Guest guest Posted December 4, 2008 Report Share Posted December 4, 2008 What Dr. Linus Pauling has to say about copper: from the " Linus Pauling Institute " Zinc: High supplemental zinc intakes of 50 mg/day or more for extended periods of time may result in copper deficiency. High dietary zinc increases the synthesis of an intestinal cell protein called metallothionein, which binds certain metals and prevents their absorption by trapping them in intestinal cells. Metallothionein has a stronger affinity for copper than zinc, so high levels of metallothionein induced by excess zinc cause a decrease in intestinal copper absorption. High copper intakes have not been found to affect zinc nutritional status. COPPER Copper (Cu) is an essential trace element for humans and animals. In the body, copper shifts between the cuprous (Cu1+) and the cupric (Cu2+) forms, though the majority of the body's copper is in the Cu2+ form. The ability of copper to easily accept and donate electrons explains its important role in oxidation-reduction (redox) reactions and the scavenging of free radicals (1). Although Hippocrates is said to have prescribed copper compounds to treat diseases as early as 400 B.C. (2), scientists are still uncovering new information regarding the functions of copper in the human body. FUNCTION Copper is a critical functional component of a number of essential enzymes, known as cuproenzymes. Some of the physiologic functions known to be copper-dependent are discussed below. Energy production The copper-dependent enzyme, cytochrome c oxidase, plays a critical role in cellular energy production. By catalyzing the reduction of molecular oxygen (O2) to water (H2O), cytochrome c oxidase generates an electrical gradient used by the mitochondria to create the vital energy-storing molecule, ATP (3). Connective tissue formation Another cuproenzyme, lysyl oxidase, is required for the cross-linking of collagen and elastin, which are essential for the formation of strong and flexible connective tissue. The action of lysyl oxidase helps maintain the integrity of connective tissue in the heart and blood vessels and plays a role in bone formation (2). Iron metabolism Two copper-containing enzymes, ceruloplasmin (ferroxidase I) and ferroxidase II have the capacity to oxidize ferrous iron (Fe2+) to ferric iron (Fe3+), the form of iron that can be loaded onto the protein transferrin for transport to the site of red blood cell formation. Although the ferroxidase activity of these two cuproenzymes has not yet been proven to be physiologically significant, the fact that iron mobilization from storage sites is impaired in copper deficiency supports their role in iron metabolism (2,4). Central nervous system A number of reactions essential to normal function of the brain and nervous system are catalyzed by cuproenzymes. Neurotransmitter synthesis: Dopamine-b-monooxygenase catalyzes the conversion of dopamine to the neurotransmitter norepinephrine (4). Metabolism of neurotransmitters: Monoamine oxidase (MAO) plays a role in the metabolism of the neurotransmitters norepinephrine, epinephrine, and dopamine. MAO also functions in the degradation of the neurotransmitter serotonin, which is the basis for the use of MAO inhibitors as antidepressants (5). Formation and maintenance of myelin: The myelin sheath is made of phospholipids whose synthesis depends on cytochrome c oxidase activity (2). Melanin formation The cuproenzyme, tyrosinase, is required for the formation of the pigment melanin. Melanin is formed in cells called melanocytes and plays a role in the pigmentation of the hair, skin, and eyes (2). Antioxidant functions Superoxide dismutase: Superoxide dismutase (SOD) functions as an antioxidant by catalyzing the conversion of superoxide radicals (free radicals or ROS) to hydrogen peroxide, which can subsequently be reduced to water by other antioxidant enzymes (6). Two forms of SOD contain copper: 1) copper/zinc SOD is found within most cells of the body, including red blood cells, and 2) extracellular SOD is a copper containing enzyme found in high levels in the lungs and low levels in blood plasma (2). Ceruloplasmin: Ceruloplasmin may function as an antioxidant in two different ways. Free copper and iron ions are powerful catalysts of free radical damage. By binding copper, ceruloplasmin prevents free copper ions from catalyzing oxidative damage. The ferroxidase activity of ceruloplasmin (oxidation of ferrous iron) facilitates iron loading onto its transport protein, transferrin, and may prevent free ferrous ions (Fe2+) from participating in harmful free radical generating reactions (6). Regulation of gene expression Copper-dependent transcription factors regulate transcription of specific genes. Thus, cellular copper levels may affect the synthesis of proteins by enhancing or inhibiting the transcription of specific genes. Genes regulated by copper-dependent transcription factors include genes for copper/zinc superoxide dismutase (Cu/Zn SOD), catalase (another antioxidant enzyme), and proteins related to the cellular storage of copper (3). Nutrient-nutrient interactionsIron: Adequate copper nutritional status appears to be necessary for normal iron metabolism and red blood cell formation. Anemia is a clinical sign of copper deficiency, and iron has been found to accumulate in the livers of copper deficient animals, indicating that copper (probably in the form of ceruloplasmin) is required for iron transport to the bone marrow for red blood cell formation (see Iron Metabolism) (2). Infants fed a high iron formula absorbed less copper than infants fed a low iron formula, suggesting that high iron intakes may interfere with copper absorption in infants (5). Zinc: High supplemental zinc intakes of 50 mg/day or more for extended periods of time may result