InteractionsGuide Index Page
Analysis Search Terms:
Copper
Nutrient Name: Copper.
Synonyms: Copper carbonate, copper citrate, copper gluconate, copper glyconate, copper lysinate, copper sebacate, copper sulfate, cupric acetate, cupric oxide; cuprum.
Elemental Symbol: Cu.
Related Substance: Chlorophyllin.
Chemistry and Forms
Copper carbonate, copper citrate, copper gluconate, copper glycinate, copper lysinate, copper sebacate, copper sulfate; copper amino acid chelates; cupric acetate, cupric oxide.
Physiology and Function
Copper is an essential trace mineral that is present in all tissues and acts as a cofactor in several key enzyme systems. The average adult body contains about 80 to 120 milligrams of copper, most of which is stored in the liver. Copper stimulates iron absorption and is an important catalyst in hemoglobin synthesis and function. Copper is necessary to make adenosine triphosphate (ATP) and acts as an essential component of cytochrome oxidase, which is necessary for energy metabolism, cellular respiration, and myelin formation.
Copper is involved in the synthesis and breakdown of several hormones. Copper serves as a cofactor in dopamine–β-hydroxylase, which oxidizes ascorbic acid and synthesizes norepinephrine. It is also involved in the catabolism of estrogenic hormones. Copper may play a role in emotional regulation and cognitive function.
Copper is absorbed in the small intestine, where it is transferred across the gut wall by albumin, and carried on transcuprein and albumin to the liver, where it is incorporated into liver enzymes and secreted into the blood on the protein ceruloplasmin. Copper absorption has been found to be greater in women (71%) than in men (64%), age 20 to 59 years, but did not differ in men and women 60 to 83 years old. Copper elimination is primarily via bile, with small amounts eliminated in urine, sweat, and epidermal shedding.
Copper plays a central role in decreasing inflammation through both ceruloplasmin and the copper-containing form of superoxide dismutase (SOD). Ceruloplasmin is a weak, broad-specificity oxidase whose main functions include copper transport and extracellular scavenging of superoxide and other oxygen radicals. Adequate ceruloplasmin levels also minimize copper toxicity by limiting absorption of copper. Copper, along with zinc, as well as manganese, is found in cytostolic SOD. SOD is a primary quencher of superoxide radical, a prevalent and highly reactive free-radical form of oxygen produced during oxidative phosphorylation, which can be quite destructive if not rapidly quenched. SOD slows age-related deterioration, protects against chemical sensitivities (along with polyphenol oxidase), and enables the normal humoral immune response. There are also copper-containing amino acid chelates that have SOD activity. During inflammatory conditions, such as acute infections, serum copper levels, as ceruloplasmin, generally increase by 20% to 30%, whereas serum iron levels decline. Plasma copper, enzymatic ceruloplasmin, and immunoreactive (RID) ceruloplasmin have been observed to be significantly higher in women than in men, but SOD and in vitro 67 Cu uptake by red blood cells does not appear to differ between the genders.
Histaminase, which breaks down histamine to control allergies and inflammation, is another copper-dependent enzyme involved in regulating inflammatory processes. Tyrosinase, an enzyme that requires copper, plays a role in melanin synthesis, enabling skin pigmentation and hair coloration, as well as keratinization of hair.
Some researchers have proposed that copper deficiency is associated with elevated cholesterol and triglycerides, the development of atherosclerosis, and increased risk of cardiovascular disease.
Copper functions in the synthesis of collagen and repair of connective tissue, providing structural elasticity not only throughout the musculoskeletal system, but also in tissues of the lungs, blood vessels, and skin. Lysil oxidase, a copper-containing enzyme secreted by connective tissue cells, is necessary for the formation of the cross-links of collagen and elastin.
Copper is an essential element and its level in the body is strictly controlled. Under most conditions, excess copper is excreted in the urine and feces (via the bile). In cases of elevated copper, the adverse effects that develop are often caused less directly by copper toxicity than by its interference with the absorption and distribution of other mineral nutrients, such as iron and zinc.
Copper sulfate, cupric acetate, and alkaline copper carbonate are among the forms of copper best absorbed in the gut. Nevertheless, even though animal studies have demonstrated that it is poorly absorbed in the gut, cupric oxide (CuO) is the form of copper most often used in over-the-counter (OTC) preparations. Chlorophyllin is a relatively new, water-soluble copper complex of chlorophyll.
Known or Potential Therapeutic Uses
Copper has been proposed as offering therapeutic benefit in a wide range of conditions. Such therapeutic action has largely been premised on the hypothesis that administration will enhance or restore healthy function in the numerous enzyme systems where copper plays a critical role. Nevertheless, direct evidence confirming copper's efficacy in treating most of the diseases proposed is largely lacking, other than to prevent or treat those directly attributable to, or exacerbated by, copper deficiency or depletion.
