1994 Oct;46(1-2):51-66

Comparative aspects of cardiac ultrastructure, morphometry, and electrocardiography of hearts from rats fed restricted dietary copper and selenium.
Wildman RE, Medeiros DM, Jenkins J

Department of Human Nutrition and Food Management, Ohio State University, Columbus, Ohio 43210-1295.

Comparative cardiac ultrastructure, morphometry, and electrocardiography after dietary copper and selenium restriction were examined. Male weanling Long-Evans rats were fed diets that were either adequate in both copper and selenium (Cu+/Se+) or restricted in either Cu (Cu-) or Se (Se-) for 8 wk. At wk 8, electrocardiograms (ECG) and dP/dts were obtained and heart tissue was utilized for electron microscopy. Upon examination, Cu- rats were anemic, exhibited a greater heart: body weight ratio, and developed concentric hypertrophy characterized by an enhanced thickening of the left and right ventricular free walls, and interventricular septum. ECG recordings from lead aVF in the Cu- group showed a greater R wave amplitude in comparison to the Cu+/Se+ group. Se- rats recorded a greater left ventricular +dP/dtmax than both the Cu+/Se+ and Cu- groups. Cardiac myofibril volume densities were decreased in both Cu- and Se- rats in comparison to the Cu+/Se+ rats. In addition Cu- rats showed a greater mitochondria:myofibril ratio. Sarcomere contractile protein disarray was present in both the Cu- and Se- groups. Se- myocytes also showed evidence of edema and mitochondrial fragmentation. The subcellular alterations suggest that similarities exist in the cardiac remodeling processes associated with copper and selenium restrictions.

Grand Forks Human Nutrition Research Center

Copper? You Bet Your Heart!
Jack Saari

Copper is essential to life. Plants growing in soil containing too little copper fail to thrive. Animals that graze on plants that have too little copper, or laboratory animals fed diets restricted in copper become ill and may die, usually of damage to the heart and blood vessels. Copper's importance to human health is obvious from the severe health consequences in malnourished infants supported only on cows' milk (which is low in copper); in patients receiving intravenous feeding with copper inadvertently omitted; and in people who have a hereditary inability to absorb and metabolize copper. Fortunately, such severe deficiency is rare among people because we eat a varied diet. But some researchers and health professionals hold that mild copper deficiency is common and may contribute to diseases of aging, such as coronary heart disease. Why do we need copper? At least twenty enzymes contain copper, and at least ten of those depend on copper to function. Because these enzymes occur in most tissues, the biochemical defects of copper deficiency are widespread. They affect functions of the cardiovascular, nervous and immune systems, as well as the lung, thyroid, pancreas and kidney. The cardiovascular system -- heart, blood and blood vessels -- seems to be particularly vulnerable to copper deficiency. In studies in my laboratory and those of other researchers, many aspects of the function of the heart and circulation have been adversely affected by copper deficiency. For instance copper-deficient diets alter the heart's electrical rhythm and this impairs the heart's ability to pump blood. Further, studies with laboratory animals indicate that hearts don't contract as strongly during copper deficiency, further reducing their pumping ability. Also, recent studies indicate that copper deficiency reduces the ability of the heart to use energy, which may contribute to reduced heart function. Blood vessels don't dilate as well in laboratory animals that lack copper. This altered blood vessel control, in addition to interfering with appropriate distribution of blood throughout the body, may contribute to the high blood pressure observed in copper-deficient animals and humans. Other cardiovascular functions are also affected by dietary copper deficiency. Copper-deficient animals and humans have fewer red blood cells (anemia), which reduces the delivery of oxygen to their tissues. Studies with laboratory animals also show that blood clotting is impaired by copper deficiency. This leads not only to increased bleeding following injury, but, once clots form, to reduced ability to dissolve those clots. And finally, copper-deficient blood vessels tend to leak excessive fluid into injured tissues, thus exaggerating swelling. The Food and Nutrition Board of the National Research Council estimates adults need between 1.5 and 3.0 mg of copper daily. But, despite the strong evidence of copper's essentiality, the Board has not established a specific Recommended Dietary Allowance (RDA). That's because it's difficult to assess the harmful effects of low copper intakes in people without risks to their health. One of the challenges of nutrition researchers at the Grand Forks Human Nutrition Research Center is to devise creative ways of assessing people's copper status and the possible serious outcomes of copper deficiency in humans without danger to them. Should the above consequences of copper deficiency alarm you, rest assured that if you eat a balanced diet that includes foods high in copper -- such as liver, legumes, shellfish, meats, nuts, seeds and whole grains -- you will avoid any such consequences and may reap benefits into old age.

NOTE: If you suspect you might not be ingesting enough copper, water-soluble supplements should be used.

Milne DB. Copper intake and assessment of copper status. Am J Clin Nutr 67:1041S-5S, 1998.