in copper deficiency. High dietary zinc increases the synthesis of an intestinal cell protein called metallothionein, which binds certain metals and prevents their absorption by trapping them in intestinal cells. Metallothionein has a stronger affinity for copper than zinc, so high levels of metallothionein induced by excess zinc cause a decrease in intestinal copper absorption. High copper intakes have not been found to affect zinc nutritional status (2,5). Fructose: High fructose diets have exacerbated copper deficiency in rats, but not in pigs whose gastrointestinal systems are more like those of humans. Very high levels of dietary fructose (20% of total calories) did not result in copper depletion in humans, suggesting that fructose intake does not result in copper depletion at levels relevant to normal diets (2,5). Vitamin C: Although vitamin C supplements have produced copper deficiency in laboratory animals, the effect of vitamin C supplements on copper nutritional status in humans is less clear. Two small studies in healthy young adult men indicate that the oxidase activity of ceruloplasmin may be impaired by relatively high doses of supplemental vitamin C. In one study, vitamin C supplementation of 1,500 mg/day for 2 months resulted in a significant decline in ceruloplasmin oxidase activity (7). In the other study, supplements of 605 mg of vitamin C/day for 3 weeks resulted in decreased ceruloplasmin oxidase activity, although copper absorption did not decline (8). Neither of these studies found vitamin C supplementation to adversely affect copper nutritional status. DEFICIENCY Clinically evident or frank copper deficiency is relatively uncommon. Serum copper levels and ceruloplasmin levels may fall to 30% of normal in cases of severe copper deficiency. One of the most common clinical signs of copper deficiency is an anemia that is unresponsive to iron therapy but corrected by copper supplementation. The anemia is thought to result from defective iron mobilization due to decreased ceruloplasmin activity. Copper deficiency may also result in abnormally low numbers of white blood cells known as neutrophils (neutropenia), a condition that may be accompanied by increased susceptibility to infection. Osteoporosis and other abnormalities of bone development related to copper deficiency are most common in copper-deficient low-birth weight infants and young children. Less common features of copper deficiency may include loss of pigmentation, neurological symptoms, and impaired growth (2,3). Individuals at risk of deficiency Cow's milk is relatively low in copper, and cases of copper deficiency have been reported in high-risk infants and children fed only cow's milk formula. High-risk individuals include: premature infants, especially those with low-birth weight, infants with prolonged diarrhea, infants and children recovering from malnutrition, individuals with malabsorption syndromes, including celiac disease, sprue, and short bowel syndrome due to surgical removal of a large portion of the intestine. Individuals receiving intravenous total parenteral nutrition or other restricted diets may also require supplementation with copper and other trace elements (2,3). Recent research indicates that cystic fibrosis patients may also be at increased risk of copper insufficiency (9). The Recommended Dietary Allowance (RDA) A variety of indicators were used to establish the recommended dietary allowance (RDA) for copper, including plasma copper concentration, serum ceruloplasmin activity, superoxide dismutase activity in red blood cells, and platelet copper concentration (5). The RDA for copper reflects the results of depletion-repletion studies and is based on the prevention of deficiency. Recommended Dietary Allowance (RDA) for Copper Life Stage Age Males (mcg/day) Females (mcg/day) Infants 0-6 months 200 (AI) 200 (AI) Infants 7-12 months 220 (AI) 220 (AI) Children 1-3 years 340 340 Children 4-8 years 440 440 Children 9-13 years 700 700 Adolescents 14-18 years 890 890 Adults 19 years and older 900 900 Pregnancy all ages - 1,000 Breastfeeding all ages - 1,300 DISEASE PREVENTION Cardiovascular diseases While it is clear that severe copper deficiency results in heart abnormalities and damage (cardiomyopathy) in some animal species, the pathology differs from atherosclerotic cardiovascular diseases prevalent in humans (5). Studies in humans have produced inconsistent results, and their interpretation is hindered by the lack of a reliable marker of copper nutritional status. Outside the body, free copper is known to be a pro-oxidant and is frequently used to produce oxidation of low density lipoprotein (LDL) in the test tube. Recently, the copper-containing protein ceruloplasmin has been found to stimulate LDL oxidation in the test tube (10), leading some scientists to propose that increased copper levels could increase the risk of atherosclerosis by promoting the oxidation of LDL. However, there is little evidence that copper or ceruloplasmin promotes LDL oxidation in the human body. Additionally, the cuproenzymes, superoxide dismutase and ceruloplasmin, are known to have antioxidant properties, leading some experts to propose that copper deficiency rather than excess copper increases the risk of cardiovascular diseases (11). Epidemiological studies: Several epidemiological studies have found increased serum copper levels to be associated with increased risk of cardiovascular disease. A recent prospective study in the U.S. examined serum copper levels in more than 4,400 men and women 30 years of age and older (12). During the following 16 years, 151 participants died from coronary heart disease (CHD). After adjusting for other risk factors of heart disease, those with serum copper levels in the two highest quartiles had a significantly greater