Cu – Copper is found in igneous rocks at 55 ppm; shale at 45 ppm; sandstone at 5 ppm; limestone 4 ppm; fresh water at 0.01 ppm; sea water at 0.003 ppm; soils at 2 to 100 ppm (copper is strongly absorbed by humus; there are known areas of the world with extreme copper deficiency); marine plants 11 ppm; land plants 14 ppm; marine animals 4 to 50 ppm; accumulates in the blood of annelids (worms), crustaceans and mollusks, especially cephalopods; land animals at 2 to 4 ppm with highest levels in the liver.
Symptoms Associated with Copper Deficiency
- White hair
- Gray hair
- Dry brittle hair (“steely wool” in sheep)
- Ptosis (sagging tissue – eye lids, skin etc.)
- Hernias (Congenital and acquired)
- Varicose veins
- Aneurysms (large artery blowouts, cerebral artery blowouts)
- Kawasaki Disease (congenital aneurysms with Streptococcal infection)
- Anemia (especially in vegan and high milk diets)
- Hypo and hyper thyroid
- Arthritis (especially where growth plate is involved)
- Ruptured vertebral disc
- Liver cirrhosis
- Violent behavior, blind rage, explosive outbursts, criminal behavior
- Learning disabilities
- Cerebral palsy and hypoplasia of the cerebellum (congenital ataxia)
- High blood cholesterol
- Iron storage disease (abnormal iron accumulation in liver)
- Reduced glucose tolerance (low blood sugar)
- Neutropenia (low neutrophils)
Copper is essential to all living organisms and is a universally important cofactor for many hundreds of metalloenzynes. Copper deficiency is widespread and appears in many forms . Copper is required in many physiological functions (RNA, DNA, lysil oxidase cofactor, melanin production (hair and skin pigment), electron transfer of oxygen subcellular respiration, tensile strength of elastic fibers in blood vessels, skin, vertebral discs, etc.).
Neonatal enzootic ataxia (sway back, lamkruis) was recognized as a clinical entity in 1937 as a copper deficiency in pregnant sheep. Copper supplements prevented the syndrome which was characterized by demyelination of the cerebellum and spinal cord. Cavitation or gelatinous lesions of the cerebral white matter, chromatolysis, nerve cell death and myelin aplasia (failure to form). These are all changes identical with human cerebral palsy.
Four to six of every 100 Americans autopsied have died of a ruptured aneurysm, an additional 40 percent have aneurysms that had not yet ruptured.
The average well-nourished adult human body contains between 80 and 120 mg of copper. Concentrations are higher in the
brain, liver, heart and kidneys. Bone and muscle have lower percentages of copper but contain 50 percent of the body total copper reserves because of their mass. It is of interest that the greatest concentration of copper is found in the newborn and their daily requirement is 0.08 mg/kg, toddlers require 0.04 mg/kg and adults only 0.03 mg/ kg.
The average plasma copper for women ranges from 87 to 153 mg/dl and for men it ranges from 89 to 137 mg/dl; about 90 percent of the plasma copper is found in ceruloplasmin.
Copper functions as a co-factor and activator of numerous cuproenzymes that are involved in the development (deficiency of Cu in the pregnant female results in congenital defects of the heart, i. e. – Kawasaki Disease and brain cerebral palsy and hypoplasia of the cerebellum) and maintenance of the cardiovascular system (deficiency results in reduced lysyl oxidase activity causing a reduction in conversion of pro elastin to elastin causing a decrease in tinsel strength of arterial walls and ruptured aneurysms and skeletal integrity (deficiency results in a specific type of arthritis of the young in the form of spurs in the bones growth plate); deficiency can result in myelin defects; deficiency results in anemia; and poor hair keratinization and loss of hair color. Neutropenia (reduced numbers of neutophillic WBC) and leukopenia (reduced total WBC) are the earliest indicators of copper deficiency in infants; infants whose diets are primarily cows milk frequently develop anemia; iron storage disease can result from chronic copper deficiency.