Copper is an essential nutrient that is important in maintaining a healthy heart and blood vessels. There is a need to know how much copper people need in order to make informed dietary recommendations. A series of 12 studies of the effects of diets that were low in copper in men and women, showed changes in some people when diets containing 1.0 milligram of copper or less per day were fed. About 20% of the people had an increase in the number of abnormal heartbeats and many showed changes in copper- containing proteins in blood cells when they ate less than one milligram of copper per day. These studies show that copper-containing proteins in blood cells are better for determining copper nutritional status in people than plasma copper. Also, at least 1.0 to 1.25 milligrams of copper are needed by adults to maintain good health. However, more than 2.6 milligrams of copper per day may be needed to recover from the effects of copper deficiency.

Klevay LM. Lack of a recommended dietary allowance for copper may be hazardous to your health. J Amer Coll Nutr 17:322-326, 1998.

There is no Recommended Dietary Allowance (RDA) for copper; rather an Estimated Safe and Adequate Daily Dietary Intake has been assigned because the Subcommittee of the Food and Nutrition Board decided that data on dietary requirements were insufficient for developing an RDA. This essay controverts this opinion. Careful reading of the first 9 editions of the Recommended Dietary Allowance reveals concern for general health as well as the prevention of deficiency diseases. This concern, with the integration of the Food and Nutrition Board into the Institute of Medicine, makes it likely that general health will receive greater emphasis when the 11th edition is written. Depletion experients have defined the copper requirement better than the requirements for magnesium, zinc and selenium, all of which have RDAs. In fact, no similar experiments have been published for these elements. Approximately one third of daily diets in the U.S. contain 1 mg of copper or less. Abnormal electyrocardiograms, hypercholesterolemia and impaired glucose clearance are likely consquences of these diets. High and low copper foods are identified so diets containing less copper than amounts proved insufficient (0.6 to 1 mg/day) in controlled experiments can be avoided. When an RDA for copper is established, copper no longer will be neglected in advice on food selection, dietary planning, dietary surveys, food and diet analysis, nutrition information, and nutritional research. The public does not benefit from the status quo.

NOTE: Whether the recommended amount of copper per day is 1 mg or as high as 3 mg per day, as long as the copper is water-soluble the body will use what it needs and excrete what it does not need.

On the experimental role of copper in cancer
A.M. Badawi, in Metal Ions in Biology and Medicine. Eds. Ph. Collery, LA. Poirier, M. Manfait, J.C. Etienne. John Libbey Eurotext Paris 1990, pp. 49-53.

Department of Application, Petroleum Research Institute, Nasr City, Cairo, Egypt

INTRODUCTION

Copper is recognized as an essential metalloelement and is primary associated with copper-dependent cellular enzymes (Sorenson, 1987). Cytochrome C oxidase is an enzyme required for cellular utilization of oxygen. Cytosolic and extracellular superoxide dismutase (SOD) are required for disproportionation of superoxides. Tyrosine is required for synthesis of dopa from tyrosine. Dopamine-B-hydroxIase is required for synthesis of norepinephrine from dopamine. Lysyl oxidase is required for synthesis of collagen and elastin from procollagen and proelastin. Amine oxidases are required for oxidation of primary amines to aldehydes in chatecholamine and other primary amine metabolism. Ceruloplasmin which represents the bulk of serum copper is required for mobilization and utilization of stored iron (Frieden, 1986).

The essentiality of copper is now understood upon its recognized need for copper-dependent enzymes that may have a role in cancer development and inhibition.

COPPER AND CELL GROWTH

The plasma tripeptide glycyl-L-histidyl-L-lysine (GHL) stimulates the growth of a wide group of cultured systems (Pickard et al., 1980). During the isolation of GHL, it was found the compound to co-isolate with copper. It is suggested that GHL may act as a copper transport factor and when added to culture media has been found to: enhance the growth of hepatoma cells; stimulate the growth of lymphocytes; and raise the viability of kidney cells, macrophages and mast cells.

COPPER AND CELL DIFFERENTIATION

Solid Ehrlich tumors taken from mice treated with Cu (II) (2,5-diisopropyl-salicylate)2, Cu (II) (3,5-DIPS)2 contained differentiated epithelial cells in duct arrangement, suggesting that Cu (11) (3,5-DIPS)2 treated did not kill tumor cells but caused them to differentiate to normal duct cells (Leuthauser, 1979). Cu (II) (3,5-DIPS)2 added to neuroblastoma culture medium caused differentiation of these neoplastic cells to normal neuronal cells in a concentration related manner (Sahu, 1979).

There is now evidence which suggests that SOD is intimately involved in cell division (Oberley et al., 1981).

