Copper

Common Names: Copper gluconate, Copper picolinate, Copper sulfate

Clinical Name: Copper

Summary

Copper

chemical name: Cu

forms: Copper gluconate, copper picolinate, copper sulfate, amino acid complex

overview of interactions:
• nutrient affected by drug: Antacids

• nutrient affected by drug: Oral Contraceptives

• nutrient affecting drug performance: Penicillamine

• nutrient affected by drug: Valproic Acid

metabolism:
• Some copper can be absorbed from the stomach, but the majority is absorbed from the small intestine. It is both actively and passively transported across the intestinal mucosa.
• Normally about 30-50% of ingested copper gets absorbed.
• Fiber doesn't have the same ability to bind onto copper as zinc.
• Most copper is excreted via the bile.

functions:
• Copper acts as a cofactor for several key enzyme systems, most notably lysyl oxidase, dopamine b hydroxylase, ceruloplasmin and superoxide dismutase.
• Collagen cross linking: Lysyl oxidase is a copper containing enzyme secreted by connective tissue cells that aid in the cross linking of elastin and collagen. This role makes copper indispensable for connective tissue repair.
• Estrogen breakdown: Copper is involved in the catabolism of estrogenic hormones.
• Anti inflammatory: During inflammatory conditions copper is increased in the serum by 20-30%. Through the action of ceruloplasmin, which acts as a radical scavenger, and superoxide dismutase (SOD), copper plays a pivotal role in decreasing inflammation. There are also copper containing amino acid chelates that have SOD activity.
• SOD: Copper, along with zinc, is found in cytostolic superoxide dismutase enzymes that are involved with disposing of superoxide anions and ceruloplasmin. Ceruloplasmin is a weak broad specificity oxidase whose main function is to carry copper around. It is also an extracellular scavenger of superoxide and other oxygen radicals.
• Myelin synthesis: It is essential for the formation of the myelin surrounding the nerves.

dietary sources: Beans, peas, green leafy vegetables, whole grain products, prunes, raisins, pomegranates, liver, seafoods (oysters, crab, lobster), meats (lamb, pork), nuts (almonds, pecans, walnuts), wheat germ, soybeans.
• Average American daily intake of copper is 1.2-1.7 mg per day.
Note: Foods rich in copper are generally those rich in iron.

deficiency:
• A deficiency of copper is not uncommon. Symptoms include hemolysis with liver and brain damage, anemia, neutropenia, degeneration of vasculature, depigmentation of skin, kinky hair, hypotonia, and hypothermia.
• Copper deficiency can come from an inborn error in metabolism known as Menkes, an X-linked defect, this condition is characterized by a lack of absorption of copper from the intestine and a lack of uptake in the liver. Copper especially accumulates in the intestinal cells.
• Anemia: Copper is essential for the mobilization of iron from the liver. A deficiency of copper results in microcytic anemia.

known or potential therapeutic uses: Anemia, aneurysms and cardiovascular disease, arthritis, decubitus ulcers, immune enhancement, osteoporosis, prevention of PVCs, rheumatoid, skin cancers, stomach cancer prevention, vitiligo.

maintenance dose:
• RDA: There is no RDA for copper.
• Estimated safe and adequate daily dietary intake for copper is from 1 to 3 mg/day.

maintenance dose:
• RDA: There is no RDA for copper.
• Estimated safe and adequate daily dietary intake for copper is from 1 to 3 mg/day.
• Average American daily intake of copper is 1.2-1.7 mg per day.
• Lab: Serum and hair levels are not very reliable. It is best to check WBC

therapeutic dose: 1.5-3 mg per day for adults.
Copper is usually dosed in relation to zinc. The optimal ratio of copper to zinc is 10:1.Some practitioners of natural medicine use zinc at dosages up to 45 mg per 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 per day are usually avoided.

nutrient antagonists: Zinc, iron and vitamin C interfere with copper absorption.

side effects: Copper can cause nausea and vomiting at doss of 10 mg and 60 mg, respectively. The adverse effects upon zinc represent the major adverse side effect of high copper intake.

toxicity: Copper can exert a lethal dose in children at levels as low as 3.5 grams. Chronic copper toxicity due to intentional intake in adults is rare. Long term doses of 10-35 mg per day are considered safe.

contraindications: Migraines, Wilson's disease.



Interactions

nutrient affected by drug: Antacids

• mechanism: Antacids may reduce absorption of copper. Antacids may induce a copper deficiency by precipitating dietary copper due to the drug-induced alkaline pH in the intestines.
(Roe DA. Diet and Drug Interactions. 1989, 85-86.)