Historical/Ethnomedicine Precedent: As the classical metal of Venus, copper was associated with the female reproductive system in ancient times.
Possible Uses
Anemia, aneurysms, atherosclerosis, athletic performance, benign prostatic hyperplasia, burns, cardiac arrhythmia, cardiovascular disease, decubitus ulcers, hypercholesterolemia, hypoglycemia, immune enhancement, Menkes’ syndrome, muscle spasms, osteoporosis, peptic ulcer, peripheral vascular disease, rheumatoid arthritis, skin cancer (prevention), sprains and strains, stomach cancer (prevention), vitiligo, wound healing.
Deficiency Symptoms
Most research into copper deficiency has focused on acute, severe deficiency. Such frank clinical copper deficiency is relatively rare in humans and animals on typical, varied diets. However, marginal, chronic deficiency is not uncommon. Dietary surveys indicate that the average dietary intake of copper in the U.S. population is only half of the recently established recommended dietary allowance (RDA). Most cases of copper deficiency involve premature infants, infants suffering from malnutrition, or children with iron deficiency anemia, severe protein malnutrition, chronic diarrhea, or other malabsorption difficulties. Overt symptoms in adults are rare but may occur with inadequate or unbalanced dietary intake over an extended time or in those who consume zinc supplements chronically without counterbalancing copper. The determination of copper needs and marginal deficiency is obscured because copper deficiency may not manifest as decreased levels of copper-dependent enzymes, but it may still significantly lower their activity.
Because copper is required for a wide range of enzyme systems and metabolic processes, a deficiency can cause a variety of disorders. Laboratory animals fed copper-deficient diets tend to develop anemia, cardiac abnormalities and abnormal electrocardiograms, and elevated levels of serum cholesterol, triglycerides, and glucose. Symptoms of copper deficiency in humans include fatigue, hypotonia, hypothermia, growth retardation, reduced resistance to infection, various nervous system disorders, anemia, neutropenia, degeneration of vasculature, cardiac damage, hemolysis with potential liver and brain damage, various cardiovascular problems, impaired respiration, emphysema, elevated low-density lipoprotein (LDL) cholesterol and reduced high-density lipoprotein (HDL) cholesterol, impaired collagen formation, breakdown of connective tissue, bone demineralization, osteoporosis, depigmentation of skin, and changes in structure and appearance of hair.
Genetic Conditions Relating to Copper
Two primary genetic diseases involve copper metabolism: Menkes’ syndrome and Wilson's disease.
Menkes’ syndrome results from an X-linked mutation of genes encoding Cu-binding P-type adenosinetriphosphatase (ATPase) for the efflux of Cu, ATP7A. Apart from the distinctive kinky or steely hair, this syndrome is also characterized by stunted growth, abnormalities in cardiovascular and skeletal development, progressive cognitive decline, and premature death. This inborn error in metabolism limits absorption of copper in the intestines and uptake in the liver. Copper subsequently accumulates in the intestinal cells and produces symptoms resembling copper deficiency.
Wilson's disease, caused by the mutation of genes encoding Cu-binding ATPase for the efflux of Cu, ATP7B, is characterized by accumulation of copper in the liver, leading to severe hepatic damage; elevated copper levels subsequently affect the brain and result in neurological problems.
Dietary Sources
Oysters are the most abundant food source of copper. Other copper-containing foods include soy, peas, and other dried legumes; dark-green leafy vegetables; whole-grain breads and cereals; seafood, including crab and lobster; lamb, pork, and other meats, especially organ meats such as liver; nuts (almonds, pecans, walnuts); raisins, prunes, and pomegranates; and tea, coffee, and chocolate.
Foods rich in copper are generally also rich in iron.
Nutrient Preparations Available
Copper sulfate, cupric acetate, cupric oxide, and alkaline copper carbonate. As previously noted, CuO is the form most often used in OTC preparations, primarily because of its low cost. Chlorophyllin is a copper complex of chlorophyll.
Copper is usually found in multimineral or multivitamin/multimineral formulations.
Copper is often taken with, although preferably ingested apart from, long-term zinc administration to counteract the tendency to copper depletion associated with zinc intake without copper. Recommended Zn/Cu ratio in formulations is 10:1 to 15:1.
Dosage Forms Available
Capsule, tablet; cupric sulfate: injection (U.S.).