ALTERED COPPER METABOLISM IN CANCER

Copper metabolism has been studied in a variety of neoplastic diseases. Elevated plasma copper concentration has been reported in adults and children with active Hodgkin's disease (Asbjornsen, 1979) and non-Hodgkin's lymphomas, cervical carcinoma, mammary carcinoma, as well as several other carcinomas (Sorenson, 1982).

ALTERED COPPER METABOLSIM IN CARCINOGENESIS

Rat, with implanted tumor undergo change in serum copper and ceruloplasmin oxidase activity with various forms' of cancer (Linder, 1983). There is a decrease in the percentage of copper in ceruloplasmin and an increase in the percentage of low molecular weight forms of copper in serum.

Copper content increased in mitochondrial and microsomal fractions, but decreased in nuclear, lysosomal, and supernate fractions in tissues of chemically induced tumor bearing strain A mice. The subcellular distribution of ceruloplasmin was lower in cell fractions (Chakravarty et al., 1984).

EFFECT OF COPPER ON CARCINOGENESIS

Although a large number of inhibitors of chemical carcinogenesis have been described, copper complexes represent a novel class of cancer chemoprotective agents (Wattenberg, 1985).

There is ample evidence to suggest reactive oxygen species participate in cell stages of carcinogenesis (Kensler, 1984). Reactive oxygen detoxifiers and scavengers such as copper complexes and SOD inhibit the biochemical and biological action of tumor promoters.

It was reported that a single application of tumor promoter to the dorsal skin of mice led to a rapid and mark diminution of epidermal SOD activity (Solanski, 1981). Repetitive treatment with the phorbol diester TPA, as occurs during tumor promotion, caused a 40 to 50 per cent decrease in total epidermal SOD activity. This reduction in activity was specific to the copper zinc form of SOD.

Application of Cu (II) (3,5-DIPS)2 before each biweekly treatment of TPA to CD-1 mice initiated with 7,12-dimethylbenzanthracene (DMBA) reduced tumor development 87 per cent in terms of tumor multiplicity, after 24 weeks (Egner et al., 1985). Analogs lacking SOD-activity, namely DIPS and ZnDIPS did not inhibit promotion (Kensler et al., 1983; Egner & Kensler, 1985).

EFFECT OF COPPER ON EXPERIMENTAL TUMOR GROWTH

A large variety of different classes of copper complexes were reported to have antitumor activity. Of the recent copper complexes reported to have antitumor activities in rodents are:

Cu (II) glycyl-glycyl-histidinate (Kimoto et al., 1983), Cu (II) 2,9-dimethyl-1,10-phenanthroline (Mohindru, 1983), Cu (II) trans -bis-sal icylaldox imate (Paavo & Elo, 1985), Cu (II), 3,4-dihydroxybenzohydroxamate (Basosi et al., *1987) and Cu (11) bis-acetato-bis-imidazole (Tamura et al., 1987). Mechanistic studies provided a great deal of information for these copper complexes concerning their possible inhibition of DNA synthesis.

A reduction in tumor growth was reported (Oberley et al., 1982) when CF1 mice were injected with a single dose of Cu Zn-SOD one hour after they implanted Sarcoma 180 tumor cells.

It was first reported that copper complexes of anti-inflammatory drugs, including Cu (II) salicylates had SOD-mimetic activity (de Alvare et al., 1976). It was then thought that small molecular weight copper complexes might have anticancer activity. Cu (II) (3,5-DIPS)2 was compared with several other copper complexes and found to be a very effective anticancer agent in CBA/J mice implanted with Ehrilich carcinoma cells (Leuthauser et al., 1981; Pottathil & Lang, 1983).

It is not known how Cu (II) (3,4-DIPS)2 inhibits tumor growth. If tumor cells are sensitive to hydrogen peroxide then addition of Cu (II) (3,5-DIPS)2 could increase hydrogen peroxide generation from superoxide and kill the cell. The protective effect of glutathione and sensitizing effect of BCNU when given with Cu (II) (3,5-DIPS)2 supports this idea. Tumor cells generate superoxide which is detoxified via either removing SOD activity in the cell or by reaction with other intracellular components such as glutathione or sulfhydryl (Leuthauser et al., 1984). A second possibility is that cancer patients have elevated levels of serum aldehydes, possibly generated by lipid peroxidation. Aldehydes inhibited immune cell function by altering membrane fluidity or surface receptors (Loven et al., 1985). Nonimmune cells might also be affected by such products (Henle et al., 1986). Addition of lipophilic compound with SOD-like activity could prevent lipid peroxidation and protect cells from aldehydes, thus allowing the host immune system to respond to the tumor. The third mechanism might involve the facilitation of synthesis of copper-dependent enzymes in biological systems (Willingham & Sorenson, 1986).

CONCLUSION

After consideration of the experimental role of copper in cancer development and inhibition, the future use of copper chelates with SOD-like activity to treat neoplastic diseases without killing transformed cells has some exciting possibilities.