• nutritional support: Individuals who take antacids for an extended period of time would benefit from copper supplementation to protect against depletion of folate. This could be in the form of a multivitamin/mineral formula.

nutrient affected by drug: Oral Contraceptives

• research: Research has consistently found the use of oral contraceptives as being positively associated with increased absorption of copper and increased serum copper concentration. Even though higher serum copper concentration in women using oral contraceptives is well known, there is still uncertainty about the influence of newer progestin compounds in oral contraceptives on serum copper concentration. In a study involving low-estrogen preparations, Liukko et al noted that copper levels rose significantly while using oral contraception over a two year period, but returned to initial levels after the contraceptives were discontinued. In a more recent epidemiological study of 610 nonpregnant and nonlactating women, Berg et al reported that while elevated serum copper concentration was found in users of all types of oral contraceptives, elevation was more pronounced among women taking oral contraceptives with antiandrogen effective progestins like antiandrogens or third generation oral contraceptives containing desogestrel.
(Liukko P, et al. Gynecol Obstet Invest 1988;25(2):113-117; Horwitt MK, et al. Am J Clin Nutr 1975 Apr;28(4):403-412; Berg G, et al. Eur J Clin Nutr 1998 Oct;52(10):711-715.)

• nutritional concerns: Recent epidemiologic studies have shown an increased mortality from cardiovascular diseases in people with higher serum copper levels. This issue is of particular interest in the light of recent findings of an increased risk of venous thromboembolism in users of oral contraceptives containing newer progestins like desogestrel compared to users of other oral contraceptives.

nutrient affecting drug performance: Penicillamine

• research: Among the primary therapeutic uses of penicillamine is the treatment of Wilson's disease where toxic deposits of copper accumulate.

• nutritional concerns: Given the therapeutic objective of reducing toxic levels of copper in the body by increasing urinary excretion of the mineral, individuals with Wilson's disease should never consume copper supplements of any kind, even in the small doses found in most multivitamin/mineral formulas. In individuals taking penicillamine to reduce copper levels the consumption of any supplemental copper would obviously have an adverse effect on the drug's performance.

nutrient affected by drug: Valproic Acid

• research: In several studies of children with epilepsy being treated with valproic acid serum copper levels remained unchanged relative to control groups.
(Sozuer DT, et al. J Basic Clin Physiol Pharmacol 1995;6(3-4):265-269; Lerman-Sagie T, et al. Clin Neuropharmacol 1987;10(1):80-86; Hurd RW, et al. Neurology 1984 Oct;34(10):1393-1395.)

However, Kaji et al found that patients treated with valproic acid, alone or in combination with other drugs, had significantly lower levels of serum copper than did normal controls. These researchers suggested that physicians should watch for potential symptoms of copper deficiency even none of their patients showed any symptoms of copper deficiency at the time of the study.
(Kaji M, et al. Epilepsia 1992 May-Jun;33(3):555-557.)

• nutritional support: No definitive evidence has emerged as to the prevalence or clinical significance of copper depletion or deficiency as a result of valproic acid. Individuals taking valproic acid should consult their prescribing physician and/or a nutritionally trained healthcare professional about the potential use of a copper supplement to restore proper trace mineral balance. Inadequate consumption of copper through dietary sources is common. Supplementation with copper at levels of 1-3 mg per day may be beneficial, being especially for anyone taking zinc supplements.

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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.


References

Berg G, Kohlmeier L, Brenner H. Effect of oral contraceptive progestins on serum copper concentration. Eur J Clin Nutr 1998 Oct;52(10):711-715.
Abstract: OBJECTIVES: Recent epidemiologic studies have shown an increased mortality from cardiovascular diseases in people with higher serum copper levels. Even though higher serum copper concentration in women using oral contraceptives is well known, there is still uncertainty about the influence of newer progestin compounds in oral contraceptives on serum copper concentration. This issue is of particular interest in the light of recent findings of an increased risk of venous thromboembolism in users of oral contraceptives containing newer progestins like desogestrel compared to users of other oral contraceptives. DESIGN: Cross-sectional epidemiologic study. Examinations included a detailed questionnaire on medical history and lifestyle factors, a seven day food record, and blood samples. SETTING: National health and nutrition survey among healthy people living in private homes in West Germany in 1987-1988. SUBJECTS: Nonpregnant and nonlactating women aged 18-44 y (n = 610). RESULTS: Overall, the use of oral contraceptives was positively associated with serum copper concentration in by bi- and multivariable linear regression models with log-transformed values of serum copper concentration as dependend variable and oral contraceptive preparations and potential confounding variables as independent variables. Serum copper concentration in women using oral contraceptives varied more strongly by different progestin compounds than by estrogen contents. The highest increase of serum copper was seen in women using oral contraceptives containing antiandrogen progestins (55%; 95% CI: 37-76%), followed by desogestrel (46%; 95% CI: 36-56%), norethisteron/lynestrenol (42%; 95% CI: 29-57%), and levonorgestrel (34%; 95% CI: 24-45%). CONCLUSION: While elevated serum copper concentration was found in users of all types of oral contraceptives, elevation was more pronounced among women taking oral contraceptives with antiandrogen effective progestins like antiandrogens or third generation oral contraceptives containing desogestrel. Further investigation is required to shed light on the possible role of high serum copper concentration in increasing cardiovascular or thrombotic risk of women using oral contraceptives.

