Copper in biology - Knowledge (XXG)

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and not generally conducted except in cases of suspected copper poisoning. Increased serum copper or ceruolplasmin levels are not reliably associated with copper toxicity as elevations in concentrations can be induced by inflammation, infection, disease, malignancies, pregnancy, and other biological stressors. Levels of copper-containing enzymes, such as cytochrome c oxidase, superoxide dismutase, and diaminase oxidase, vary not only in response to copper state but also in response to a variety of other physiological and biochemical factors and therefore are inconsistent markers of excess copper status.

685:, with a specific role in plasma copper transport Several or all of these copper-binding molecules may participate in serum copper transport. Copper from portal circulation is primarily taken up by the liver. Once in the liver, copper is either incorporated into copper-requiring proteins, which are subsequently secreted into the blood. Most of the copper (70 – 95%) excreted by the liver is incorporated into ceruloplasmin, the main copper carrier in blood. Copper is transported to extra-hepatic tissues by ceruloplasmin, albumin and amino acids, or excreted into the 1419:(which picks up and binds copper and enables patients to excrete excess copper accumulated in the liver), therapy with zinc sulfate or zinc acetate, and restrictive dietary metal intake, such as the elimination of chocolate, oysters, and mushrooms. Zinc therapy is now the treatment of choice. Zinc produces a mucosal block by inducing metallothionein, which binds copper in mucosal cells until they slough off and are eliminated in the feces. and it competes with copper for absorption in the intestine by 1214:

Cu/d) developed signs suggesting copper toxicity (e.g., elevated serum copper levels, hepatomegaly). However, other co-occurring exposures to pesticidal agents or in mining and smelting may contribute to these effects. Effects of copper inhalation are being thoroughly investigated by an industry-sponsored program on workplace air and worker safety. This multi-year research effort is expected to be finalized in 2011.

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that vegetarian diets provided larger quantities of copper. Fetuses and infants of severely copper deficient women have increased risk of low birth weights, muscle weaknesses, and neurological problems. Copper deficiencies in these populations may result in anemia, bone abnormalities, impaired growth, weight gain, frequent infections (colds, flu, pneumonia), poor motor coordination, and low energy.

195: 1115:(Aβ) in the brain. There is an association between a diet rich in copper and iron together with saturated fat and Alzheimer's disease. On the other hand, studies also demonstrate potential beneficial roles of copper in treating rather than causing Alzheimer's disease. For example, copper has been shown to 1) promote the non-amyloidogenic processing of amyloid beta precursor protein ( 1299:. Mutational defects in the gene encoding the copper ATPase cause copper to remain trapped in the lining of the small intestine. Hence, copper cannot be pumped out of the intestinal cells and into the blood for transport to the liver and consequently to rest of the body. The disease therefore resembles a severe nutritional copper deficiency despite adequate ingestion of copper. 1338:

altered mice, are designed to help researchers understand the root cause of copper deficiency in Menkes disease. The genetic makeup of transgenic mice is altered in ways that help researchers garner new perspectives about copper deficiency. The research to date has been valuable: genes can be turned off gradually to explore varying degrees of deficiency.

565:, and other proteins. The majority of blood copper (or serum copper) is bound to ceruloplasmin. The proportion of ceruloplasmin-bound copper can range from 70 to 95% and differs between individuals, depending, for example, on hormonal cycle, season, and copper status. Intracellular copper is routed to sites of synthesis of copper-requiring enzymes and to 1485:

cases appear to develop in children who are exclusively breastfed or who receive only low levels of copper in water supplies. The currently prevailing hypothesis is that ICT is due to a genetic lesion resulting in impaired copper metabolism combined with high copper intake. This hypothesis was supported by the frequency of occurrence of parental

1147:) has spurred research into the molecular genetics and biology of copper homeostasis (for further information, refer to the following section on copper genetic diseases). Much attention has focused on the potential consequences of copper toxicity in normal and potentially susceptible populations. Potentially susceptible subpopulations include 1131:

fluid levels of Aβ42, a toxic peptide and biomarker of the disease. More research is needed to understand metal homeostasis disturbances in Alzheimer's disease patients and how to address these disturbances therapeutically. Since this experiment used Cu-(II)-orotate-dihydrate, it does not relate to the effects of cupric oxide in supplements.

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Upon administration with a specific copper chelator, copper complexes would be formed at a relatively high level in tumors. Copper complexes are often toxic to cells, therefore tumor cells were killed, while normal cells in the whole body remained alive for the lower level of copper. Researchers have also recently found that

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condition may develop. If too much copper is ingested, an excess condition can result. Both of these conditions, deficiency and excess, can lead to tissue injury and disease. However, due to homeostatic regulation, the human body is capable of balancing a wide range of copper intakes for the needs of healthy individuals.

908:, or rice along with legumes (beans) or small amounts of fish or meat, some fruits and vegetables, and some vegetable oil are likely to obtain adequate copper if their total food consumption is adequate in calories. In developed countries where consumption of red meat is high, copper intake may also be adequate. 4504:

Duce, James A.; Tsatsanis, Andrew; Cater, Michael A.; James, Simon A.; Robb, Elysia; Wikhe, Krutika; Leong, Su Ling; Perez, Keyla; Johanssen, Timothy; Greenough, Mark A.; Cho, Hyun-Hee; Galatis, Denise; Moir, Robert D.; Masters, Colin L.; McLean, Catriona; Tanzi, Rudolph E.; Cappai, Roberto; Barnham,

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Stern, Bonnie Ransom; Solioz, Marc; Krewski, Daniel; Aggett, Peter; Aw, Tar-Ching; Baker, Scott; Crump, Kenny; Dourson, Michael; Haber, Lynne; Hertzberg, Rick; Keen, Carl; Meek, Bette; Rudenko, Larisa; Schoeny, Rita; Slob, Wout; Starr, Tom (2007). "Copper and Human Health: Biochemistry, Genetics, and

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The trace element copper had been found promoting tumor growth. Several evidence from animal models indicates that tumors concentrate high levels of copper. Meanwhile, extra copper has been found in some human cancers. Recently, therapeutic strategies targeting copper in the tumor have been proposed.

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Wilson's disease is produced by mutational defects of a protein that transports copper from the liver to the bile for excretion. The disease involves poor incorporation of copper into ceruloplasmin and impaired biliary copper excretion and is usually induced by mutations impairing the function of the

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to the central nervous system, some of the severe neurological problems may be avoided and survival prolonged. However, Menkes disease patients retain abnormal bone and connective-tissue disorders and show mild to severe intellectual disability. Even with early diagnosis and treatment, Menkes disease

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Menkes disease, a genetic condition of copper deficiency, was first described by John Menkes in 1962. It is a rare X-linked disorder that affects approximately 1/200,000 live births, primarily boys. Livers of Menkes disease patients cannot absorb essential copper needed for patients to survive. Death

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The diseases arise from defects in two similar copper pumps, the Menkes and the Wilson Cu-ATPases. The Menkes ATPase is expressed in tissues like skin-building fibroblasts, kidneys, placenta, brain, gut and vascular system, while the Wilson ATPase is expressed mainly in the liver, but also in mammary

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No effects of copper supplementation on serum liver enzymes, biomarkers of oxidative stress, and other biochemical endpoints have been observed in healthy young human volunteers given daily doses of 6 to 10 mg/d of copper for up to 12 weeks. Infants aged 3–12 months who consumed water containing

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Full-term and premature infants are more sensitive to copper deficiency than adults. Since the fetus accumulates copper during the last 3 months of pregnancy, infants that are born prematurely have not had sufficient time to store adequate reserves of copper in their livers and therefore require more

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processes which ensure a constant and sufficient supply of the micronutrient while simultaneously avoiding excess levels. If an insufficient amount of copper is ingested for a short period of time, copper stores in the liver will be depleted. Should this depletion continue, a copper health deficiency

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A new candidate biomarker for copper excess as well as deficiency has emerged in recent years. This potential marker is a chaperone protein, which delivers copper to the antioxidant protein SOD1 (copper, zinc superoxide dismutase). It is called "copper chaperone for SOD1" (CCS), and excellent animal

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Although a number of indicators are useful in diagnosing copper deficiency, there are no reliable biomarkers of copper excess resulting from dietary intake. The most reliable indicator of excess copper status is liver copper concentration. However, measurement of this endpoint in humans is intrusive

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If insufficient quantities of copper are ingested, copper reserves in the liver will become depleted and a copper deficiency leading to disease or tissue injury (and in extreme cases, death). Toxicity from copper deficiency can be treated with a balanced diet or supplementation under the supervision

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Copper supplements can prevent copper deficiency. Copper supplements are not prescription medicines, and are available at vitamin and herb stores and grocery stores and online retailers. Different forms of copper supplementation have different absorption rates. For example, the absorption of copper

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In North America, the IOM has set the RDA for pregnancy at 1.0 mg/day and for lactation at 1.3 mg/day. The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA. PRI for pregnancy

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Araya, Magdalena; Chen, Bingheng; Klevay, Leslie M; Strain, J.J; Johnson, LuAnn; Robson, Paula; Shi, Wei; Nielsen, Forrest; Zhu, Huigang; Olivares, Manuel; Pizarro, Fernando; Haber, Lynne T (2003). "Confirmation of an acute no-observed-adverse-effect and low-observed-adverse-effect level for copper

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Some copper chelators get more effective or novel bioactivity after forming copper-chelator complexes. It was found that Cu2+ was critically needed for PDTC induced apoptosis in HL-60 cells. The copper complex of salicylaldehyde benzoylhydrazone (SBH) derivatives showed increased efficacy of growth

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Furthermore, long-term copper treatment (oral intake of 8 mg copper (Cu-(II)-orotate-dihydrate)) was excluded as a risk factor for Alzheimer's disease in a noted clinical trial on humans and a potentially beneficial role of copper in Alzheimer's disease has been demonstrated on cerebral spinal

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Research has been ongoing over the past two decades to determine whether copper is a causative or a preventive agent of Alzheimer's disease. For example, as a possible causative agent or an expression of a metal homeostasis disturbance, studies indicate that copper may play a role in increasing the

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may also be at higher risk for copper deficiency due to special needs that increase the daily requirements. Vegetarians may have decreased copper intake due to the consumption of plant foods in which copper bioavailability is low. On the other hand, Bo Lönnerdal commented that Gibson's study showed

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For full-term infants, the North American recommended safe and adequate intake is approximately 0.2 mg/day. For premature babies, it is considerably higher: 1 mg/day. The World Health Organization has recommended similar minimum adequate intakes and advises that premature infants be given

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In cases of ICC, the elevated copper intake is due to heating and/or storing milk in copper or brass vessels. ICT cases, on the other hand, are due to elevated copper concentrations in water supplies. Although exposures to elevated concentrations of copper are commonly found in both diseases, some

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Ongoing research into Menkes disease is leading to a greater understanding of copper homeostasis, the biochemical mechanisms involved in the disease, and possible ways to treat it. Investigations into the transport of copper across the blood/brain barrier, which are based on studies of genetically

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Dermal exposure has not been associated with systemic toxicity but anecdotal reports of allergic responses may be a sensitization to nickel and cross-reaction with copper or a skin irritation from copper. Workers exposed to high air levels of copper (resulting in an estimated intake of 200 mg

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There are conflicting reports on the extent of deficiency in the U.S. One review indicates approximately 25% of adolescents, adults, and people over 65, do not meet the Recommended Dietary Allowance for copper. Another source states less common: a federal survey of food consumption determined that

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Turley, Eithne; McKeown, Andrea; Bonham, Maxine P.; O'Connor, Jacqueline M.; Chopra, Mridula; Harvey, Linda J.; Majsak-Newman, Gosia; Fairweather-Tait, Susan J.; Bügel, Susanne; Sandström, Brittmarie; Rock, Edmond; Mazur, Andrzej; Rayssiguier, Yves; Strain, J.J. (2000). "Copper supplementation in

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ICT appears to be vanishing as a result of greater genetic diversity within the affected populations in conjunction with educational programs to ensure that tinned cooking utensils are used instead of copper pots and pans being directly exposed to cooked foods. The preponderance of cases of early

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It has been suggested that heterozygote carriers of the Wilson's disease gene mutation may be potentially more susceptible to elevated copper intake than the general population. A heterozygotic frequency of 1/90 people has been estimated in the overall population. However, there is no evidence to

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other than liver injury. Chronic copper poisoning leading to liver failure was reported in a young adult male with no known genetic susceptibility who consumed 30–60 mg/d of copper as a mineral supplement for 3 years. Individuals residing in U.S. households supplied with tap water containing

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Many popular vitamin supplements include copper as small inorganic molecules such as cupric oxide. These supplements can result in excess free copper in the brain as the copper can cross the blood-brain barrier directly. Normally, organic copper in food is first processed by the liver which keeps

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or iron can also affect copper absorption, reminding us of the fact that micronutrients need to be consumed as a balanced mixture. This is one reason why extreme intakes of any one single micronutrient are not advised. Individuals with chronic digestive problems may be unable to absorb sufficient

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Daily dietary standards for copper have been set by various health agencies around the world. Standards adopted by some nations recommend different copper intake levels for adults, pregnant women, infants, and children, corresponding to the varying need for copper during different stages of life.