risk of dying from CHD. Three other case-control studies conducted in Europe had similar findings. Serum copper largely reflects serum ceruloplasmin, and is not a sensitive indicator of copper nutritional status. Serum ceruloplasmin levels are known to increase by 50% or more under certain conditions of physical stress, such as trauma, inflammation, or disease. Because over 90% of serum copper is carried in ceruloplasmin, elevated serum copper may simply be a marker of the inflammation that accompanies atherosclerosis. In contrast to the serum copper findings, two autopsy studies found copper levels in heart muscle to be lower in patients who died of CHD than those who died of other causes (13). Additionally, the copper content of white blood cells has been positively correlated with the degree of patency of coronary arteries in CHD patients (14, 15), and patients with a history of myocardial infarction (MI) had lower concentrations of extracellular superoxide dismutase (SOD) than those without a history of MI (16). Experimental studies: While studies in very small numbers of adults fed experimental diets low in copper have demonstrated adverse changes in blood cholesterol levels, including increased total and LDL-cholesterol levels and decreased HDL-cholesterol levels (17), other studies have not confirmed those results (18). Copper supplementation of 2-3 mg/day for 4 to 6 weeks did not result in clinically significant changes in cholesterol levels (11, 19). Recent research has also failed to find evidence that increased copper intake increases oxidative stress. In a multi-center placebo-controlled study, copper supplementation of 3 and 6 mg/day for 6 weeks did not result in increased susceptibility of LDL to oxidation induced outside the body (ex vivo) by copper or peroxynitrite (a reactive nitrogen species) (20). Moreover, supplementation with 3 and 6 mg/day of copper decreased the in vitro oxidizability of red blood cells (21), indicating that relatively high intakes of copper do not increase the susceptibility of LDL or red blood cells to oxidation. Summary: Although free copper and ceruloplasmin can promote LDL oxidation in the test tube, there is little evidence that increased dietary copper increases oxidative stress in humans. Increased serum copper levels have been associated with increased cardiovascular disease risk, but the significance of these findings is unclear due to the association between serum ceruloplasmin levels and inflammatory conditions. Clarification of the relationships between copper nutritional status, ceruloplasmin levels, and cardiovascular disease risk requires further research. Immune system function Copper is known to play an important role in the development and maintenance of immune system function, but the exact mechanism of its action is not yet known. Neutropenia (abnormally low numbers of white blood cells called neutrophils) is a clinical sign of copper deficiency in humans. Adverse effects of insufficient copper on immune function appear most pronounced in infants. Infants with Menkes disease, a genetic disorder that results in severe copper deficiency, suffer from frequent and severe infections (22, 23). In a study of 11 malnourished infants with evidence of copper deficiency, the ability of certain white blood cells to engulf pathogens increased significantly after one month of copper supplementation (24). More recently, 11 men on a low-copper diet (0.66 mg copper/day for 24 days and 0.38 mg/day for another 40 days) showed a decreased proliferation response when white blood cells called mononuclear cells isolated from their blood were presented with an immune challenge in cell culture (25). While severe copper deficiency has adverse effects on immune function, the effects of marginal copper insufficiency in humans are not yet clear. Osteoporosis The copper-dependent enzyme, lysyl oxidase, is required for the maturation (cross-linking) of collagen, a key element in the organic matrix of bone. Osteoporosis has been observed in infants and adults with severe copper deficiency, but it is not clear whether marginal copper deficiency contributes to osteoporosis. Research regarding the role of copper nutritional status in age-related osteoporosis is limited. Serum copper levels of 46 elderly patients with hip fractures were reported to be significantly lower than matched controls (26). A small study in perimenopausal women, who consumed an average of 1 mg of dietary copper daily, reported decreased loss of bone mineral density (BMD) from the lumbar spine after copper supplementation of 3 mg/day for 2 years (27). Marginal copper intake of 0.7 mg/day for 6 weeks significantly increased a measurement of bone resorption (breakdown) in healthy adult males (28). However, copper supplementation of 3 to 6 mg/day for 6 weeks had no effect on biochemical markers of bone resorption or bone formation in a study of healthy adult men and women (29). Although severe copper deficiency is known to adversely affect bone health, the effects of marginal copper deficiency and copper supplementation on bone metabolism and age-related osteoporosis require further research before conclusions can be drawn. The RDA for copper (900 mcg/day for adults) is sufficient to prevent deficiency, but the lack of clear indicators of copper nutritional status in humans makes it difficult to determine the level of copper intake most likely to promote optimum health or prevent chronic disease. A varied diet should provide enough copper for most people. For those who are concerned that their diet may not provide adequate copper, a multivitamin/multimineral supplement will generally provide at least the RDA for copper. Quote Link to comment Share on other sites More sharing options...
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