Menkes’ Kinky Hair Syndrome is thought to be a sex-linked recessive defect of copper absorption. The affected infants exhibit retarded growth, defective keratin formation and loss of hair pigment, low body temperature, degeneration and fracture of aortic elastin (aneurysms), arthritis in the growth plate of long bones, and a progressive mental deterioration (brain tissue is totally free of the essential enzyme Cytochrome c oxidase). Because of absorption problems of metallic copper, injections of copper are useful.
Serum and plasma copper increase 100 % in pregnant women and women using oral contraceptives. Serum copper levels are also elevated during acute infections, liver disease and pellagra (niacin deficiency).
Accumulations of copper in the cornea form – Kayser Fleischer rings.
Copper deficiency and thyroid function
Rats were fed diets containing adequate, marginal or deficient amounts of copper for 35 days. Copper deficiency resulted in a significant increase in serum cholesterol levels and a significant decline in plasma thyroxine concentrations and body temperatures. Compared with rats fed the adequate diet, those fed the marginal and deficient diets had significantly lower plasma concentrations of triiodothyronine (T3) and significantly higher TSH levels. The activity of thyroxine 5′-monodeiodinase (the enzyme that converts T4 to T3) was reduced in the liver and brown adipose tissue of copper deficient rats.
COMMENT: This study suggests that copper deficiency interferes with thyroid hormone metabolism and can promote hypothyroidism, as indicated by a reduction in T3 levels and body temperatures and an increase in TSH. Copper, zinc and selenium all have been shown to play a role in the metabolism of thyroid hormones, and a deficiency of any one of these trace minerals might be a contributing factor in patients who exhibit hypothyrold symptoms.
Dr. Carl Pfeiffer has pointed out that an excessive body burden of copper can result in various neuropsychiatric symptoms. Because of Pfeiffer’s work, many clinicians view copper primarily as a toxic mineral (because copper supplements are not as water-soluble as they should be). Indeed, a number of popular multivitamin/mineral formulas are advertised as being “copper free.” However, copper is also an essential nutrient, and the average American diet provides only about half the RDA (about 1 mg/day). Therefore, mild copper deficiency may be a more common problem than copper excess.
Lukaski H C et al. Body temperature and thyroid hormone metabolism of copper deficient rats. Nutr Biochem 1995;6:445-451.
Copper is an essential trace mineral. The body of an adult contains 100 mg to 150 mg of copper. Though copper is present in all tissues, including red cells, the liver is the main site of copper storage. Most of serum copper is bound to ceruloplasmin, the copper transport protein synthesized by the liver. Ceruloplasmin also aids in iron transportation and storage. Like most trace minerals, copper functions as an enzyme cofactor by activating certain key enzymes required to strengthen the structural protein collagen, which in turn strengthens cartilage, tendons, bones, and blood vessels. Copper also serves as a cofactor of a protein in the blood that helps maintain lung tissue and prevent emphysema; and it is essential for insulating (mylination) nerve cells. As a cofactor for the enzyme superoxide dismutase, copper helps prevent oxidative damage by a highly reactive form of oxygen and thus is classified as an antioxidant. Copper functions as a cofactor for cytochrome oxidase of mitochondria, the enzyme complex that ultimately transfers electrons from the oxidation of fat, carbohydrate and protein to oxygen for energy production. Copper also serves as a cofactor in the synthesis of norepinephrine, an important neurotransmitter and adrenal hormone.
The estimated safe and adequate daily intake of copper for normal adults is 2 to 3 mg. About 30% of dietary copper is assimilated. Good sources of copper include liver, kidneys, shellfish, nuts, seeds, fruit and dried legumes. Cow’s milk is low in copper. The standard American diet is copper deficient and between 66 and 75% of the U.S. population do not consume enough copper. Dieters, elderly persons and chronic alcoholics are especially vulnerable. The following factors increase the need for copper: excessive dietary fiber, high zinc supplements (50 mg or more daily), cadmium, excessive vitamin C and excessive sugar (fructose) intake (at least in rats).