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Episodes of acute gastrointestinal upset following single or repeated ingestion of drinking water containing elevated levels of copper (generally above 3–6 mg/L) are characterized by nausea, vomiting, and stomach irritation. These symptoms resolve when copper in the drinking water source is

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Supplementation is generally not recommended for healthy adults who consume a well-balanced diet which includes a wide range of foods. However, supplementation under the care of a physician may be necessary for premature infants or those with low birth weights, infants fed unfortified formula or

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recommends a minimal acceptable intake of approximately 1.3 mg/day. These values are considered to be adequate and safe for most of the general population. In North America, the U.S. Institute of Medicine (IOM) set the Recommended Dietary Allowance (RDA) for copper for healthy adult men and

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Various national and international organizations concerned with nutrition and health have standards for copper intake at levels judged to be adequate for maintaining good health. These standards are periodically changed and updated as new scientific data become available. The standards sometimes

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Three experimental studies were conducted that demonstrate a threshold for acute gastrointestinal upset of approximately 4–5 mg/L in healthy adults, although it is not clear from these findings whether symptoms are due to acutely irritant effects of copper and/or to metallic, bitter, salty

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are working together to define the precise copper levels that are required for essentiality, while avoiding deficient or excess copper intakes. Results from these studies are expected to be used to fine-tune governmental dietary recommendation programs which are designed to help protect public

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mechanisms which attempt to ensure a constant supply of available copper, while eliminating excess copper whenever this occurs. However, like all essential elements and nutrients, too much or too little nutritional ingestion of copper can result in a corresponding condition of copper excess or

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Copper excess is a subject of much current research. Distinctions have emerged from studies that copper excess factors are different in normal populations versus those with increased susceptibility to adverse effects and those with rare genetic diseases. This has led to statements from health

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of a doctor. On the contrary, like all substances, excess copper intake at levels far above World Health Organization limits can become toxic. Acute copper toxicity is generally associated with accidental ingestion. These symptoms abate when the high copper food source is no longer ingested.

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In many regions of the world, copper tubing that conveys drinking water can be a source of dietary copper. Copper tube can leach a small amount of copper, particularly in its first year or two of service. Afterwards, a protective surface usually forms on the inside of copper tubes that slows

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Several copper transporters have been identified that can move copper across cell membranes. Other intestinal copper transporters may exist. Intestinal copper uptake may be catalyzed by Ctr1. Ctr1 is expressed in all cell types so far investigated, including enterocytes, and it catalyzes the

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In case reports of humans intentionally or accidentally ingesting high concentrations of copper salts (doses usually not known but reported to be 20–70 grams of copper), a progression of symptoms was observed including abdominal pain, headache, nausea, dizziness, vomiting and diarrhea,

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Menkes patients exhibit severe neurological abnormalities, apparently due to the lack of several copper-dependent enzymes required for brain development, including reduced cytochrome c oxidase activity. The brittle, kinky hypopigmented hair of steely appearance is due to a deficiency in an

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In humans, the liver is the primary organ of copper-induced toxicity. Other target organs include bone and the central nervous and immune systems. Excess copper intake also induces toxicity indirectly by interacting with other nutrients. For example, excess copper intake produces anemia by

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showed promising results. Tetrathiomolybdate appears to be an excellent form of initial treatment in patients who have neurologic symptoms. In contrast to penicillamine therapy, initial treatment with tetrathiomolybdate rarely allows further, often irreversible, neurologic deterioration.

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Johnson, David K.; Murphy, Terrance B.; Rose, Norman J.; Goodwin, William H.; Pickart, Loren (1982). "Cytotoxic chelators and chelates 1. Inhibition of DNA synthesis in cultured rodent and human cells by aroylhydrazones and by a copper(II) complex of salicylaldehyde benzoyl hydrazone".

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In 1996, the International Program on Chemical Safety, a World Health Organization-associated agency, stated "there is greater risk of health effects from deficiency of copper intake than from excess copper intake". This conclusion was confirmed in recent multi-route exposure surveys.

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carriers of Wilson disease genetic defects (i.e., those having one normal and one mutated Wilson copper ATPase gene) but who do not have the disease (which requires defects in both relevant genes). However, to date, no data are available that either support or refute this hypothesis.

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Araya, Magdalena; McGoldrick, Marie Clare; Klevay, Leslie M.; Strain, J.J.; Robson, Paula; Nielsen, Forrest; Olivares, Manuel; Pizarro, Fernando; Johnson, LuAnn; Poirier, Kenneth A. (2001). "Determination of an Acute No-Observed-Adverse-Effect Level (NOAEL) for Copper in Water".

187:. The biological role for copper commenced with the appearance of oxygen in Earth's atmosphere. Several copper proteins, such as the "blue copper proteins", do not interact directly with substrates; hence they are not enzymes. These proteins relay electrons by the process called 1445:

for severe mutations (e.g., those truncating the protein) have earlier disease onset. Disease severity may also be a function of environmental factors, including the amount of copper in the diet or variability in the function of other proteins that influence copper homeostasis.

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Xia, Yong; Fan, Chuan-Dong; Zhao, Bao-Xiang; Zhao, Jing; Shin, Dong-Soo; Miao, Jun-Ying (2008). "Synthesis and structure–activity relationships of novel 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide hydrazone derivatives as potential agents against A549 lung cancer cells".

1021:, cardiovascular disease, colon cancer, and chronic conditions involving bone, connective tissue, heart and blood vessels. nervous system and immune system. Copper deficiency alters the role of other cellular constituents involved in antioxidant activities, such as iron, 644:

Some forms of copper are not soluble in stomach acids and cannot be absorbed from the stomach or small intestine. Also, some foods may contain indigestible fiber that binds with copper. High intakes of zinc can significantly decrease copper absorption. Extreme intakes of

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associated with different types of cancers has been investigated. A copper chelator, tetrathiomolybdate, which depletes copper stores in the body, is under investigation as an anti-angiogenic agent in pilot and clinical trials. The drug may inhibit tumor angiogenesis in

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taste. In an experimental study with healthy adults, the average taste threshold for copper sulfate and chloride in tap water, deionized water, or mineral water was 2.5–3.5 mg/L. This is just below the experimental threshold for acute gastrointestinal upset.

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are not well understood, research indicates that, among several other key observations, iron, aluminum, and copper accumulate in the brains of Alzheimer's patients. However, it is not yet known whether this accumulation is a cause or a consequence of the disease.

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Bile is the major pathway for the excretion of copper and is vitally important in the control of liver copper levels. Most fecal copper results from biliary excretion; the remainder is derived from unabsorbed copper and copper from desquamated mucosal cells.

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organizations that could be confusing to the uninformed. For example, according to a U.S. Institute of Medicine report, the intake levels of copper for a significant percentage of the population are lower than recommended levels. On the other hand, the U.S.

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Ainscough, Eric W; Brodie, Andrew M; Denny, William A; Finlay, Graeme J; Gothe, Scott A; Ranford, John D (1999). "Cytotoxicity of salicylaldehyde benzoylhydrazone analogs and their transition metal complexes: quantitative structure–activity relationships".

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Copper concentrations in soil are not uniform around the world. In many areas, soils have insufficient levels of copper. Soils that are naturally deficient in copper often require copper supplements before agricultural crops, such as cereals, can be grown.

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As a natural element in the Earth's crust, copper exists in most of the world's surface water and groundwater, although the actual concentration of copper in natural waters varies geographically. Drinking water can comprise 20–25% of dietary copper.

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Copper deficiencies in soil can lead to crop failure. Copper deficiency is a major issue in global food production, resulting in losses in yield and reduced quality of output. Nitrogen fertilizers can worsen copper deficiency in agricultural soils.

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Salicylaldehyde pyrazole hydrazone (SPH) derivatives were found to inhibit the growth of A549 lung carcinoma cells. SPH has identical ligands for Cu as SBH. The Cu-SPH complex was found to induce apoptosis in A549, H322 and H1299 lung cancer cells.

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Lewis, Al, 2009, The Hygienic Benefits of Antimicrobial Copper Alloy Surfaces in Healthcare Settings, a compilation of information and data for the International Copper Association Inc., 2009, available from International Copper Association Inc.,

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levels, and other biochemical endpoints.) Serum ceruloplasmin was transiently elevated in the exposed infant group at 9 months and similar to controls at 12 months, suggesting homeostatic adaptation and/or maturation of the homeostatic response.

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spurts, are at elevated risk for copper deficiencies. Fortunately, diagnosis of copper deficiency in children is clear and reliable once the condition is suspected. Supplements under a physician's supervision usually facilitate a full recovery.

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Fan, Chuandong; Zhao, Jing; Zhao, Baoxiang; Zhang, Shangli; Miao, Junying (2009). "Novel Complex of Copper and a Salicylaldehyde Pyrazole Hydrazone Derivative Induces Apoptosis through Up-Regulating Integrin β4 in Vascular Endothelial Cells".

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The disease, which affects about 1/30,000 infants of both genders, may become clinically evident at any time from infancy through early adulthood. The age of onset of Wilson's disease ranges from 3 to 50 years of age. Initial symptoms include

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intake, pregnant women prescribed iron supplements to treat anemia or zinc supplements to treat colds should consult physicians to be sure that the prenatal supplements they may be taking also have nutritionally-significant amounts of copper.

381:. Copper is an integral part of the antioxidant enzyme copper-zinc superoxide dismutase, and has a role in iron homeostasis as a cofactor in ceruloplasmin. A list of some key copper-containing enzymes and their functions is summarized below: 1860:

Schneider, Lisa K.; Wüst, Anja; Pomowski, Anja; Zhang, Lin; Einsle, Oliver (2014). "No Laughing Matter: The Unmaking of the Greenhouse Gas Dinitrogen Monoxide by Nitrous Oxide Reductase". In Peter M.H. Kroneck; Martha E. Sosa Torres (eds.).

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processes. Also, in humans, copper helps maintain the nervous system, immune system, brain development, and activates genes, as well as assisting in the production of connective tissues, blood vessels, and energy. The human body has complex

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When newborn babies are breastfed, the babies' livers and the mothers' breast milk provide sufficient quantities of copper for the first 4–6 months of life. When babies are weaned, a balanced diet should provide adequate sources of copper.

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Pickart, Loren; Goodwin, William H.; Burgua, William; Murphy, Terrance B.; Johnson, David K. (1983). "Inhibition of the growth of cultured cells and an implanted fibrosarcoma by aroylhydrazone analogs of the Gly-His-Lys-Cu (II) complex".

573:. Another set of these transporters carries copper into subcellular compartments. Certain mechanisms exist to release copper from the cell. Specialized transporters return excess unstored copper to the liver for additional storage and/or 1541:

SBHs can react with many kinds of transition metal cations and thereby forming a number of complexes. Copper-SBH complexes were more cytotoxic than complexes of other transitional metals (Cu > Ni > Zn = Mn > Fe = Cr > Co) in

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Fan, ChuanDong; Su, Hua; Zhao, Jing; Zhao, BaoXiang; Zhang, ShangLi; Miao, JunYing (2010). "A novel copper complex of salicylaldehyde pyrazole hydrazone induces apoptosis through up-regulating integrin β4 in H322 lung carcinoma cells".