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998.

Horwitt MK, Harvey CC, Dahm CH Jr. Relationship between levels of blood lipids, vitamins C, A, and E, serum copper compounds, and urinary excretions of tryptophan metabolites in women taking oral contraceptive therapy. Am J Clin Nutr 1975 Apr;28(4):403-412.
Abstract: To evaluate which women using oral contraceptive agents might be at risk, biochemical indices known to be affected by the estrogens and progestogens were studied in women who take oral contraceptive agents, in women who do not use oral contraceptive agents, in women in third trimester of pregnancy and 6 weeks after parturition, and in men with normal and high blood lipid levels. The most consistent changes due to oral contraceptive agents were in serum levels of copper, triglycerides, and vitamin A and in the urinary excretion of xanthurenic acid and niacin derivatives before and after a tryptophan load test. There was only a slight suggestion, with no statistical significance, that serum vitamin C levels decreased when the serum levels of ceruloplasmin were high. The highest blood pressures and serum triglycerides and vitamin A levels were obtained in those women who ingested the highest level of estrogens. Pregnant women had the lowest levels of serum vitamin A. The oral contraceptive agents users had the lowest average levels of carotenoids corresponding to the highest average levels of vitamin A in the serum. Thus, estrogens not only increase the rate of change of tryptophan to niacin but may also increase the rate of conversion of carotene to vitamin A. Relative reactivity to oral contraceptive agents and possible risk to a patient might be evaluated by a profile of blood pressure and serum triglycerides, copper, and vitamin A.

Hurd RW, Van Rinsvelt HA, Wilder BJ, Karas B, Maenhaut W, De Reu L. Selenium, zinc, and copper changes with valproic acid: possible relation to drug side effects. Neurology 1984 Oct;34(10):1393-1395.
Abstract: Side effects of treatment with the anticonvulsant valproic acid (VPA) suggested the possibility of alteration of trace metal status. Administration of VPA for 1 week produced significant depletion of zinc and selenium in plasma of rats and a one-third reduction of hepatic selenium. Patients who were treated chronically, with VPA as the sole anticonvulsant medication, had decreased plasma selenium levels. Most cases of VPA-associated hepatotoxicity occur in children. This could be due to decreased selenium concentrations when mechanisms for protection against peroxidative damage are not fully developed.

Kaji M, Ito M, Okuno T, Momoi T, Sasaki H, Yamanaka C, Yorifuji T, Mikawa H. Serum copper and zinc levels in epileptic children with valproate treatment. Epilepsia 1992 May-Jun;33(3):555-557.
Abstract: Valproate (VPA) induces zinc (Zn) deficiency in experimental animals, but whether VPA treatment induces deterioration of serum trace metal homeostasis in humans is uncertain. We measured serum copper (Cu) and Zn levels in epileptic children treated with VPA and/or other antiepileptic drugs (AEDs). Patients treated with VPA monotherapy had significantly lower levels of serum Cu (82.2 +/- 16.6 micrograms/dl) than normal controls (97.3 +/- 23.0 micrograms/dl). Patients treated with VPA in addition to some other AED also had significantly lower levels of serum Cu (84.8 +/- 20.0 micrograms/dl). Serum Cu concentrations in patients treated with AEDs except for VPA (87.7 +/- 19.1 micrograms/dl) were not statistically different from those of control subjects. In contrast to the reported results of animal experiments, serum Zn levels were not altered in patients with VPA treatment. Although none of our patients showed any symptoms of Cu deficiency, we should pay attention to potential Cu deficiency in patients with VPA treatment.

Lerman-Sagie T, Statter M, Szabo G, Lerman P. Effect of valproic acid therapy on zinc metabolism in children with primary epilepsy. Clin Neuropharmacol 1987;10(1):80-86.
Abstract: The effect of long-term treatment with valproic acid (VPA) on zinc (Zn) metabolism was studied in 15 children with absence seizures. During treatment with VPA the erythrocyte Zn content was significantly lower than that found in controls matched for sex and age. Plasma and urine values of Zn and of copper were within normal limits. It is suggested that the anticonvulsive action of VPA may be mediated through its effect on the metabolism of Zn in the brain and the concomitant changes in the activity of the enzymes glutamic acid decarboxylase and carbonic anhydrase.