Low copper consumption increases the risk of high blood cholesterol and coronary heart disease, lowered immunity, gout, diabetes, high blood pressure, anemia, nervous disorders, decreased pigmentation of skin, fragile bones and erratic heartbeat. Low dietary copper is linked with an increased risk of heart attack. Evidence also links copper deficiency with increased oxidative damage to cell membranes. Levels of norepinephrine in the brain are decreased with copper deficiency but may be restored by supplemental copper. There are certain precautions to keep in mind for copper supplements. Consumption of 10 to 15 mg of copper daily can cause side effects. Patients with a rare copper accumulation disease (Wilson’s disease) should not use copper supplements. An excessive copper overload has been linked to various psychiatric syndromes. A green stain in the sink from a faucet drip, or in a teakettle, suggests excessive copper in drinking water, leached from copper plumbing.
Prohaska, Joseph R. and Failla, Mark L., “Copper and Immunity,” in Human Nutrition–A Comprehensive Treatise, vol. 8 of Nutrition and Immunology, Klurfeld, David M., ed. New York: Plenum Press, 1993.
Also, included from: Minerals in Animal and Human Nutrition
By Lee Russell McDowell
Copper is required for cellular respiration, bone formation, proper cardiac function, connective tissue development, myelination of the spinal cord, keratinization, and tissue pigmentation. Copper is an essential component of several physiologically important metalloenzymes including cytochrome oxidase, lysyl oxidase, superoxide dismutase, dopamine-beta-hydroxylase, and tyrosinase.
1. IRON METABOLISM AND CELLULAR RESPIRATION
Along with Fe, Cu is necessary for hemoglobin synthesis. Copper is not contained in hemoglobin, but a trace of it is necessary to serve as a catalyst before the body can utilize Fe for hemoglobin formation. Anemia can develop with either a Fe or Cu deficiency. With Cu deficiency there is an apparent delay in maturation and shortened life span of red blood cells (Baxter and Van Wyk, 1953).
Copper plays a key role in Fe absorption and mobilization. Serum Fe levels tend to be low in Cu deficiency, and hypochromic anemia develops while intestinal mucosa and liver Fe levels are higher than normal. Ceruloplasmin (ferroxidase), which is synthesized in the liver and contains Cu, is necessary for the oxidation of Fe, permitting it to bind with the Fe-transport protein, transferrin. Ceruloplasmin (Evans, 1978) is a multifunctional enzyme involved in Fe metabolism, transport of Cu, and regulation of certain amines.
Iron must be converted to the ferrous form to be mobilized from stored ferritin and/or to be incorporated into hemoglobin or myoglobin. For storage as ferritin or for transport as transferrin, Fe must be converted to the ferric form (Curzon, 1961), a reaction performed by ceruloplasmin.
Copper is a constituent of the important metalloenzyme, cytochrome oxidase. This enzyme is the terminal oxidase in the respiratory chain; it catalyzes the reduction of 0, to water, an essential step in cellular respiration.
2. CROSS-LINKING OF CONNECTIVE TISSUE
With a Cu deficiency, there is failure of collagen to undergo cross-linking and maturation (Harris and O’Dell, 1974). The key Cu-containing enzyme in the formation of the cross-links in collagen and elastin is lysyl oxidase, which is necessary to add a hydroxyl group to lysine residues in collagen, allowing crosslinking between collagen fibers. These cross-links give the proteins structural rigidity and elasticity. Aortic aneurysms and ruptures result from failure to convert lysine to desmosine, the cross-linking residue in elastin.
3. PIGMENTATION AND KERATINIZATION OF HAIR AND WOOL
Achromotrichia (lack of pigmentation) is a principal manifestation of Cu deficiency in many species. It is commonly observed in the hair and wool of mammals, and is usually attributed to lack of tyrosinase (polyphenyl oxidase) activity. A breakdown in the conversion of tyrosine to melanin is the probable explanation.