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O'Connor, J.M.; Bonham, M.P.; Turley, E.; McKeown, A.; McKelvey-Martin, V.J.; Gilmore, W.S.; Strain, J.J. (2003). "Copper Supplementation Has No Effect on Markers of DNA Damage and Liver Function in Healthy Adults (FOODCUE Project)".

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concluded in its report Copper in Drinking Water that there is concern for copper toxicity in susceptible populations and recommended that additional research be conducted to identify and characterize copper-sensitive populations.

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Symptoms of the disease include coarse, brittle, depigmented hair and other neonatal problems, including the inability to control body temperature, intellectual disability, skeletal defects, and abnormal connective tissue growth.

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childhood cirrhosis identified in Germany over a period of 10 years were not associated with either external sources of copper or with elevated hepatic metal concentrations Only occasional spontaneous cases of ICT arise today.

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support this speculation. Further, a review of the data on single-allelic autosomal recessive diseases in humans does not suggest that heterozygote carriers are likely to be adversely affected by their altered genetic status.

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These diseases are inherited and cannot be acquired. Adjusting copper levels in the diet or drinking water will not cure these conditions (although therapies are available to manage symptoms of genetic copper excess disease).

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Ferenci, Peter; Caca, Karel; Loudianos, Georgios; Mieli-Vergani, Georgina; Tanner, Stuart; Sternlieb, Irmin; Schilsky, Michael; Cox, Diane; Berr, Frieder (2003). "Diagnosis and phenotypic classification of Wilson disease".

1639:, a sheep disease associated with copper deficiency, imposes enormous costs on farmers worldwide, particularly in Europe, North America, and many tropical countries. For pigs, copper has been shown to be a growth promoter. 1546:, an established human T-cell leukemia cell line. SBHs, especially their copper complexes appeared to be potent inhibitors of DNA synthesis and cell growth in several human cancer cell lines, and rodent cancer cell lines. 999:

for women and men over the age of 19, average consumption from foods and beverages was 1.11 and 1.54 mg/day, respectively. For women, 10% consumed less than the Estimated Average Requirement; for men, fewer than 3%.

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Singh, Itender; Sagare, Abhay P.; Coma, Mireia; Perlmutter, David; Gelein, Robert; Bell, Robert D.; Deane, Richard J.; Zhong, Elaine; Parisi, Margaret; Ciszewski, Joseph; Kasper, R. Tristan; Deane, Rashid (2007-11-03).

1462:(ICC), endemic Tyrolean copper toxicosis (ETIC), and idiopathic copper toxicosis (ICT), also known as non-Indian childhood cirrhosis. ICT is a genetic disease recognized in the early twentieth century primarily in the 6976:

Koh, L.L; Kon, O.L; Loh, K.W; Long, Y.C; Ranford, J.D; Tan, A.L.C; Tjan, Y.Y (1998). "Complexes of salicylaldehyde acylhydrazones: Cytotoxicity, QSAR and crystal structure of the sterically hindered t-butyl dimer".

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Almost always, death occurs if the disease is untreated. Fortunately, identification of the mutations in the Wilson ATPase gene underlying most cases of Wilson's disease has made DNA testing for diagnosis possible.

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U.S. National Research Council. 2000. Copper in drinking water. Committee on Copper in Drinking Water, Board on Environmental Studies and Toxicology, Commission of Life Sciences. Washington, DC: National Academy

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Kessler, Holger; Pajonk, Frank-Gerald; Bach, Daniela; Schneider-Axmann, Thomas; Falkai, Peter; Herrmann, Wolfgang; Multhaup, Gerd; Wiltfang, Jens; Schäfer, Stephanie; Wirths, Oliver; Bayer, Thomas A. (2008).

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In mammals copper is absorbed in the stomach and small intestine, although there appear to be differences among species with respect to the site of maximal absorption. Copper is absorbed from the stomach and

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for the production of specific proteins involved in the absorption and distribution of copper. When these proteins are dysfunctional, copper either builds up in the liver or the body fails to absorb copper.

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in rats and from the lower small intestine in hamsters. The site of maximal copper absorption is not known for humans, but is assumed to be the stomach and upper intestine because of the rapid appearance of

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The transport and metabolism of copper in living organisms is currently the subject of much active research. Copper transport at the cellular level involves the movement of extracellular copper across the

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Wilson copper ATPase. These genetic mutations produce copper toxicosis due to excess copper accumulation, predominantly in the liver and brain and, to a lesser extent, in kidneys, eyes, and other organs.

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The study of genetic copper metabolism diseases and their associated proteins are enabling scientists to understand how human bodies use copper and why it is important as an essential micronutrient.

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Lu, Yi-Heng; Lu, Yu-Wei; Wu, Cheng-Li; Shao, Qun; Chen, Xiao-Ling; Bimbong, Rosa Ngo Biboum (2006). "UV–visible spectroscopic study of the salicyladehyde benzoylhydrazone and its cobalt complexes".

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Denoyer, Delphine; Clatworthy, Sharnel A.S.; Cater, Michael A. (2018). "Chapter 16. Copper Complexes in Cancer Therapy". In Sigel, Astrid; Sigel, Helmut; Freisinger, Eva; Sigel, Roland K.O. (eds.).

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Spinazzi, Marco; De Lazzari, Franca; Tavolato, Bruno; Angelini, Corrado; Manara, Renzo; Armani, Mario (2007). "Myelo-optico-neuropathy in copper deficiency occurring after partial gastrectomy".

1526:. The copper complex of a synthetic salicylaldehyde pyrazole hydrazone (SPH) derivative induced human umbilical endothelial cell (HUVEC) apoptosis and showed anti-angiogenesis effect in vitro. 960:

or on diets), 3) patients taking medications that block the body's use of copper, 4) anemia patients who are treated with iron supplements, 5) anyone taking zinc supplements, and 6) those with

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Brewer, George J.; Dick, Robert D.; Johnson, Virginia D.; Brunberg, James A.; Kluin, Karen J.; Fink, John K. (1998). "Treatment of Wilson's disease with zinc: XV long-term follow-up studies".

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Kessler, Holger; Bayer, Thomas A.; Bach, Daniela; Schneider-Axmann, Thomas; Supprian, Tillmann; Herrmann, Wolfgang; Haber, Manfred; Multhaup, Gerd; Falkai, Peter; Pajonk, Frank-Gerald (2008).

2987:

Greger, JL; Mulvaney, Jude (1985). "Absorption and Tissue Distribution of Zinc, Iron and Copper by Rats Fed Diets Containing Lactalbumin, Soy and Supplemental Sulfur-Containing Amino Acids".

1364:) recessive genetic disorder of copper transport that causes an excess of copper to build up in the liver. This results in liver toxicity, among other symptoms. The disease is now treatable. 944:

cow's milk during the first year of life, and malnourished young children. Physicians may consider copper supplementation for 1) illnesses that reduce digestion (e.g., children with frequent

2694:

Strickland, GT; Beckner, WM; Leu, ML; O'Reilly, S (1972). "Turnover studies of copper in homozygotes and heterozygotes for Wilson's disease and controls: isotope tracer studies with 67 Cu".

6789:

Chen, Jie; Du, Changsheng; Kang, Jiuhong; Wang, Jianmin (2008). "Cu2+ is required for pyrrolidine dithiocarbamate to inhibit histone acetylation and induce human leukemia cell apoptosis".

1404:, a rusty brown discoloration at the outer rims of the iris due to copper deposition noted in 90% of patients, become evident as copper begins to accumulate and affect the nervous system. 3302:

Bligh, S.W.Annie; Boyle, Helena A.; Mcewen, Andrew B.; Sadler, Peter J.; Woodham, Robert H. (1992). "1H NMR studies of reactions of copper complexes with human blood plasma and urine".

577:

excretion. These mechanisms ensure that free unbound toxic ionic copper is unlikely to exist in the majority of the population (i.e., those without genetic copper metabolism defects).

76:

have diverse roles in biological electron transport and oxygen transportation, processes that exploit the easy interconversion of Cu(I) and Cu(II). Copper is essential in the aerobic

3823:

Stern, Bonnie Ransom (2007). "U-Shaped Dose-Response Curve for Risk Assessment of Essential Trace Elements: Copper as a Case Study". In Robson, Mark G.; Toscano, William A. (eds.).

2659:

Strickland, GT; Beckner, WM; Leu, ML (1972). "Absorption of copper in homozygotes and heterozygotes for Wilson's disease and controls: isotope tracer studies with 67 Cu and 64 Cu".

6039:

Brewer, George J.; Johnson, Virginia; Dick, Robert D.; Kluin, Karen J.; Fink, John K.; Brunberg, James A. (1996). "Treatment of Wilson Disease With Ammonium Tetrathiomolybdate".

5008:

Brewer, George J. (2000). "Editorial: Is heterozygosity for a Wilson's disease gene defect an important underlying cause of infantile and childhood copper toxicosis syndromes?".

279:

Copper's essentiality was first discovered in 1928, when it was demonstrated that rats fed a copper-deficient milk diet were unable to produce sufficient red blood cells. The

6341:"A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil, and leucovorin for metastatic colorectal cancer" 6275:

Dieter, HH; Schimmelpfennig, W; Meyer, E; Tabert, M (1999). "Early childhood cirrhoses (ECC) in Germany between 1982 and 1994 with special consideration of copper etiology".

1534:, a copper-induced mechanism of mitochondrial-related cell death, has been implicated as a breakthrough in the treatment of cancer and has become a new treatment strategy. 1193:

The long-term toxicity of copper has not been well studied in humans, but it is infrequent in normal populations that do not have a hereditary defect in copper homeostasis.

923:, as the copper helps stabilise bonds in the white as it is beaten and whipped. Small amounts of copper may leach from the bowl during the process and enter the egg white. 3741:

Sadhra, Steven S.; Wheatley, Andrew D.; Cross, Hilary J. (2007). "Dietary exposure to copper in the European Union and its assessment for EU regulatory risk assessment".

4965: 4058:

Goodman, B P; Bosch, E P; Ross, M A; Hoffman-Snyder, C; Dodick, D D; Smith, B E (2009). "Clinical and electrodiagnostic findings in copper deficiency myeloneuropathy".

3998: 769:

Hepatic uptake, sequestration and excretion effect homeostasis; glutathione-dependent uptake of copper; binding to metallothionein; and lysosomal excretion of copper

1284:

usually occurs in early childhood: most affected individuals die before the age of 10 years, although several patients have survived into their teens and early 20s.

1205:

2 mg Cu/L for 9 months did not differ from a concurrent control group in gastrointestinal tract (GIT) symptoms, growth rate, morbidity, serum liver enzyme and

268:

Copper is an essential trace element (i.e., micronutrient) that is required for plant, animal, and human health. It is also required for the normal functioning of

2288:

Ralph, A., and McArdle, H. J. 2001. Copper metabolism and requirements in the pregnant mother, her fetus, and children. New York: International Copper Association

7618: 3220:"Characterization of mouse embryonic cells deficient in the ctr1 high affinity copper transporter: Identification of a Ctr1-independent copper transport system" 6660: 365:

are known at the molecular level. Copper's essentiality is due to its ability to act as an electron donor or acceptor as its oxidation state fluxes between Cu(

3604:

Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc

1002:

Acquired copper deficiency has recently been implicated in adult-onset progressive myeloneuropathy and in the development of severe blood disorders including

6084:"High prevalence of the very rare wilson disease gene mutation Leu708Pro in the Island of Gran Canaria (Canary Islands, Spain): A genetic and clinical study" 5318:

Buchanan, Sharunda D.; Diseker, Robert A.; Sinks, Thomas; Olson, David R.; Daniel, Jack; Flodman, Thomas (1999). "Copper in Drinking Water, Nebraska, 1994".

3795:"Copper-2 Ingestion, Plus Increased Meat Eating Leading to Increased Copper Absorption, Are Major Factors Behind the Current Epidemic of Alzheimer's Disease" 1151:

patients and individuals with chronic liver disease. Recently, concern was expressed about the potential sensitivity to liver disease of individuals who are

240:, which are the focus of intense international research activity, has shed insight into how human bodies use copper, and why it is important as an essential 7200: 1029:

is elevated. A marginal, i.e., 'mild' copper deficiency, believed to be more widespread than previously thought, can impair human health in subtle ways.