Dosage Range
Adult
Dietary: 1.0 to 1.5 mg/day
Supplemental/Maintenance: 1 to 2 mg/day
Pharmacological/Therapeutic: 2+ mg/day
Pharmacological doses of copper in scientific studies usually range from 2 to 4 mg per day. Copper dose is usually based on zinc intake. Many experts consider the optimal zinc/copper ratio as 10:1. Some practitioners of nutritional therapeutics use zinc at dosages up to 45 mg/day as part of therapeutic protocols. In such cases, LDL and HDL cholesterol levels need to be monitored. Zinc may need to be reduced or copper increased; even so, doses of copper greater than 3 mg/day are usually avoided.
Pediatric (<18 Years)
Supplemental/Maintenance: 0.5 to 1.0 mg/day
Pharmacological/Therapeutic: 1 to 2 mg/day
Laboratory Values
Serum ceruloplasmin concentrations and white blood cell (WBC) levels have been considered the most reliable methods of evaluation but often are insensitive to subtle changes in copper status. Copper-containing enzymes, such as Cu-Zn SOD, cytochrome- c oxidase, and diamine oxidase, may be more reliable, but evidence to date is not conclusive. 1 LDL and HDL cholesterol levels are sometimes used.
Serum, plasma, urinary, or hair copper concentrations are not considered particularly reliable because these monitoring parameters are subject to many variables and may not accurately demonstrate actual copper load; when used, such determinations are recommended monthly.
Overview
Copper is generally considered safe when taken at customary dietary or typical supplemental dosage levels. Chronic copper toxicity from intentional intake in adults is rare. Long-term doses of 10 to 35 mg per day are considered safe. The tolerable upper limit (UL) of copper intake established by the U.S. National Institute of Medicine for adults is 10 mg per day, combining dietary and supplemental sources. However, research has suggested that the body cannot eliminate more than 3 mg/day, so in individuals who are copper replete or overloaded, greater than 3 mg/day dietary copper may contribute to further accumulation.
Nutrient Adverse Effects
General Adverse Effects
In adults, 10 mg of copper daily can induce nausea, and 60 mg may cause vomiting. Tissue elevations usually occur only when intake is 300 to 500 times above normal. The adverse effects on zinc metabolism represent the primary adverse effect of excessive copper levels.
Mutagenicity
No human data are available. Results from short-term tests on mutagenicity have been negative or inconclusive.
Adverse Effects Among Specific Populations
Copper intake exerts particular risk for individuals with Wilson's disease, a genetic disorder that causes a toxic accumulation of copper in the liver, kidneys, central nervous system (CNS), and cornea. Maximum safe daily dosages of copper intake for individuals with severe liver or kidney disease are of concern but have not been determined. Copper toxicity has occasionally been reported in individuals living in houses where copper from water pipes has leached into the drinking water.
Pregnancy and Nursing
Maximum safe daily dosages of copper intake for pregnant or nursing women have not been determined. There are no reports in the literature reviewed of teratogenicity or embryotoxicity in humans induced by excess copper intake. However, animal studies indicate that a deficiency or excess of copper in the body can cause significant harm to developing embryos.
Infants and Children
Maximum safe daily dosages of copper intake for infants and young children have not been determined. Copper can exert a lethal dose in children at levels as low as 3.5 g. The copper (and zinc) status of epileptic children taking valproate derivatives should be monitored.
Toxicity Signs and Symptoms
Symptoms of moderate copper toxicity include weakness, dizziness, fainting, headache (severe or continuing), burning sensation in the throat, gastrointestinal disturbances, loss of appetite, vomiting, excess salivation, metallic taste in mouth, dyspepsia, epigastric pain, painful urination, and low back pain. Severe cases can result in hemolytic anemia, hypertension, liver damage, jaundice, hemochromatosis, hemoglobinuria, hematuria, kidney failure, coma, and death. O’Donohue et al. 2 reported a case of adult chronic copper self-intoxication, after daily doses of 30 to 60 mg for 3 years, which resulted in severe liver cirrhosis necessitating orthotopic liver transplantation.
Contraindications
Biliary disease, cancer, heart bypass patients, liver disease, migraines, Wilson's disease. Copper is also contraindicated during the course of anticopper therapies. Some individuals may have a total body excess of copper resulting from a lifetime of drinking water from copper plumbing, and copper supplementation may not be desirable in such people.
Precautions and Warnings
Some individuals may become sensitized to copper sulfate and develop allergic contact dermatitis.
Strategic Considerations
Many medications may deplete copper or interfere with its metabolic functions, sometimes incidentally, but often intentionally. Copper supplementation may be appropriate to correct drug-induced depletion patterns. In certain cases, however, such action is central to the therapeutic strategy, and supplementation is contraindicated, except in response to specific episodes of adverse effects of excessive copper deficiency caused by depletion. Conversely, in some situations, drugs such as allopurinol may provide benefit by reducing copper levels.
