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Micronutrient Research for Optimum Health

 
 
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Micronutrient Information Center

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Copper

Copper (Cu) is an essential trace element for humans and animals. In the body, copper shifts between the cuprous (Cu¹⁺) and 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 in scavenging 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 also 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 at 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 interactions

Iron

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 copper absorption. In contrast, 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 guinea pigs (7), animals requiring dietary vitamin C, 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 two months resulted in a significant decline in ceruloplasmin oxidase activity (8). In the other study, supplements of 605 mg of vitamin C/day for three weeks resulted in decreased ceruloplasmin oxidase activity, although copper absorption did not decline (9). 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, and 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 (10). 

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.

 

Disease Prevention

Cardiovascular disease

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 disease that is 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 (11), 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 (12).

Epidemiological studies

Several epidemiological studies have found increased serum copper levels to be associated with increased risk of cardiovascular disease. A prospective study in the U.S. examined serum copper levels in more than 4,500 men and women 30 years of age and older (13). 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. One small study in 60 patients with chronic heart failure or ischemic heart disease reported that serum copper was a predictor of short-term outcome (14). A recent prospective study in 4,035 middle-aged men reported that high serum copper levels were significantly related to a 50% increase in all-cause mortality; however, serum copper was not significantly associated with cardiovascular mortality in this study (15). It is important to note that 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, which is increased in many inflammatory conditions, elevated serum copper may simply be a marker of inflammation that accompanies atherosclerosis. In fact, serum copper was recently found to be elevated in patients with rheumatic heart disease (16). In contrast to the epidemiological findings linking serum copper to heart disease, two autopsy studies found copper levels in heart muscle were actually lower in patients who died of CHD than those who died of other causes (17). Additionally, the copper content of white blood cells has been positively correlated with the degree of patency of coronary arteries in CHD patients (18, 19). Further, patients with a history of myocardial infarction (MI) had lower concentrations of extracellular superoxide dismutase (SOD) than those without a history of MI (20). Thus, due to a lack of a reliable biomarker of copper nutritional status, it is not clear whether copper is related to cardiovascular disease.

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 (21), other studies have not confirmed those results (22). Copper supplementation of 2-3 mg/day for four to six weeks did not result in clinically significant changes in cholesterol levels (12, 23). 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 six 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) (24). Moreover, supplementation with 3 and 6 mg/day of copper decreased the in vitro oxidizability of red blood cells (25), 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 the human body. 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 (26, 27). 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 (28). 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, were isolated from their blood and presented with an immune challenge in cell culture (29). 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 (30). 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 two years (31). Additionally, a two-year double-blind, placebo-controlled trial in 59 postmenopausal women found that a combination of supplemental calcium and trace minerals, including 2.5 mg of copper daily, resulted in maintenance of spinal bone density, whereas supplemental calcium or trace minerals, alone, were not effective in preventing loss of bone density (32). A study in 11 healthy adult males found that marginal copper intake of 0.7 mg/day for six weeks significantly increased a measurement of bone resorption (breakdown) in healthy adult males (33). However, copper supplementation of 3 to 6 mg/day for six weeks had no effect on biochemical markers of bone resorption or bone formation in a study of healthy adult men and women (34). 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.

Sources

Food sources

Copper is found in a wide variety of foods and is most plentiful in organ meats, shellfish, nuts, and seeds. Wheat bran cereals and whole- grain products are also good sources of copper. According to national surveys, the average dietary intake of copper in the U.S. is approximately 1.0 to 1.1 mg (1,000 to 1,100 mcg)/day for adult women and 1.2 to 1.6 mg (1,200 to 1,600 mcg)/day for adult men (5). The copper content of some foods that are relatively rich in copper is listed in micrograms (mcg) in the table below. For more information on the nutrient content of foods, search the USDA food composition database.

 

Supplements

Copper supplements are available as cupric oxide, copper gluconate, copper sulfate, and copper amino acid chelates (35).

Safety

Toxicity

Copper toxicity is rare in the general population. Acute copper poisoning has occurred through the contamination of beverages by storage in copper-containing containers as well as from contaminated water supplies (36). In the U.S., the health-based guideline for a maximum water copper concentration of 1.3 mg/liter is enforced by the Environmental Protection Agency (EPA) (37). Symptoms of acute copper toxicity include abdominal pain, nausea, vomiting, and diarrhea, which help prevent additional ingestion and absorption of copper. More serious signs of acute copper toxicity include severe liver damage, kidney failure, coma, and death. Of more concern from a nutritional standpoint is the possibility of liver damage resulting from long-term exposure to lower doses of copper. In generally healthy individuals, doses of up to 10,000 mcg (10 mg) daily have not resulted in liver damage. For this reason, the U.S. Food and Nutrition Board (FNB) set the tolerable upper level of intake (UL) for copper at 10 mg/day from food and supplements (5). It should be noted that individuals with genetic disorders affecting copper metabolism (e.g., Wilson's disease, Indian childhood cirrhosis, and idiopathic copper toxicosis) may be at risk for adverse effects of chronic copper toxicity at significantly lower intake levels. Recent evidence suggests that the UL of 10 mg/day may be too high. Specifically, men in a research study consumed 7.8 mg Cu/day for 147 days. They accumulated copper during that time, and some indices of immune function and antioxidant status suggested that these functions may have been adversely affected by the high copper intake (38, 39).

Drug Interactions

Relatively little is known about the interaction of copper with drugs. Penicillamine is used to bind copper and enhance its elimination in Wilson's disease, a genetic disorder resulting in copper overload. Because penicillamine dramatically increases the urinary excretion of copper, individuals taking the medication for reasons other than copper overload may have an increased copper requirement. Additionally, antacids may interfere with copper absorption when used in very high amounts (2).

Linus Pauling Institute Recommendation

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.

Adults over the age of 50

Because aging has not been associated with significant changes in the requirement for copper, our recommendation for older adults is the same as that for adults 50 and younger (40).

References

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Written in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in July 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in July 2007 by:
Judith R. Turnlund, Ph.D., R.D.
Collaborator and Professor of Nutrition, Emeritus
Western Human Nutrition Research Center
University of California, Davis

Copyright 2001-2013  Linus Pauling Institute

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