Liukko P, Erkkola R, Pakarinen P, Jarnstrom S, Nanto V, Gronroos M. Trace elements during 2 years' oral contraception with low-estrogen preparations. Gynecol Obstet Invest 1988;25(2):113-117.
Abstract: In 17 healthy women, taking either a combination of 0.030 mg of ethinyl estradiol and 0.150 mg of levonorgestrel (n = 9) or a combination of 0.030 mg of ethinyl estradiol and 0.150 mg of desogestrel (n = 8) for oral contraception, the profiles of iron, calcium, copper, and zinc levels were investigated. The blood samplings were performed prior to oral contraception and after 3, 12, and 24 months' contraception, as well as within 2 months after discontinuation of the pill. No changes occurred in iron, calcium, and zinc levels. On the other hand, the copper level was significantly increased during oral contraception, yet returned to the initial level after discontinuation of contraception. No differences occurred between the two preparations for oral contraception.

Powanda MC, Blackburn BS, Bostian KA, Fowler JP, Hauer EC, Pekarek RS. Clofibrate-induced alterations in zinc, iron and copper metabolism. Biochem Pharmacol 1978 Jan 1;27(1):125-127.

Robinson C, Weigly E. Basic Nutrition and Diet Therapy. New York: MacMillan, 1984.

Roe DA. Diet and Drug Interactions. New York: Van Nostrand Reinhold, 1989.

Roe DA. Drug-induced Nutritional Deficiencies. 2nd ed. Westport, CT: Avi Publishing, 1985.

Roe DA. Risk factors in drug-induced nutritional deficiencies. In: Roe DA, Campbell T, eds. Drugs and Nutrients: The Interactive Effects. New York: Marcel Decker, 1984: 505-523.

Schilsky ML. Wilson disease: genetic basis of copper toxicity and natural history. Semin Liver Dis 1996 Feb;16(1):83-95. (Review)
Abstract: The discovery that the gene for Wilson disease encodes a copper-transporting ATPase has greatly improved our understanding of the pathophysiology of this disorder and of copper metabolism in humans. The abundance of disease-specific mutations and their location at multiple sites across the genome have limited molecular genetic diagnosis to kindred of known patients, and confirm the necessity for de novo screening by well-proven clinical and biochemical means. It is uncertain whether the variety of specific mutations will account for the wide range of presenting clinical signs and symptoms of Wilson disease, and environmental and extragenic factors are likely to be important contributing factors. Chelation therapy with penicillamine and trientine remain effective treatment for most symptomatic hepatic and neurologic Wilson disease. Zinc salts may be used for some asymptomatic patients, and OLT for fulminant hepatitis and patients for whom pharmacotherapy is ineffective. The chelating agent tetrathiomolybdate is under investigation for the treatment of neurologic Wilson disease. Gene therapy is the new horizon for treatment of Wilson disease. However, the ability to treat this disorder effectively by this means awaits further characterization of the gene product and more efficient methods for gene delivery to all hepatocytes in the liver.

Sozuer DT, Barutcu UB, Karakoc Y, Yalcin E, Onen S. The effects of antiepileptic drugs on serum zinc and copper levels in children. J Basic Clin Physiol Pharmacol 1995;6(3-4):265-269.
Abstract: The results of previous studies that examined serum trace metal status of epileptic patients receiving antiepileptic drug (AED) therapy were variable. We measured serum zinc (Zn) and copper (Cu) levels in 52 epileptic children who were treated with either carbamazepine (CBZ) or valproic acid (VPA) or with a combination of CBZ and VPA. Serum Zn levels were significantly lower in the epileptics than in the two control groups which consisted of 7 untreated epileptics and 12 normal children (p < 0.05). Combination therapy and monotherapy with CBZ increased serum Cu levels (p < 0.05). No significant alteration in serum Cu levels was observed with VPA monotherapy. Serum Zn and serum Cu concentrations of the untreated epileptics were not significantly different from those of normal controls. Our results indicate that serum trace metal homeostasis may be affected by AED therapy, but not by the convulsive disorder itself.

Suzuki T, Koizumi J, Moroji T, Shiraishi H, Hori T, Baba A, Kawai N, Tada K. Effects of long-term anticonvulsant therapy on copper, zinc, and magnesium in hair and serum of epileptics. Biol Psychiatry 1992 Mar 15;31(6):571-581.

Threlkeld DS, ed. Miscellaneous Products, Penicillamine. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Aug 1996.

Trovato A, Nuhlicek DN, Midtling JE. Drug-nutrient interactions. Am Fam Physician 1991 Nov;44(5):1651-1658. (Review)

Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997. (Review)