1600:

The world's two most important food crops, rice and wheat, are highly susceptible to copper deficiency. So are several other important foods, including

1584:

In addition to being an essential nutrient for humans, copper is vital for the health of animals and plants and plays an important role in agriculture.

657:

Excess copper (as well as other heavy metal ions like zinc or cadmium) may be bound by metallothionein and sequestered within intracellular vesicles of

244:. The studies have also resulted in successful treatments for genetic copper excess conditions, empowering patients whose lives were once jeopardized. 2895:

Cousins, Robert J (1985). "Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin".

377:(i.e., oxidation-reduction) reactions in essential metabolic processes such as mitochondrial respiration, synthesis of melanin, and cross-linking of 4554: 1036:, low-birth-weight infants, infants fed cow's milk instead of breast milk or fortified formula, pregnant and lactating mothers, patients receiving 7385: 6683:"Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells" 1065: 5117:

Pizarro, F.; Olivares, M.; Gidi, V.; Araya, M. (1999). "The Gastrointestinal Tract and Acute Effects of Copper in Drinking Water and Beverages".

3024:"Fructose metabolizing enzymes in the rat liver and metabolic parameters: Interactions between dietary copper, type of carbohydrates, and gender" 5291:

O'Donohue, J; Reid, M; Varghese, A; Portmann, B; Williams, R (1999). "A case of adult chronic copper self-intoxication resulting in cirrhosis".

3417:

Cousins, RJ (1985). "Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin".

1411:

If diagnosed and treated early enough, patients with Wilson's disease may live long and productive lives. Wilson's disease is managed by copper

4465:

Bartzokis, George; Sultzer, David; Cummings, Jeffrey; Holt, Lori E.; Hance, Darwood B.; Henderson, Victor W.; Mintz, Jim (February 28, 2000).

7167: 4466: 3832: 3619: 2131: 1987: 1919: 1878: 1742: 1722: 1119:), thereby lowering amyloid beta (Aβ) production in cell culture systems 2) increase lifetime and decrease soluble amyloid production in APP 6180:

Wijmenga, C; Müller, T; Murli, I S; Brunt, T; Feichtinger, H; Schönitzer, D; Houwen, R H J; Müller, W; Sandkuijl, L A; Pearson, P L (1998).

6131:

Ha-Hao, Duc; Hefter, Harald; Stremmel, Wolfgang; Castañeda-Guillot, Carlos; Hernández, Ana Hernández; Cox, Diane W; Auburger, Georg (1998).

2229:

Stern, Bonnie Ransom (2010). "Essentiality and Toxicity in Copper Health Risk Assessment: Overview, Update and Regulatory Considerations".

1573: 1275:

glands and possibly in other specialized tissues. This knowledge is leading scientists towards possible cures for genetic copper diseases.

1044:, individuals with chronic diseases that result in low food intake, such as alcoholics, and persons with eating disorders. The elderly and 6604:

Díez, M.; Arroyo, M.; Cerdàn, F.J.; Muñoz, M.; Martin, M.A.; Balibrea, J.L. (1989). "Serum and Tissue Trace Metal Levels in Lung Cancer".

3687:

Georgopoulos, PG; Roy, A; Yonone-Lioy, MJ; Opiekun, RE; Lioy, PJ (2001). "Environmental copper: its dynamics and human exposure issues".

1345:

in the cells of a Menkes patient can be repaired. In time, the procedures needed to repair damaged genes in the human body may be found.

6082:

Garciavillarreal, L; Daniels, S; Shaw, S; Cotton, D; Galvin, M; Geskes, J; Bauer, P; Sierrahernandez, A; Buckler, A; Tugores, A (2000).

3671:"Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies" 1623:

The most effective strategy to counter copper deficiency is to supplement the soil with copper, usually in the form of copper sulfate.

6339:

Gartner, Elaina M.; Griffith, Kent A.; Pan, Quintin; Brewer, George J.; Henja, Gwen F.; Merajver, Sofia D.; Zalupski, Mark M. (2009).

7084:

Winner, Brooke; Peipert, Jeffrey F.; Zhao, Qiuhong; Buckel, Christina; Madden, Tessa; Allsworth, Jenifer E.; Secura, Gina M. (2012).

5605: 3473: 2524:

Stern, B.R. et al., 2007, Copper And Human Health: Biochemistry, Genetics, And Strategies for Modeling Dose-Response Relationships,

2328: 1806: 1769: 1489:

in most of these cases, which is absent in areas with elevated copper in drinking water and in which these syndromes do not occur.

1432: 1083:

of copper may be responsible for some of its toxicity in excess ingestion cases. At high concentrations copper is known to produce

5764: 5517:"Copper in Infant Nutrition: Safety of World Health Organization Provisional Guideline Value for Copper Content of Drinking Water" 5355:"Gastrointestinal symptoms and blood indicators of copper load in apparently healthy adults undergoing controlled copper exposure" 2114:

Vest, Katherine E.; Hashemi, Hayaa F.; Cobine, Paul A. (2013). "The Copper Metallome in Eukaryotic Cells". In Banci, Lucia (ed.).

1705:

Vest, Katherine E.; Hashemi, Hayaa F.; Cobine, Paul A. (2013). "The Copper Metallome in Eukaryotic Cells". In Banci, Lucia (ed.).

7085: 7809: 7540: 4506: 3651: 3995: 336:

Most well-nourished children have adequate intakes of copper. Health-compromised children, including those who are premature,

7704: 7193: 856: 183:. Instead of reversibly binding oxygen, these proteins hydroxylate substrates, illustrated by their role in the formation of 6734:"A cuproptosis-associated long non-coding RNA signature for the prognosis and immunotherapy of lung squamous cell carcinoma" 217:

Chemical compounds which were developed for treatment of Wilson's disease have been investigated for use in cancer therapy.

7982: 5021: 3122: 1111:

growth of protein clumps in Alzheimer's disease brains, possibly by damaging a molecule that removes the toxic buildup of

598:

Absorption of copper ranges from 15 to 97%, depending on copper content, form of the copper, and composition of the diet.

7133: 3922: 855:(ULs) for vitamins and minerals when evidence is sufficient. In the case of copper, the UL is set at 10 mg/day. The 7604: 2476:"Maintaining copper homeostasis: regulation of copper-trafficking proteins in response to copper deficiency or overload" 1431:

Over 100 different genetic defects leading to Wilson's disease have been described and are available on the Internet at

1400:. A peculiar type of tremor in the upper extremities, slowness of movement, and changes in temperament become apparent. 852: 7611: 5480:

humans does not affect the susceptibility of low density lipoprotein to in vitro induced oxidation (FOODCUE project)".

4963:

Brewer, George J. (2012). "Copper toxicity in Alzheimer's disease: Cognitive loss from ingestion of inorganic copper".

4866:"Intake of copper has no effect on cognition in patients with mild Alzheimer's disease: a pilot phase 2 clinical trial" 4101:

Kumar, Neeraj; Elliott, Michelle A.; Hoyer, James D.; Harper, Charles M.; Ahlskog, J. Eric; Phyliky, Robert L. (2005).

6304: 3670: 2930:

Oestreicher, Paul; Cousins, Robert J (1985). "Copper and Zinc Absorption in the Rat: Mechanism of Mutual Antagonism".

4916:"Effect of copper intake on CSF parameters in patients with mild Alzheimer's disease: a pilot phase 2 clinical trial" 4664: 4629:

Llanos, Roxana M.; Mercer, Julian F.B. (2002). "The Molecular Basis of Copper Homeostasis Copper-Related Disorders".

813:

Functional defects, such as lysyl oxidase and superoxide dismutase activities reduced; impaired substrate metabolism

641:) inhibit dietary absorption of copper. Furthermore, low levels of dietary copper appear to inhibit iron absorption. 3148:

Lutsenko, Svetlana; Kaplan, Jack H. (1995). "Organization of P-type ATPases: significance of structural diversity".

8007: 1459: 1248: 1037: 5353:

Araya, Magdalena; Olivares, Manuel; Pizarro, Fernando; González, Mauricio; Speisky, Hernán; Uauy, Ricardo (2003).

1441:). Even in individuals who are homozygous for a mutation, onset and severity of the disease may vary. Individuals 8028: 7862: 7186: 2013:"Imaging Cu2+ binding to charged phospholipid membranes by high-throughput second harmonic wide-field microscopy" 1393: 1116: 847: 437: 93: 3267:

Marceau, N; Aspin, N; Sass-Kortsak, A (1970). "Absorption of copper 64 from gastrointestinal tract of the rat".

2731:"Copper absorption and retention in young men at three levels of dietary copper by use of the stable isotope Cu" 1801:

S.J. Lippard, J.M. Berg "Principles of bioinorganic chemistry" University Science Books: Mill Valley, CA; 1994.

900:

In both developed and developing countries, adults, young children, and adolescents who consume diets of grain,

7576: 3183:

Solioz, Marc; Vulpe, Christopher (1996). "CPx-type ATPases: a class of P-type ATPases that pump heavy metals".

2860:

Baker, David H. (1999). "Cupric Oxide Should Not be Used as a Copper Supplement for Either Animals or Humans".

1507: 1003: 601:

Various factors influence copper absorption. For example, copper absorption is enhanced by ingestion of animal

3947:

Georgopoulos, Panos G; Wang, Sheng Wei; Georgopoulos, Ioannis G; Yonone-Lioy, Mary Jean; Lioy, Paul J (2006).

1296: 4507:"Iron-Export Ferroxidase Activity of β-Amyloid Precursor Protein Is Inhibited by Zinc in Alzheimer's Disease" 7581: 6133:"His1069Gln and six novel Wilson disease mutations: analysis of relevance for early diagnosis and phenotype" 4382:

Kelsay, JL (1987). "Effects of fiber, phytic acid, and oxalic acid in the diet on mineral bioavailability".

1627:

is also used in some areas to replenish agricultural land with organics and trace metals, including copper.

1519: 1401: 557:

and into the cell by specialized transporters. In the bloodstream, copper is carried throughout the body by

256: 211: 3105: 7874: 7443: 7213: 5252:"Limits of metabolic tolerance to copper and biological basis for present recommendations and regulations" 1658: 1481:

and presentation. Both appear to have a genetic component and a contribution from elevated copper intake.

1438: 1397: 1288: 1103: 937: 5637:

Kaler, Stephen G. (1998). "Metabolic and molecular bases of Menkes disease and occipital horn syndrome".

4558: 7814: 7689: 7558: 7349: 7313: 7230: 4142:

Cordano, A (1978). "Copper deficiency in clinical medicine". In Hambidge, K. M.; Nichols, B. L. (eds.).

2968:

Lee, D; Schroeder, J; Gordon, DT (January 1984). "The effect of phytic acid on copper bioavailability".

2629: 1124: 6302:

Goodman, Vicki; Brewer, George; Merajver, Sofia (2005). "Control of Copper Status for Cancer Therapy".

5683:

Kaler, Stephen G. (1996). "Menkes disease mutations and response to early copper histidine treatment".

171:). Because hemocyanin is blue, these organisms have blue blood rather than the red blood of iron-based 3876:

McGee, Harold J.; Long, Sharon R.; Briggs, Winslow R. (1984). "Why whip egg whites in copper bowls?".

3564:

WHO/FAO/IAEA, (1996), Trace Elements in Human Nutrition and Health. World Health Organization, Geneva)

1143:

The identification of genetic disorders of copper metabolism leading to severe copper toxicity (i.e.,

7987: 7699: 7659: 7649: 7644: 7550: 7532: 7292: 7287: 7282: 6942: 4974: 4696: 4271:

Salem, Harry; Green, Sidney; Bigelow, Sanford; Borzelleca, Joseph; Baskin, Steven (1992). "Preface".

3885: 3750: 3696: 3376:

Linder, Maria C; Wooten, Lisa; Cerveza, Philip; Cotton, Steven; Shulze, Roman; Lomeli, Norma (1998).

2813:"Nutrient Balance Studies in Premature Infants Fed Premature Formula or Fortified Preterm Human Milk" 2238: 2174: 2020: 1018: 519: 427: 105: 89: 77: 6515: 353:

Copper is absorbed, transported, distributed, stored, and excreted in the body according to complex

302:

period. These supplies are necessary to carry out such metabolic functions as cellular respiration,

7857: 7824: 7784: 7684: 4685:"Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance" 4195:

Klevay, LM (1980). "The influence of copper and zinc on the occurrence of ischemic heart disease".