Oral Contraceptives: Monophasic, Biphasic, and Triphasic Estrogen Preparations (Synthetic Estrogen and Progesterone Analogs)
Hormone Replacement Therapy (HRT): Estrogen-Containing and Synthetic Estrogen and Progesterone Analog Medications
Probability: XXX
Evidence Base: XXX
Effect and Mechanism of Action
Penicillamine, trientine (trienthylene tetramine), and tetrathiomolybdate are chelating agents that bind metals and carry them out of the body. Tetrathiomolybdate was initially developed as a less toxic copper chelator than penicillamine and is now considered the treatment of choice for Wilson's disease, with zinc acetate maintenance after the copper levels are sufficiently low. Oral administration of copper, as well as aluminum, iron, and magnesium salts, and possibly other minerals (e.g., calcium, zinc), may decrease the GI absorption and bioavailability of these chelating agents, and vice versa. The medication's chelation of polyvalent metal ions resulting in a nonabsorbable complex constitutes the operative mechanism.
Research
Penicillamine is used to treat people with Wilson's disease, cystinuria, and severe rheumatoid arthritis. Wilson's disease (WD) is an autosomal recessive disease that causes excessive copper deposition in the liver, basal ganglia, kidney, cornea, and other tissues, with resultant hepatic, neurological, and visual sequelae. Medical research continues to clarify the pathophysiology of WD, with major advances in recent years. The key strategy of current conventional medical treatment focuses on reducing the amount of copper in the liver and other tissues by administering both copper-chelating agents and a low-copper diet. Although major progress has been achieved in the treatment of WD, significant controversy remains as to the optimal treatment of individuals in the various stages of the disease. Specifically, the relative roles of penicillamine, trientene, and tetrathiomolybdate in the initial treatment of the symptomatic patient with WD continue to be researched, debated, and emergent. 9,38,39 Copper control using these agents has also emerged as an antiangiogenic anticancer therapy. 40,41
Penicillamine prevents the formation or promotes the solubilization of copper-rich particles occurring in lysosomes of hepatocytes and Kupffer cells in the livers of individuals with WD. Once chelated with
Penicillamine use is associated with numerous adverse effects, often severe, such as systemic lupus erythematosus (SLE) and nephrotic syndrome, which occur in 20% to 25% of all patients. In cases where
Again, among the primary therapeutic uses of chelating agents such as penicillamine and trientine is the treatment of WD, in which toxic deposits of copper accumulate. Penicillamine is also used to treat individuals with cystinuria and severe rheumatoid arthritis. 33,38,45
Copper also plays an essential role in promoting angiogenesis. Tumors that become angiogenic acquire the ability to enter a phase of rapid growth and exhibit increased metastatic potential, the major cause of morbidity and mortality in cancer patients. Human and animal research on breast, lung, and other cancers indicates that copper deficiency induced by chelating agents, such as tetrathiomolybdate, significantly impairs tumor growth and angiogenesis through suppression of nuclear factor kappa B (NF-κB), contributing to a global inhibition of NF-κB–mediated transcription of proangiogenic factors. 46,47 NF-κB expression is also associated with the development of both chemotherapy and radiation resistance in cancer cells.
- Note:
Given the high risk of teratogenicity, based on animal studies, and the known adverse effects associated with many chelating agents, Brewer et al. 48 and other researchers have investigated the treatment of WD using tetrathiomolybdate, followed by zinc monotherapy or complementary use of zinc salts, using zinc in particular during pregnancy and with children.
Clinical Implications and Adaptations
Given the therapeutic objective of reducing toxic levels of copper in the body by increasing urinary excretion of the mineral, individuals with WD should minimize dietary intake of copper and avoid consuming copper supplements of any kind, even in the small doses found in most multivitamin/mineral formulas. In individuals taking any of these chelating agents to reduce copper levels, the consumption of any supplemental copper would obviously have an adverse effect on the drug's performance.
If copper (or iron) supplementation is incidental to the consumption of other medications or supplements or therapeutically indicated in some extraordinary circumstance, substances containing such minerals should be taken 2 hours before or after penicillamine, trientine, or tetrathiomolybdate to minimize interference with the medication's effects.
- Note:
Clinicians should also be aware of chlorophyllin, a water-soluble copper complex of chlorophyll that is becoming increasingly popular as a nutritional supplement. Chlorophyllin has antimutagenic and anticarcinogenic properties, but it is also a source of copper and needs to be considered as part of the standard supplement inventory inquiry.
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