Impaired keratinization of hair and wool are noted in Cu.-deficient animals. The characteristic physical properties of wool, including crimp, are dependent on disulfide groups that provide cross-linkages or bonding of keratin and on alignment or orientation of long-chain keratin fibrillae in the fiber. Straight steely wool has more sulfhydryl groups and fewer disulfide groups than normal (Marston, 1946). Copper is required for formation or incorporation of disulfide groups in keratin synthesis.
4. CENTRAL NERVOUS SYSTEM
The link between Cu deficiency and the integrity of the central nervous system, i.e., swayback (enzootic ataxia) of lambs, results from a reduction in cytochrome oxidase activity and thus incomplete myelin formation (Howell and Davidson, 1959). Myelin is composed largely of phospholipid. Loss of cytochrome oxidase in Cu deficiency leads to depressed phospholipid synthesis by liver mitochondria. The inhibition of myelin synthesis results in the ensuing neurological disturbances. Other central nervous system effects of Cu deficiency are reduction of at least two neurotransmitters, dopamine and norepinephrine (O’Dell, 1984).
Reproductive failure is commonly observed in mammals fed Cu-deficient diets (Underwood, 1977). For rats and guinea pigs, Cu deficiency has resulted in fetal death and resorption. Embryos from Cu-deficient hens exhibited anemia, retarded development, and a high incidence of hemorrhage after 72 to 96 hours of incubation, and a reduction in monoamine oxidase activity. The anemia, hemorrhages, and mortality are probably caused by defects in red blood cell and connective tissue formation during early embryonic development.
6. IMMUNE SYSTEM
Copper metabolism affects T and B cells, neutrophils, and macrophages. An impaired humoral immune response (i.e., decreased numbers of antibody-producing cells) was observed in mice with hypocuprosis (Prohaska et al., 1983). The magnitude of this impairment was highly correlated with the degree of its functional deficiency. In a literature review, Miller et al (1979) concluded that the relationship of Cu to the immune system is through superoxide dismutase, a Zn-, Cu-, and Mn-dependent enzyme, and its role in the microbial systems of phagocytes.
In cattle affected by Cu deficiency induced by Mo, neutrophils were impaired in their ability to kill ingested Candida albicans (Boyne and Arthur, 1986). The ability of polymorphonuclear leukocytes to phagocytose C. albicans in sheep with low Cu status is comparatively lower than that of sheep on a normal Cu diet (Olkowski et al 1990). A decreased resistance to infection has been observed in sheep affected by Cu deficiency (Wooliams et A, 1986).
7. LIPID MATABOLISM
A number of studies have demonstrated the effect of Cu deficiency on lipid metabolism. Petering et al (1977) reported that Cu deficiency results in elevated levels of serum triglyceride, phospholipids, and cholesterol in the rat. Altered heart function of rats fed low Cu is associated with alterations in lipid and long-chain fatty acid metabolism (Cunnane et al., 1987), which may be attributable to the predominant role of Cu in the superoxide dismutase enzyme system.ool r PhysiologyCOPPER: The Missing Link in Your Diet
By Sherry A. Rogers, M.D.
When we think of copper, we often think of toxic or high levels from copper tubing and water pipes. In reality, the majority of Americans are deficient in copper. The National Institutes of Health did a study showing that 81 percent of people have less than two-thirds of the recommended daily allowance of copper. Another study revealed that hospital meals provide only 0.76 mg of copper per day, whereas people need 2-4 mg for health, and even more for healing.
A study by the Food and Drug Administration showed that, in an analysis, 234 foods that constitute the core of the American diet provided less than 80 percent of the RDA of copper. A study of 270 United States Navy SEAL trainees, all of them highly selected healthy young men, revealed that 37 percent had low plasma copper levels, and plasma copper, as you will see, is a very insensitive indicator of copper status.
One study showed that 80 percent of Americans get 1 mg of copper per day, and another study, which analyzed 20 different types of U.S. diets, showed that only 25 percent of the people got 2 mg of copper a day and the majority of the diets provided 0.78 mg of copper per day.
So all copper studies seem to point to the majority of people being deficient.