2355:

Camakaris, J.; Voskoboinik, I.; Mercer, J.F. (1999). "Molecular Mechanisms of Copper Homeostasis".

1569: 1353: 1080: 4684: 2540:"Absorption of Cu64, Zn65, Mo99, and Fe59 from ligated segments of the rat gastrointestinal tract" 7992: 7951: 7776: 7654: 7568: 7115: 6586: 6543: 6460: 6211: 6162: 6113: 6064: 5935: 5708: 5662: 5546: 5420: 5142: 4945: 4799: 4781: 4604: 4253: 4083: 4040: 3978: 3901: 3720: 3633: 3249: 2842: 2262: 2198: 1937: 1653: 1424: 472: 199: 113: 6641:"Diagnostic and prognostic significance of serum and tissue trace elements in breast malignancy" 6516:"Copper Control as an Antiangiogenic Anticancer Therapy: Lessons from Treating Wilson's Disease" 6390:"A Phase II Trial of Tetrathiomolybdate After Surgery for Malignant Mesothelioma: Final Results" 1757: 1749: 689:. By regulating copper release, the liver exerts homeostatic control over extra-hepatic copper. 3599: 298:'s liver stores fall rapidly after birth, supplying copper to the fast-growing body during the 7961: 7931: 7899: 7894: 7879: 7852: 7799: 7789: 7694: 7669: 7639: 7514: 7163: 7107: 7066: 7030: 6994: 6958: 6915: 6876: 6806: 6771: 6753: 6733: 6714: 6652: 6621: 6578: 6535: 6496: 6452: 6411: 6370: 6321: 6284: 6257: 6203: 6154: 6105: 6056: 6021: 5986: 5927: 5888: 5847: 5806: 5743: 5700: 5654: 5587: 5538: 5497: 5461: 5412: 5376: 5335: 5300: 5273: 5232: 5191: 5134: 5099: 5063: 4990: 4937: 4895: 4846: 4773: 4765: 4724: 4646: 4596: 4536: 4486: 4447: 4391: 4364: 4323: 4288: 4245: 4204: 4177: 4124: 4075: 4032: 3970: 3828: 3766: 3712: 3625: 3615: 3547: 3520: 3479: 3469: 3434: 3399: 3358: 3319: 3284: 3241: 3200: 3165: 3087: 3043: 3004: 2947: 2912: 2877: 2834: 2793: 2752: 2711: 2676: 2641: 2610: 2561: 2497: 2456: 2412: 2372: 2334: 2324: 2254: 2190: 2137: 2127: 2038: 1993: 1983: 1967: 1925: 1915: 1884: 1874: 1842: 1802: 1753: 1745: 1738: 1728: 1718: 1515: 1412: 990:

The health conditions of non-genetic copper deficiency and copper excess are described below.

977: 570: 504: 468: 225: 188: 117: 3783:

World Health Organization. 1998. Copper. Environmental Health Criteria 200. Geneva: IPCS, WHO

7926: 7884: 7430: 7221: 7097: 7058: 7022: 6986: 6950: 6907: 6868: 6837: 6798: 6761: 6745: 6704: 6694: 6681:

Daniel, Kenyon G; Chen, Di; Orlu, Shirley; Cui, Qiuzhi; Miller, Fred R; Dou, Q Ping (2005).

6613: 6570: 6527: 6488: 6442: 6401: 6388:

Pass, Harvey I.; Brewer, George J.; Dick, Robert; Carbone, Michele; Merajver, Sofia (2008).

6360: 6352: 6313: 6247: 6193: 6144: 6095: 6048: 6013: 5976: 5966: 5919: 5878: 5837: 5798: 5735: 5692: 5646: 5577: 5528: 5489: 5451: 5404: 5366: 5327: 5263: 5222: 5181: 5173: 5126: 5091: 5055: 5025: 5017: 4982: 4927: 4885: 4877: 4836: 4826: 4755: 4714: 4704: 4638: 4588: 4526: 4518: 4478: 4437: 4354: 4315: 4280: 4235: 4169: 4114: 4067: 4024: 3960: 3893: 3849: 3758: 3704: 3607: 3510: 3461: 3426: 3389: 3350: 3311: 3276: 3231: 3192: 3157: 3077: 3035: 2996: 2939: 2904: 2869: 2824: 2783: 2742: 2703: 2668: 2600: 2592: 2551: 2487: 2446: 2404: 2364: 2246: 2182: 2119: 2069: 2028: 1975: 1907: 1866: 1832: 1710: 1251:) are associated with the improper use of copper in the body. All of these diseases involve 1170: 1084: 626: 614: 269: 237: 6431:"Cancer Therapy With Tetrathiomolybdate: Antiangiogenesis by Lowering Body Copper—A Review" 5515:

Olivares, Manuel; Pizarro, Fernando; Speisky, Hernán; Lönnerdal, Bo; Uauy, Ricardo (1998).

4813:

Kaden, Daniela; Bush, Ashley I.; Danzeisen, Ruth; Bayer, Thomas A.; Multhaup, Gerd (2011).

432:

Terminal oxidase enzyme in mitochondrial respiratory chain, involved in electron transport

7997: 7889: 7829: 7794: 7679: 7664: 7522: 7468: 7304: 6561:

Lowndes, Sarah A.; Harris, Adrian L. (2005). "The Role of Copper in Tumour Angiogenesis".

5609: 4744:"Copper and iron in Alzheimer's disease: a systematic review and its dietary implications" 4002: 3338: 1949: 1648: 1559: 1463: 1416: 1326: 1316: 1287:

The protein produced by the Menkes gene is responsible for transporting copper across the

1197: 1120: 1058: 957: 745:

Gastrointestinal metallothionein induced (possible differing effects of acute and chronic

341: 333:

are depleted in copper. Most formulas are now fortified with copper to prevent depletion.

307: 229: 73: 42: 6052: 4505:

Kevin J.; Ciccotosto, Giuseppe D.; Rogers, Jack T.; Bush, Ashley I. (September 8, 2010).

1635:

In livestock, cattle and sheep commonly show indications when they are copper deficient.

1458:

Other diseases in which abnormalities in copper metabolism appear to be involved include

283:

was corrected by the addition of copper-containing ash from vegetable or animal sources.

6946: 6766: 6732:

Hou, Chunlan; Wu, Xiuping; Li, Caoyang; Wang, Chao; Liu, Jinbo; Luo, Qing (2023-01-15).

4978: 4700: 4467:"In Vivo Evaluation of Brain Iron in Alzheimer Disease Using Magnetic Resonance Imaging" 4173: 3889: 3754: 3700: 2242: 2178: 2058:"Iron nutrition. VII: Copper is a supplement to iron for hemoglobin building in the rat" 2024: 1777: 872:

formula supplemented with extra copper to prevent the development of copper deficiency.

55:

deficiency in the body, each of which has its own unique set of adverse health effects.

7941: 7936: 7921: 7909: 7250: 6709: 6682: 6365: 6340: 5981: 5954: 5768: 5186: 5161: 4890: 4865: 4841: 4814: 4719: 4531: 3465: 2605: 2580: 2451: 2434: 1663: 1437:

Many Wilson's patients carry different mutations on each chromosome 13 (i.e., they are

1389: 1144: 1096: 1033: 1026: 1014: 758:

Plateau of absorption maintained; homeostatic mechanisms regulate absorption of copper

622: 618: 508: 451: 330: 299: 273: 164: 68: 38: 6990: 6911: 6841: 6017: 5802: 5739: 5493: 3196: 2074: 1196:

There is little evidence to indicate that chronic human exposure to copper results in

889: 8022: 8002: 7966: 7956: 7914: 7904: 7448: 7397: 6872: 6406: 6389: 5923: 5533: 5516: 4306:

Kaegi, Jeremias H. R.; Schaeffer, Andreas (1988). "Biochemistry of metallothionein".

3848:

National Research Council (US) Committee on Copper in Drinking Water (15 July 2023).

3724: 3315: 3280: 3039: 2829: 2812: 1687: 1624: 1523: 1486: 1361: 1308: 919:

In France and some other countries, copper bowls are traditionally used for whipping

823:

Peripheral pools disrupted; gross dysfunction and disturbance of metabolism of other

562: 554: 529: 525: 500: 479: 443: 412: 398: 241: 34: 23: 7119: 6590: 6547: 6215: 6182:"Endemic Tyrolean infantile cirrhosis is not an allelic variant of Wilson's disease" 6166: 6117: 5939: 5550: 5424: 5146: 4949: 4608: 4257: 4087: 4044: 3982: 3762: 3637: 3452:

Winge, Dennis R.; Mehra, Rajesh K. (1990). "Host Defenses against Copper Toxicity".

3253: 2846: 2202: 1032:

Populations susceptible to copper deficiency include those with genetic defects for

7819: 7323: 6464: 6068: 5712: 5666: 4785: 3905: 2596: 2266: 1543: 1511: 1502: 1260: 1152: 1148: 1112: 1088: 1045: 961: 933: 682: 248: 203: 85: 3579: 3430: 2908: 2492: 2475: 2408: 194: 7062: 7026: 5842: 5825: 4592: 2123: 1979: 1714: 1538:

inhibition in several cancer cell lines, when compared with the metal-free SBHs.

532:

enzyme involved in defense against reactive oxygen species (e.g., destruction of

7867: 7804: 7505: 7412: 7407: 7380: 7278: 7273: 5130: 5095: 4986: 3949:"Assessment of human exposure to copper: A case study using the NHEXAS database" 3574: 2729:

Turnlund, Judith R; Keyes, William R; Anderson, Helen L; Acord, Lorra L (1989).

2090: 1870: 1330: 1228: 1166: 1007: 789:

Hepatic deposit(s) reduced; conservation of endogenous copper; gastrointestinal

674: 658: 464: 416: 362: 354: 306:

pigment and connective tissue synthesis, iron metabolism, free radical defense,

51: 18: 7178: 6531: 6317: 5789:

Mercer, Julian F B (2001). "The molecular basis of copper-transport diseases".

4642: 4522: 3708: 3126: 881:

is 1.6 mg/day, for lactation 1.6 mg/day – higher than the U.S. RDAs.

7755: 7402: 7269: 7209: 6954: 6802: 6574: 6356: 6252: 6235: 5582: 5565: 4932: 4915: 4881: 4760: 4743: 4442: 4425: 4284: 4028: 3082: 3065: 2581:"Observations on the mechanism of absorption of copper by the small intestine" 2319:

Dameron, C.; et al. (International Programme on Chemical Safety) (1998).

2250: 2186: 2089:

Water, National Research Council (US) Committee on Copper in Drinking (2000),

1911: 1442: 1244: 1231:) for copper deficiency as well as excess. CCS is currently being tested as a 1025:, and glutathione, and therefore plays an important role in diseases in which 678: 566: 541: 533: 458: 337: 291: 252: 180: 172: 152: 109: 104:

molecule to reduce it to two molecules of water. Copper is also found in many

81: 46: 6757: 6447: 6430: 5331: 5227: 5210: 5162:"Acute gastrointestinal effects of graded levels of copper in drinking water" 4769: 4482: 4071: 3515: 3498: 3394: 3377: 2873: 2788: 2771: 2338: 198:

Photosynthesis functions by an elaborate electron transport chain within the

7390: 6198: 6181: 6149: 6132: 6100: 6083: 5883: 5866: 5456: 5439: 5371: 5354: 5268: 5251: 4709: 4359: 4342: 3354: 2747: 2730: 2057: 1837: 1820: 1668: 1617: 1477:

ICC, ICT, and ETIC are infancy syndromes that are similar in their apparent

1423:(Divalent Metal transporter 1). More recently, experimental treatments with 1381: 1357: 1323: 1322:

With early diagnosis and treatment consisting of daily injections of copper

1252: 1232: 1206: 1174: 920: 731:

Gross dysfunction and disturbance of metabolism of other nutrients; hepatic

646: 610: 592: 160: 7111: 7070: 7034: 6998: 6962: 6919: 6810: 6775: 6718: 6582: 6539: 6500: 6456: 6415: 6374: 6325: 6288: 6109: 5990: 5931: 5851: 5810: 5658: 5501: 5416: 5380: 5339: 5304: 5236: 5160:

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5138: 5103: 5067: 5059: 4994: 4941: 4899: 4850: 4777: 4728: 4650: 4600: 4540: 4490: 4128: 4079: 4036: 3974: 3965: 3948: 3770: 3716: 3629: 3551: 3245: 3236: 3219: 3047: 3000: 2943: 2881: 2645: 2614: 2565: 2501: 2460: 2416: 2376: 2368: 2258: 2194: 2141: 2042: 1997: 1929: 1888: 1846: 1732: 1576:

that is considered to be one of the most effective forms of birth control.

1315:

polymerization and corresponding connective-tissue abnormalities including

1040:, individuals with "malabsorption syndrome" (impaired dietary absorption), 373:). As a component of about a dozen cuproenzymes, copper is involved in key 317:

Since copper availability in the body is hindered by an excess of iron and

7137: 7102: 6880: 6749: 6656: 6625: 6261: 6207: 6158: 6060: 6025: 5892: 5747: 5704: 5650: 5591: 5542: 5465: 5277: 5195: 4831: 4451: 4395: 4368: 4327: 4292: 4249: 4208: 4181: 3926: 3524: 3483: 3438: 3403: 3362: 3323: 3288: 3204: 3169: 3091: 3008: 2951: 2916: 2838: 2811:

Ehrenkranz, Richard A.; Gettner, Patricia A.; Nelli, Catherine M. (1989).

2797: 2756: 2715: 2680: 2556: 2539: 1177:, massive gastrointestinal bleeding, liver and kidney failure, and death. 7946: 7839: 7747: 7731: 7371: 7358: 7328: 7318: 7264: 7239: 5971: 5209:

Zacarías, I; Yáñez, CG; Araya, M; Oraka, C; Olivares, M; Uauy, R (2001).

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supplements is lower than that from copper gluconate, copper sulfate, or

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The Metal-Driven Biogeochemistry of Gaseous Compounds in the Environment

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or infections; alcoholics), 2) insufficient food consumption (e.g., the

100:

between a copper and an iron; the protein transfers 4 electrons to the O

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Brewer, George J. (2010). "Copper toxicity in the general population".

3689:

Journal of Toxicology and Environmental Health Part B: Critical Reviews

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Harris, Edward D. (2000). "Cellular copper transport and metabolism".

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that is vital to the health of all living things (plants, animals and

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3023: 673:(i.e., thin membrane lining) capillaries where it binds to albumin, 499:

Multifunction enzyme involved in maturation and modification of key

6935:

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy

3611: 1013:

Other conditions linked to copper deficiency include osteoporosis,

859:

reviewed the same safety question and set its UL at 5 mg/day.

650:

amounts of copper, even though the foods they eat are copper-rich.

7458: 7438: 1256: 905: 374: 311: 193: 17: 5022:

10.1002/1520-670X(2000)13:3<249::AID-JTRA1>3.0.CO;2-L

897:

Foods contribute virtually all of the copper consumed by humans.

681:

in the portal blood. There is also evidence for a small protein,

7481: 7476: 7375: 7259: 5082:

in bottled drinking water in a multi-site international study".

1605: 1471: 1420: 686: 318: 22:

Normal absorption and distribution of copper. Cu = copper, CP =

7600: 7182: 5953:

Baldari, Silvia; Di Rocco, Giuliana; Toietta, Gabriele (2020).

1612:

and carrots. On the other hand, some foods including coconuts,

1243:

Several rare genetic diseases (Wilson disease, Menkes disease,

1201:>3 mg/L of copper exhibited no adverse health effects. 41:). In humans, copper is essential to the proper functioning of 5320:

International Journal of Occupational and Environmental Health

3538:

Aggett, PJ (1999). "An overview of the metabolism of copper".

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Interrelations between Essential Metal Ions and Human Diseases

1970:. In Sigel, Astrid; Sigel, Helmut; Sigel, Roland K.O. (eds.). 1392:, severe clotting abnormalities, occasionally associated with 1342: 1341:

Researchers have also demonstrated in test tubes that damaged

1006:. Fortunately, copper deficiency can be confirmed by very low 1227:

data supports its use as a marker in accessible cells (e.g.,

629:

is not absorbed. Elevated levels of dietary zinc, as well as

422:

Multi-copper oxidase in plasma, essential for iron transport

6234:

Müller, Thomas; Müller, Wilfried; Feichtinger, Hans (1998).

5438:

Pratt, William B; Omdahl, John L; Sorenson, John RJ (1985).

4224:"Newer aspects of micronutrients in chronic disease: copper" 1620:, are not particularly sensitive to copper-deficient soils. 972:

Copper deficiency and excess health conditions (non-genetic)

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Journal of Exposure Analysis and Environmental Epidemiology

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Institute of Medicine (US) Panel on Micronutrients (2001).

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Crampton, R. F.; Matthews, D. M.; Poisner, Roselle (1965).

1966:

Scheiber, Ivo; Dringen, Ralf; Mercer, Julian F. B. (2013).

1906:. Vol. 18. Berlin: de Gruyter GmbH. pp. 469–506. 851:

women at 0.9 mg/day. As for safety, the IOM also sets

4103:"'Myelodysplasia,' Myeloneuropathy, and Copper Deficiency" 2314: 1904:

Metallo-Drugs: Development and Action of Anticancer Agents

1076:, and diarrhea and can lead to tissue injury and disease. 661:(i.e., predominant cells in the small intestinal mucosa). 5211:"Determination of the taste threshold of copper in water" 4815:"Disturbed Copper Bioavailability in Alzheimer's Disease" 2312: 2310: 2308: 2306: 2304: 2302: 2300: 2298: 2296: 2294: 3864:

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2435:"Copper Homeostasis: The Role of Cellular Transporters" 2323:(Technical report). Geneva: World Health Organization. 546:

Enzyme catalyzing melanin and other pigment production

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Journal of Toxicology and Environmental Health, Part A

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Journal of Toxicology and Environmental Health, Part B

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Strategies for Modeling Dose-response Relationships".

1384:

symptomatology. The disease progresses with deepening

210:

A unique tetranuclear copper center has been found in

96:. Cytochrome c oxidase is the protein that binds the O 5521:

Journal of Pediatric Gastroenterology & Nutrition

5440:"Lack of effects of copper gluconate supplementation" 1010:

metal and ceruloplasmin concentrations in the blood.

779:

Biliary excretion and gastrointestinal uptake normal

5955:"Current biomedical use of copper chelation therapy" 1434:. Some of the mutations have geographic clustering. 1376:, neurologic, or psychiatric disorders and, rarely, 496:

Peptidylglycine alpha-amidating mono-oxygenase (PAM)

7975: 7838: 7775: 7713: 7632: 7567: 7549: 7531: 7513: 7504: 7467: 7429: 7348: 7341: 7303: 7249: 7238: 7229: 7220: 4800:"Protective role for copper in Alzheimer's disease" 4060:

Journal of Neurology, Neurosurgery & Psychiatry

2817:

Journal of Pediatric Gastroenterology and Nutrition

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"Menkes disease". 5293:European Journal of Medical Research 4665:"Copper link to Alzheimer's disease" 4228:Proceedings of the Nutrition Society 4144:Zinc and Copper in Clinical Medicine 3540:European Journal of Medical Research 3499:"Human whole-body copper metabolism" 2772:"Human whole-body copper metabolism" 1574:long-acting reversible contraception 1239:Hereditary copper metabolic diseases 467:, involved in iron transport across 446:metabolism, catalyzes conversion of 310:, and the normal functioning of the 7717: (Core six elements) 4174:10.1146/annurev.nu.08.070188.001315 3224:The Journal of Biological Chemistry 2062:The Journal of Biological Chemistry 1688:"Copper - Fact sheet for consumers" 1102:While the cause and progression of 403:Group of enzymes oxidizing primary 6645:Indian Journal of Medical Sciences 6186:European Journal of Human Genetics 6137:European Journal of Human Genetics 5397:Annals of Nutrition and Metabolism 3793:Brewer, George J. 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A central link in this chain is 14: 6979:Journal of Inorganic Biochemistry 6900:Journal of Inorganic Biochemistry 6520:Experimental Biology and Medicine 5482:Free Radical Biology and Medicine 5166:Environmental Health Perspectives 4426:"Manifestations of copper excess" 1319:, loose skin, and fragile bones. 1127:in Alzheimer's disease patients. 1087:to biological systems, including 6407:10.1016/j.athoracsur.2008.03.016 5924:10.1034/j.1600-0676.2003.00824.x 5534:10.1097/00005176-199803000-00003 4748:The British Journal of Nutrition 3743:Science of the Total Environment 3281:10.1152/ajplegacy.1970.218.2.377 2830:10.1097/00005176-198901000-00012 314:and immune systems in infants. 26:, green = ATP7B carrying copper. 7541:Phosphoric acids and phosphates 7090:New England Journal of Medicine 6791:Chemico-Biological Interactions 6481:Chemical Research in Toxicology 5119:Reviews on Environmental Health 3763:10.1016/j.scitotenv.2006.12.041 2097:, National Academies Press (US) 2017:The Journal of Chemical Physics 1825:Journal of Experimental Biology 569:by specialized proteins called 92:, which is the last protein in 7705:Biological aspects of fluorine 6394:The Annals of Thoracic Surgery 4920:Journal of Neural Transmission 4870:Journal of Neural Transmission 4471:Archives of General Psychiatry 3185:Trends in Biochemical Sciences 2628:Bearn, AG; Kunkel, HG (1955). 2597:10.1113/jphysiol.1965.sp007618 2091:"Physiological Role of Copper" 1554:Contraception with copper IUDs 857:European Food Safety Authority 742:>5.0 mg/kg body weight 287:Fetuses, infants, and children 155:is the oxygen carrier in most 1: 7983:Composition of the human body 7274:Ferroportin (SLC11A3/SLC40A1) 6991:10.1016/S0162-0134(98)10075-2 6912:10.1016/S0162-0134(99)00131-2 6842:10.1016/S0020-1693(00)85058-6 6236:"Idiopathic copper toxicosis" 6018:10.1016/s0022-2143(98)90039-7 5803:10.1016/S1471-4914(01)01920-7 5740:10.1016/S0065-3101(24)00096-3 5494:10.1016/S0891-5849(00)00409-3 3431:10.1152/physrev.1985.65.2.238 3197:10.1016/S0968-0004(96)20016-7 2909:10.1152/physrev.1985.65.2.238 2493:10.1016/j.jnutbio.2004.02.004 2409:10.1146/annurev.nutr.20.1.291 2075:10.1016/S0021-9258(20)74028-7 1692:National Institutes of Health 853:Tolerable upper intake levels 7063:10.1016/j.ejmech.2009.12.048 7027:10.1016/j.ejmech.2008.01.021 6873:10.1016/0006-2952(83)90164-8 6738:Biomolecules and Biomedicine 6435:Integrative Cancer Therapies 6400:(2): 383–9, discussion 390. 5843:10.1053/j.gastro.2003.05.010 5791:Trends in Molecular Medicine 4593:10.1016/j.clinph.2009.12.015 3316:10.1016/0006-2952(92)90270-S 3040:10.1016/0955-2863(95)80005-W 2770:Turnlund, Judith R. 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J. (1994). 3966:10.1038/sj.jea.7500462 3516:10.1093/ajcn/67.5.960S 3509:(5 Suppl): 960S–964S. 3395:10.1093/ajcn/67.5.965S 3388:(5 Suppl): 965S–971S. 3237:10.1074/jbc.M208002200 2970:Federation Proceedings 2874:10.1093/jn/129.12.2278 2789:10.1093/ajcn/67.5.960S 2782:(5 Suppl): 960S–964S. 2369:10.1006/bbrc.1999.1073 1659:List of micronutrients 1501:The role of copper in 1439:compound heterozygotes 1402:Kayser–Fleischer rings 1398:chronic kidney disease 1289:gastrointestinal tract 894: 207: 27: 7848:Argyria (Silver) 7690:Molybdenum in biology 7559:Magnesium transporter 7350:Iron-binding proteins 7314:Duodenal cytochrome B 7158:McDonald, P. (2022). 7103:10.1056/NEJMoa1110855 6750:10.17305/bb.2022.8481 6041:Archives of Neurology 5884:10.1093/ajcn/63.5.842 5651:10.1007/s100249900011 5606:"Hereditary Diseases" 5457:10.1093/ajcn/42.4.681 5372:10.1093/ajcn/77.3.646 5269:10.1093/ajcn/63.5.846 4424:Bremner, Ian (1998). 4360:10.1093/ajcn/63.5.821 3419:Physiological Reviews 3355:10.1093/ajcn/63.5.797 2897:Physiological Reviews 2748:10.1093/ajcn/49.5.870 1522:, breast cancer, and 1125:cerebral spinal fluid 892: 810:5.2 μg/kg body weight 800:8.5 μg/kg body weight 791:absorption increased 755:100 μg/kg body weight 221:Optimal copper levels 197: 112:by converting it (by 106:superoxide dismutases 21: 7988:Lithium (medication) 7700:Arsenic biochemistry 7660:Manganese in biology 7650:Potassium in biology 7645:Magnesium in biology 7551:Magnesium metabolism 7533:Phosphate metabolism 7283:Transferrin receptor 5972:10.3390/ijms21031069 5178:10.1289/ehp.99107117 4631:DNA and Cell Biology 4017:Journal of Neurology 4005:. Table A14: Copper. 3001:10.1093/jn/115.2.200 2944:10.1093/jn/115.2.159 1831:(Pt 12): 1777–1782. 1019:rheumatoid arthritis 893:Foods rich in copper 776:11 μg/kg body weight 766:34 μg/kg body weight 520:Superoxide dismutase 428:Cytochrome c oxidase 90:cytochrome c oxidase 7858:Beryllium poisoning 7685:Selenium in biology 7627:Elements in biology 6947:2006AcSpA..65..695L 5912:Liver International 4979:2012JTEMB..26...89B 4832:10.4061/2011/345614 4701:2013PNAS..11014771S 4320:10.1021/bi00423a001 4241:10.1079/PNS19940067 3890:1984Natur.308..667M 3755:2007ScTEn.374..223S 3701:2001JTEHB...4..341G 3162:10.1021/bi00048a001 3129:on October 15, 2010 2557:10.1093/jn/86.2.120 2243:2010JTEHA..73..114S 2179:2007JTEHB..10..157S 2025:2021JChPh.155r4704L 1572:(IUD) is a type of 1570:intrauterine device 1297:blood–brain barrier 1104:Alzheimer's disease 1081:oxidation potential 820:2 μg/kg body weight 786:9 μg/kg body weight 703: 386: 272:(oxygen-requiring) 7952:Thallium poisoning 7655:Calcium in biology 7569:Calcium metabolism 4001:2015-01-06 at the 3378:"Copper transport" 2528:Part B, 10:157–222 1780:on 22 October 2008 1654:Essential nutrient 1425:tetrathiomolybdate 1334:is usually fatal. 1247:copper toxicosis, 895: 701: 473:portal circulation 384: 208: 200:thylakoid membrane 169:Limulus polyphemus 114:disproportionation 28: 8016: 8015: 7962:Toxic heavy metal 7947:Selenium toxicity 7932:Mercury poisoning 7900:Fluoride toxicity 7895:Cadmium poisoning 7880:Chromium toxicity 7853:Arsenic poisoning 7695:Iodine in biology 7675:Copper in biology 7670:Cobalt in biology 7640:Sodium in biology 7594: 7593: 7590: 7589: 7515:Sodium metabolism 7500: 7499: 7431:Copper metabolism 7425: 7424: 7421: 7420: 7337: 7336: 7169:978-1-292-25166-0 7096:(21): 1998–2007. 6618:10.1159/000226722 6493:10.1021/tx900111y 5697:10.1038/ng0596-21 5409:10.1159/000070486 3834:978-1-118-42406-3 3621:978-0-309-07279-3 2868:(12): 2278–2279. 2708:10.1042/cs0430605 2673:10.1042/cs0430617 2439:Nutrition Reviews 2133:978-94-007-5560-4 2034:10.1063/5.0063362 1989:978-94-007-7500-8 1921:978-3-11-047073-4 1880:978-94-017-9268-4 1743:978-94-007-5561-1 1724:978-94-007-5560-4 1516:colorectal cancer 1474:region of India. 1413:chelation therapy 1327:intraperitoneally 1189:Chronic exposures 994:Copper deficiency 978:Copper deficiency 830: 829: 825:nutrients; death 571:metallochaperones 550: 549: 505:neurotransmitters 484:Cross-linking of 469:intestinal mucosa 255:, nutrition, and 232:can be either of 226:Copper deficiency 189:electron transfer 128:+ 2H → Cu-SOD + H 118:hydrogen peroxide 88:, it is found in 8036: 8029:Copper in health 7927:Lithium toxicity 7885:Cobalt poisoning 7621: 7614: 7607: 7598: 7511: 7346: 7247: 7236: 7227: 7222:Transition metal 7214:Metal metabolism 7203: 7196: 7189: 7180: 7174: 7173: 7160:Animal Nutrition 7155: 7149: 7148: 7146: 7145: 7136:. Archived from 7130: 7124: 7123: 7105: 7081: 7075: 7074: 7045: 7039: 7038: 7009: 7003: 7002: 6973: 6967: 6966: 6941:(3–4): 695–701. 6930: 6924: 6923: 6894: 6885: 6884: 6855: 6846: 6845: 6824: 6815: 6814: 6786: 6780: 6779: 6769: 6729: 6723: 6722: 6712: 6702: 6678: 6672: 6671: 6669: 6668: 6659:. Archived from 6636: 6630: 6629: 6601: 6595: 6594: 6558: 6552: 6551: 6511: 6505: 6504: 6475: 6469: 6468: 6450: 6426: 6420: 6419: 6409: 6385: 6379: 6378: 6368: 6336: 6330: 6329: 6299: 6293: 6292: 6272: 6266: 6265: 6255: 6231: 6220: 6219: 6201: 6177: 6171: 6170: 6152: 6128: 6122: 6121: 6103: 6079: 6073: 6072: 6036: 6030: 6029: 6001: 5995: 5994: 5984: 5974: 5950: 5944: 5943: 5906: 5897: 5896: 5886: 5862: 5856: 5855: 5845: 5830:Gastroenterology 5826:"Wilson disease" 5821: 5815: 5814: 5786: 5780: 5779: 5777: 5776: 5767:. Archived from 5761: 5752: 5751: 5723: 5717: 5716: 5680: 5671: 5670: 5634: 5621: 5620: 5618: 5617: 5608:. Archived from 5602: 5596: 5595: 5585: 5561: 5555: 5554: 5536: 5512: 5506: 5505: 5476: 5470: 5469: 5459: 5435: 5429: 5428: 5391: 5385: 5384: 5374: 5350: 5344: 5343: 5315: 5309: 5308: 5288: 5282: 5281: 5271: 5247: 5241: 5240: 5230: 5206: 5200: 5199: 5189: 5157: 5151: 5150: 5114: 5108: 5107: 5078: 5072: 5071: 5042: 5036: 5035: 5033: 5005: 4999: 4998: 4960: 4954: 4953: 4935: 4910: 4904: 4903: 4893: 4861: 4855: 4854: 4844: 4834: 4810: 4804: 4803: 4796: 4790: 4789: 4763: 4739: 4733: 4732: 4722: 4712: 4679: 4673: 4672: 4661: 4655: 4654: 4626: 4613: 4612: 4576: 4570: 4569: 4567: 4566: 4551: 4545: 4544: 4534: 4501: 4495: 4494: 4462: 4456: 4455: 4445: 4421: 4415: 4411: 4400: 4399: 4379: 4373: 4372: 4362: 4338: 4332: 4331: 4303: 4297: 4296: 4268: 4262: 4261: 4243: 4219: 4213: 4212: 4192: 4186: 4185: 4157: 4148: 4147: 4139: 4133: 4132: 4122: 4120:10.4065/80.7.943 4098: 4092: 4091: 4055: 4049: 4048: 4012: 4006: 3993: 3987: 3986: 3968: 3944: 3938: 3937: 3935: 3934: 3925:. Archived from 3919: 3910: 3909: 3898:10.1038/308667a0 3873: 3867: 3860: 3854: 3853: 3845: 3839: 3838: 3820: 3799: 3798: 3790: 3784: 3781: 3775: 3774: 3738: 3729: 3728: 3684: 3678: 3677: 3675: 3667: 3661: 3660: 3658: 3648: 3642: 3641: 3595: 3582: 3571: 3565: 3562: 3556: 3555: 3535: 3529: 3528: 3518: 3494: 3488: 3487: 3449: 3443: 3442: 3414: 3408: 3407: 3397: 3373: 3367: 3366: 3349:(5): 797S–811S. 3334: 3328: 3327: 3299: 3293: 3292: 3264: 3258: 3257: 3239: 3215: 3209: 3208: 3180: 3174: 3173: 3156:(48): 15607–13. 