When we studied 228 of our patients, 165 (or 72 percent) were deficient in copper. So, no matter whose studies you look at over the last 20 years, there is a wealth of data showing that copper deficiency is rampant in the United States. But the best test for copper deficiency is intracellular, or red blood cell (RBC), while serum or plasma copper tests are too insensitive, and hence not worth obtaining.
Why Copper Is Needed
So why do we need copper? Copper is present in about 21 different enzymes, and its importance has been known since 1928. For example, one important enzyme is histaminase, which breaks down histamine. So all allergic people, who overproduce histamine, certainly need to ensure that they have normal copper levels. Another copper-dependent enzyme is cytochrome oxidase, which is necessary for energy metabolism. Indeed, some people with weakness and chronic fatigue have marked copper deficiencies.
Copper is also present in superoxide dismutase, an enzyme which is useful in protecting us from developing chemical sensitivity. For example, a 33-year-old lab technician for years could not tolerate shopping malls, auto exhaust fumes and many businesses because of chemical sensitivity. She felt confused, suffered from headaches, and became weak and tired when she breathed the higher levels of chemicals commonly encountered in these environments. When we found that she had a copper deficiency and corrected it, within one month she was no longer as chemically sensitive, and could tolerate these exposures without symptoms.
Remember that chemical sensitivity requires multiple factors, one of which is that the person must be deficient in certain nutrients that are necessary for the detoxification pathways to operate normally. Once the deficiencies in these pathways are corrected many times, the chemical sensitivity is corrected.
As well, the enzyme superoxide dismutase (SOD) plays a role in the retarding of aging, arthritis and general body deterioration. In fact, in nearly all diseases, lower than normal levels of SOD are found. For example, people with colitis were found to have much lower levels of superoxide dismutase in the bowel, and people with Alzheimer’s disease were found to have much lower levels of superoxide dismutase in the brain. In other studies, chemically induced tumors were analyzed and found to be low in copper-containing protective superoxide dismutase.
There are many other enzyme pathways where copper is used for the detoxification of chemicals besides superoxide dismutase. For example, it is in polyphenol oxidase, which is necessary for the breakdown of phenols that emit gas from common household cleaning products. Also copper is necessary for the action of glutathione peroxidase and catalase pathways, even though it is not directly used in those enzymes. Studies on rats show that those which were deficient in copper developed severe liver necroses (tissue death) when exposed to carbon tetrachloride. But when the copper deficiency was corrected, they did not develop the expected chemical toxicity and suffer death.
Just as important, copper has a very important role in mood chemistry. For example, the enzyme dopamine beta-hydroxyl is responsible for the metabolism of norepinephrine, which affects depression and fatigue. It is also important in the synthesis of other mood hormones, like dopamine and serotonin (the one that many antidepressants -like Prozac -work on), and in the major stress (adrenal) hormone, epinephrine. And copper has an even’ greater influence on our moods, for it is necessary for the action of aminoxidases, which influence the metabolism of many neurotransmitter proteins in the brain that are responsible for moods and thoughts.
The Heart Protector
With all of these benefits, copper is still essential for many more enzymes. It is very important in protecting against arteriolosclerosis and hypercholesterolemia; aneurysms (weakened blood vessels that burst and can cause sudden death); EKG abnormalities; hypercoagulable states which lead to heart attacks and strokes; and sugar metabolism. As an example, many people with high cholesterol lack minerals like copper to properly metabolize their cholesterol. It is an error to prescribe cholesterol-lowering drugs without checking the RBC copper status.
For example, copper is important in an enzyme deta-9-desaturase. This has to do with the propermetabolism of essential fatty acids that make up the structural integrity of cell membranes. Remember that the most important membranes are the cell walls, from which allergic reactions, degenerative diseases and autoimmune diseases emanate.
Calcium channel blockers are commonly prescribed expensive drugs to control blood pressure and heart arrhythmias, but the reason the membrane calcium channels must be blocked has to do with minerals and essential fatty acid deficiencies in the membranes. A headache isn’t an aspirin deficiency, so we should be less inclined to “drug” every symptom and more inclined to find the nutrient deficiency behind the symptom. For example, if the mitochondrial membrane wall, where energy is created, is deficient, we can get chronic fatigue.
Furthermore, another very important membrane is the nuclear membrane, which protects our genetic DNA material from damage from chemicals. When the nuclear membrane is weak, chemicals can penetrate the nucleus and damage DNA; this is one of the mechanisms for instigating cancers as well as other degenerative diseases. Another Very important membrane complex is the endoplasmic reticulum, where detoxification of everyday home, office and outdoor chemicals must, be done.
At this point, you might be eager to run out and comer the market on copper and consume it, but this can be dangerous without knowing the proper level of copper, or the proper level of complementary, but antagonistic, minerals such as (RBC) zinc, (RBC) molybdenum and iron. By taking copper, one can lower the values of these important minerals and create secondary deficiencies.
Foods that are high in copper include nuts, legumes (peas and beans), seeds, organ meats and shellfish, in particular. Foods especially low in copper are processed foods in general, especially white flour, white sugar and fructose (fruit sugars).
Man is still trying to figure out why there are such folk remedies as copper bracelets for the care of arthritis. Some researchers presume that the copper is actually absorbed and incorporated into the anti-inflammatory enzyme superoxide dismutase, which tends to turn off inflammatory conditions like arthritis or Lupus.
Bob, a 54-year-old engineer, had 10 years of headaches. Allergy injections, dietary changes, and correction of nutrient deficiencies documented on blood tests corrected other symptoms, but they did not relieve his headaches. However, when a RBC copper deficiency was found and corrected, within one month his headaches disappeared. Certainly, people like this teach us that copper is the “missing link.”
About the author: Sherry A. Rogers, M.D., has a private practice in environmental and nutritional medicine.
COPPER DEFICIENCY AND MULTIPLE SCLEROSIS
A nervous disorder in sheep characterized by uncoordination of gait has been recognized for many years. This disorder is most common in sheep but it has also been reported in goat kids and more rarely in calves and piglets. Various local names have been given to this condition but swayback is the most common. Voisin prefers the term enzootic ataxia. In Trail, British Columbia, young dogs and cats could not be raised without encountering similar disabilities until more effective pollution controls were introduced in the early 1930s. More recently young foals brought into the Trail area suffered similar problems whereas older horses survived.
These problems seemingly were all associated with a copper deficiency in the locality or with the presence of too much lead which element nullifies the copper present in the fodder or in the atmosphere.
The enzootic ataxia in sheep parallels multiple sclerosis in humans. Both diseases are characterized by demyelination, that is, destruction of the myelin sheath.
In multiple sclerosis Plumb and Hansen found normal total copper values both in serum and in cerebrospinal fluid but in the serum they found reduced activity in copper oxidase. The same writers noted “this new finding does not yet appear to have attracted comment and its confirmation and further investigation will be awaited with interest, since vital clues to the role of trace minerals in myelination are badly needed.”
Voisin wrote “Australian biochemists, able specialists in deficiency diseases, set to work and found that one could prevent the disease by administering copper salts orally to the ewes”. Ruth Allcroft obtained similar results in England.
A few years ago Dr Jean Haine, from Gloucester in England, suggested that it might be worthwhile to add small copper supplements in some appropriate form to those persons whose blood contained too little copper. However this suggestion has apparently met with no support, at least in British Columbia. This suggestion would seem to be worth investigating.
A variety of symptoms have been associated with copper deficiency in animals, many of which are seen also in humans; they include hypochromic anemia, neutropenia (low neutrophils), hypopigmentation (graying) of the hair and skin, abnormal bone formation with skeletal fragility and osteoporosis, vascular abnormalities and uncrimped or steely hair. There is no single specific indicator of copper deficiency. Measurements which, despite major limitations, are currently considered to be of value in establishing a range for normal copper status include serum copper (normal range 0.64-1.56 ug/ml), ceruloplasmin (0.18-0.40mg/ml), urinary copper (32-64pg/24h) and hair copper (10-20 ug/g), all of which are depressed in frankly copper-deficient subjects but are less sensitive to a marginal copper status. The possibility that a decline in erythrocyte copper-zinc superoxide dismutase, normally 0.47 + 0.07 (SEM) mg/g of hemoglobin, may provide a more suitable and early indication of deficiency is being investigated.
Neutropenia is nowadays regarded as a sufficiently constant feature of copper deficiency in humans to be of diagnostic value, while evidence of a rapid decline in plasma enkephalins warrants further investigation.
As late as the early to mid-1920s a new trace element, copper, was suggested, on the basis of empirical evidence, to be of value in the diet of rats (Bodansky, 192 1; McHargue, 1925, 1926). Copper deficiency was subsequently shown to inhibit hematopoiesis in the rat (Hart et al., 1928) and in exclusively milk-fed human infants (Josephs, 1931). However, it was later discovered that copper is required for the formation of aortic elastin (O’Dell et al., 1961), and thus is of crucial importance for heart functioning. Following these findings, chronic copper deficiency, or a relative copper deficiency induced by high zinc intakes, has been suggested to be a major etiological factor in human ischemic heart disease (Klevay, 1975). Copper-deficient laboratory animals have since been found to be hypercholesterolemic and hyperuricemic and to exhibit glucose intolerance and abnormalities of cardiac function. They also show abnormal connective tissues and lipid deposits in the arteries. Deficient animals may die suddenly with a ruptured heart, caused by thinning of the aortic wall. These findings have ominous significance in the light of recent copper estimates in typical human diets in the United States; 75% of the diets examined furnished less than 2 mg of copper per day, the amount thought to be required by adults (Klevay, 1982).
Copper is widely distributed in biological tissues, where it occurs largely in the form of organic complexes, many of which are metalloproteins and function as enzymes. Copper enzymes are involved in a variety of metabolic reactions, such as the utilization of oxygen during cell respiration and energy utilization. They are also involved in the synthesis of essential compounds, such as the complex proteins of connective tissues of the skeleton and blood vessels, and in a range of neuroactive compounds concerned in nervous tissue function. It has been estimated that the adult human body contains 80 mg of copper, with a range of 50-120 mg. Tissue copper levels range from < 1 ug/g (dry weight) in many organs to > 10 ug/g (dry weight) in the liver and brain. Copper levels in the fetus and young infant differ from those in the adult. Concentrations of copper may be 6-10-fold greater in the liver of infants where, during the first 2 months of postnatal life, it presumably serves as a store of copper to tide the infant over the period when intake from breast milk is relatively small.
Copper in human blood is principally distributed between the erythrocytes and the plasma. In erythrocytes, most copper (60%) occurs as the copper-zinc metalloenzyme superoxide dismutase, the remaining 40% being loosely bound to other proteins and amino acids. Total erythrocyte copper in normal humans is around 0.9-1.0 ug/ml of packed red cells.
In plasma, about 93% of copper is firmly bound to the enzyme ceruloplasmin, believed to be involved in iron mobilization by maintaining the supply of oxidized iron transported after its incorporation into transferrin. The remaining plasma copper (7%) is bound less firmly to albumin and amino acids, and constitutes transport copper capable of reacting with receptor proteins or of diffusing, probably in the form of charged complexes, across cell membranes. Plasma or serum copper in normal humans is in the range 0.8-1.2 ug/ml and is not significantly influenced by cyclical rhythms or by feeding. The mean value for females is about 10% higher than that for males and is elevated by a factor of up to 3 in late pregnancy and in women taking estrogen-based oral contraceptives.Am J Clin Nutr 1998 May;67(5 Suppl):1041S-1045S
Copper intake and assessment of copper status.
US Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202-9034, USA.
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.
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.
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.
Decreased hepatic copper levels. A possible chemical marker for the pathogenesis of aortic aneurysms in man.
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.
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!
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
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).
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.