3145: 3139: 3138: 3136: 3134: 3125:. Archived from 3119: 3110: 3109: 3102: 3096: 3095: 3085: 3061: 3052: 3051: 3019: 3013: 3012: 2984: 2978: 2977: 2965: 2956: 2955: 2927: 2921: 2920: 2892: 2886: 2885: 2857: 2851: 2850: 2832: 2808: 2802: 2801: 2791: 2767: 2761: 2760: 2750: 2726: 2720: 2719: 2696:Clinical Science 2691: 2685: 2684: 2661:Clinical Science 2656: 2650: 2649: 2625: 2619: 2618: 2608: 2576: 2570: 2569: 2559: 2535: 2529: 2522: 2516: 2512: 2506: 2505: 2495: 2471: 2465: 2464: 2454: 2430: 2421: 2420: 2392: 2381: 2380: 2352: 2343: 2342: 2316: 2289: 2286: 2271: 2270: 2226: 2207: 2206: 2161: 2146: 2145: 2111: 2105: 2104: 2103: 2102: 2086: 2080: 2079: 2077: 2053: 2047: 2046: 2036: 2008: 2002: 2001: 1963: 1954: 1953: 1947: 1943: 1941: 1933: 1899: 1893: 1892: 1857: 1851: 1850: 1840: 1816: 1810: 1799: 1790: 1789: 1787: 1785: 1766: 1760: 1737:electronic-book 1736: 1702: 1696: 1695: 1684: 1518:, head and neck 1354:Wilson's disease 1349:Wilson's disease 1317:aortic aneurisms 1198:systemic effects 1171:hemolytic anemia 1085:oxidative damage 958:eating disorders 713:Health outcomes 704: 615:copper gluconate 387: 238:genetic diseases 33:is an essential 8044: 8043: 8039: 8038: 8037: 8035: 8034: 8033: 8019: 8018: 8017: 8012: 7998:Oxygen toxicity 7971: 7890:Copper toxicity 7834: 7771: 7709: 7680:Zinc in biology 7665:Iron in biology 7628: 7625: 7595: 7586: 7563: 7545: 7527: 7496: 7469:Zinc metabolism 7463: 7417: 7363: 7333: 7305:Iron(III) oxide 7299: 7241: 7231:Iron metabolism 7216: 7207: 7177: 7170: 7157: 7156: 7152: 7143: 7141: 7132: 7131: 7127: 7083: 7082: 7078: 7047: 7046: 7042: 7021:(11): 2347–53. 7011: 7010: 7006: 6985:(3–4): 155–62. 6975: 6974: 6970: 6932: 6931: 6927: 6906:(3–4): 125–33. 6896: 6895: 6888: 6867:(24): 3868–71. 6857: 6856: 6849: 6826: 6825: 6818: 6788: 6787: 6783: 6731: 6730: 6726: 6700:10.1186/bcr1322 6693:(6): R897–908. 6680: 6679: 6675: 6666: 6664: 6638: 6637: 6633: 6603: 6602: 6598: 6560: 6559: 6555: 6513: 6512: 6508: 6477: 6476: 6472: 6428: 6427: 6423: 6387: 6386: 6382: 6338: 6337: 6333: 6301: 6300: 6296: 6274: 6273: 6269: 6233: 6232: 6223: 6179: 6178: 6174: 6130: 6129: 6125: 6081: 6080: 6076: 6047:(10): 1017–25. 6038: 6037: 6033: 6003: 6002: 5998: 5952: 5951: 5947: 5908: 5907: 5900: 5864: 5863: 5859: 5823: 5822: 5818: 5788: 5787: 5783: 5774: 5772: 5763: 5762: 5755: 5725: 5724: 5720: 5685:Nature Genetics 5682: 5681: 5674: 5636: 5635: 5624: 5615: 5613: 5604: 5603: 5599: 5563: 5562: 5558: 5514: 5513: 5509: 5488:(11): 1129–34. 5478: 5477: 5473: 5437: 5436: 5432: 5393: 5392: 5388: 5352: 5351: 5347: 5317: 5316: 5312: 5290: 5289: 5285: 5262:(5): 846S–52S. 5249: 5248: 5244: 5215:Chemical Senses 5208: 5207: 5203: 5159: 5158: 5154: 5116: 5115: 5111: 5080: 5079: 5075: 5044: 5043: 5039: 5007: 5006: 5002: 4962: 4961: 4957: 4912: 4911: 4907: 4863: 4862: 4858: 4812: 4811: 4807: 4798: 4797: 4793: 4741: 4740: 4736: 4695:(36): 14771–6. 4681: 4680: 4676: 4663: 4662: 4658: 4628: 4627: 4616: 4578: 4577: 4573: 4564: 4562: 4553: 4552: 4548: 4503: 4502: 4498: 4464: 4463: 4459: 4423: 4422: 4418: 4412: 4403: 4381: 4380: 4376: 4340: 4339: 4335: 4314:(23): 8509–15. 4305: 4304: 4300: 4270: 4269: 4265: 4221: 4220: 4216: 4194: 4193: 4189: 4159: 4158: 4151: 4141: 4140: 4136: 4100: 4099: 4095: 4057: 4056: 4052: 4014: 4013: 4009: 4003:Wayback Machine 3994: 3990: 3946: 3945: 3941: 3932: 3930: 3921: 3920: 3913: 3884:(5960): 667–8. 3875: 3874: 3870: 3862:McGee, Harold. 3861: 3857: 3847: 3846: 3842: 3835: 3822: 3821: 3802: 3792: 3791: 3787: 3782: 3778: 3749:(2–3): 223–34. 3740: 3739: 3732: 3686: 3685: 3681: 3673: 3669: 3668: 3664: 3656: 3650: 3649: 3645: 3622: 3597: 3596: 3585: 3572: 3568: 3563: 3559: 3537: 3536: 3532: 3496: 3495: 3491: 3476: 3451: 3450: 3446: 3416: 3415: 3411: 3375: 3374: 3370: 3336: 3335: 3331: 3301: 3300: 3296: 3266: 3265: 3261: 3230:(43): 40253–9. 3217: 3216: 3212: 3182: 3181: 3177: 3147: 3146: 3142: 3132: 3130: 3121: 3120: 3113: 3104: 3103: 3099: 3063: 3062: 3055: 3021: 3020: 3016: 2986: 2985: 2981: 2967: 2966: 2959: 2929: 2928: 2924: 2894: 2893: 2889: 2859: 2858: 2854: 2810: 2809: 2805: 2769: 2768: 2764: 2728: 2727: 2723: 2693: 2692: 2688: 2658: 2657: 2653: 2627: 2626: 2622: 2578: 2577: 2573: 2537: 2536: 2532: 2523: 2519: 2513: 2509: 2473: 2472: 2468: 2432: 2431: 2424: 2394: 2393: 2384: 2354: 2353: 2346: 2331: 2318: 2317: 2292: 2287: 2274: 2228: 2227: 2210: 2163: 2162: 2149: 2134: 2113: 2112: 2108: 2100: 2098: 2088: 2087: 2083: 2055: 2054: 2050: 2010: 2009: 2005: 1990: 1965: 1964: 1957: 1944: 1934: 1922: 1901: 1900: 1896: 1881: 1859: 1858: 1854: 1818: 1817: 1813: 1800: 1793: 1783: 1781: 1768: 1767: 1763: 1725: 1704: 1703: 1699: 1686: 1685: 1681: 1677: 1649:Dietary mineral 1645: 1633: 1590: 1582: 1566: 1560:IUD with copper 1558:Main articles: 1556: 1499: 1456: 1417:D-penicillamine 1396:, and advanced 1380:, skeletal, or 1351: 1281: 1259:containing the 1241: 1220: 1191: 1162: 1160:Acute exposures 1137: 1121:transgenic mice 1061: 1059:Copper toxicity 1055: 996: 980: 974: 929: 927:Supplementation 887: 878: 865: 844: 835: 695: 667: 583: 351: 342:catch-up growth 331:infant formulas 308:gene expression 289: 266: 223: 146: 142: 135: 131: 127: 116:) to oxygen or 103: 99: 74:Copper proteins 71: 65: 12: 11: 5: 8042: 8040: 8032: 8031: 8021: 8020: 8014: 8013: 8011: 8010: 8005: 8000: 7995: 7990: 7985: 7979: 7977: 7973: 7972: 7970: 7969: 7964: 7959: 7954: 7949: 7944: 7942:Nickel allergy 7939: 7937:Metal toxicity 7934: 7929: 7924: 7922:Lead poisoning 7919: 7918: 7917: 7910:Iron poisoning 7907: 7902: 7897: 7892: 7887: 7882: 7877: 7872: 7871: 7870: 7865: 7855: 7850: 7844: 7842: 7836: 7835: 7833: 7832: 7827: 7822: 7817: 7812: 7807: 7802: 7797: 7792: 7787: 7781: 7779: 7773: 7772: 7770: 7769: 7761: 7753: 7745: 7737: 7729: 7720: 7718: 7711: 7710: 7708: 7707: 7702: 7697: 7692: 7687: 7682: 7677: 7672: 7667: 7662: 7657: 7652: 7647: 7642: 7636: 7634: 7630: 7629: 7626: 7624: 7623: 7616: 7609: 7601: 7592: 7591: 7588: 7587: 7585: 7584: 7579: 7573: 7571: 7565: 7564: 7562: 7561: 7555: 7553: 7547: 7546: 7544: 7543: 7537: 7535: 7529: 7528: 7526: 7525: 7519: 7517: 7508: 7502: 7501: 7498: 7497: 7495: 7494: 7489: 7484: 7479: 7473: 7471: 7465: 7464: 7462: 7461: 7456: 7451: 7446: 7441: 7435: 7433: 7427: 7426: 7423: 7422: 7419: 7418: 7416: 7415: 7410: 7405: 7400: 7395: 7394: 7393: 7383: 7378: 7368: 7365: 7364: 7362: 7361: 7355: 7353: 7343: 7339: 7338: 7335: 7334: 7332: 7331: 7326: 7321: 7316: 7310: 7308: 7301: 7300: 7298: 7297: 7296: 7295: 7290: 7276: 7267: 7262: 7260:DMT1 (SLC11A2) 7256: 7254: 7251:Iron(II) oxide 7244: 7233: 7224: 7218: 7217: 7208: 7206: 7205: 7198: 7191: 7183: 7176: 7175: 7168: 7150: 7125: 7076: 7057:(4): 1438–46. 7040: 7004: 6968: 6925: 6886: 6847: 6816: 6781: 6744:(4): 624–633. 6724: 6673: 6651:(10): 227–32. 6631: 6596: 6569:(4): 299–310. 6553: 6506: 6487:(9): 1517–25. 6470: 6421: 6380: 6331: 6294: 6267: 6221: 6172: 6123: 6094:(6): 1329–36. 6074: 6031: 5996: 5945: 5898: 5877:(5): 842S–5S. 5857: 5836:(6): 1868–77. 5816: 5781: 5753: 5718: 5672: 5622: 5597: 5556: 5507: 5471: 5430: 5386: 5345: 5310: 5283: 5242: 5201: 5152: 5109: 5073: 5037: 5000: 4973:(2–3): 89–92. 4955: 4926:(12): 1651–9. 4905: 4856: 4805: 4791: 4734: 4674: 4656: 4614: 4571: 4546: 4496: 4457: 4416: 4401: 4374: 4353:(5): 821S–9S. 4333: 4298: 4263: 4214: 4203:(2–3): 281–7. 4187: 4149: 4134: 4093: 4050: 4007: 3988: 3959:(5): 397–409. 3939: 3911: 3868: 3855: 3840: 3833: 3800: 3785: 3776: 3730: 3679: 3662: 3643: 3620: 3612:10.17226/10026 3583: 3580:Copper in diet 3566: 3557: 3530: 3489: 3474: 3444: 3425:(2): 238–309. 3409: 3368: 3329: 3294: 3259: 3210: 3175: 3140: 3111: 3097: 3053: 3034:(7): 373–379. 3014: 2979: 2957: 2922: 2903:(2): 238–309. 2887: 2852: 2803: 2762: 2721: 2686: 2651: 2620: 2571: 2530: 2517: 2507: 2466: 2422: 2403:(1): 291–310. 2382: 2344: 2329: 2290: 2272: 2208: 2173:(3): 157–222. 2147: 2132: 2106: 2081: 2048: 2003: 1988: 1955: 1946:|journal= 1920: 1894: 1879: 1852: 1811: 1791: 1774:Horseshoe crab 1761: 1723: 1697: 1678: 1676: 1673: 1672: 1671: 1666: 1664:Micronutrients 1661: 1656: 1651: 1644: 1641: 1632: 1629: 1589: 1586: 1581: 1578: 1555: 1552: 1498: 1495: 1455: 1452: 1390:encephalopathy 1350: 1347: 1280: 1279:Menkes disease 1277: 1240: 1237: 1219: 1216: 1190: 1187: 1161: 1158: 1145:Wilson disease 1136: 1133: 1097:macromolecules 1057:Main article: 1054: 1051: 1034:Menkes disease 1027:oxidant stress 1015:osteoarthritis 995: 992: 976:Main article: 973: 970: 928: 925: 886: 883: 877: 874: 864: 861: 843: 840: 834: 831: 828: 827: 821: 818: 815: 814: 811: 808: 805: 804: 801: 798: 794: 793: 787: 784: 781: 780: 777: 774: 771: 770: 767: 764: 760: 759: 756: 753: 750: 749: 743: 740: 736: 735: 729: 727: 724: 723: 720: 718: 715: 714: 711: 708: 694: 691: 666: 663: 623:copper sulfate 619:copper acetate 582: 579: 548: 547: 544: 538: 537: 523: 516: 515: 509:neuroendocrine 497: 493: 492: 482: 476: 475: 461: 455: 454: 452:norepinephrine 440: 434: 433: 430: 424: 423: 420: 409: 408: 401: 399:Amine oxidases 395: 394: 391: 350: 347: 300:breast feeding 288: 285: 274:microorganisms 265: 262: 222: 219: 165:horseshoe crab 149: 148: 144: 140: 137: 133: 129: 125: 101: 97: 69:Copper protein 67:Main article: 64: 61: 39:microorganisms 13: 10: 9: 6: 4: 3: 2: 8041: 8030: 8027: 8026: 8024: 8009: 8006: 8004: 8003:Soil salinity 8001: 7999: 7996: 7994: 7991: 7989: 7986: 7984: 7981: 7980: 7978: 7974: 7968: 7967:Zinc toxicity 7965: 7963: 7960: 7958: 7957:Tin poisoning 7955: 7953: 7950: 7948: 7945: 7943: 7940: 7938: 7935: 7933: 7930: 7928: 7925: 7923: 7920: 7916: 7915:Iron overload 7913: 7912: 7911: 7908: 7906: 7905:Halotolerance 7903: 7901: 7898: 7896: 7893: 7891: 7888: 7886: 7883: 7881: 7878: 7876: 7873: 7869: 7866: 7864: 7861: 7860: 7859: 7856: 7854: 7851: 7849: 7846: 7845: 7843: 7841: 7837: 7831: 7828: 7826: 7823: 7821: 7818: 7816: 7813: 7811: 7808: 7806: 7803: 7801: 7798: 7796: 7793: 7791: 7788: 7786: 7783: 7782: 7780: 7778: 7774: 7768: 7766: 7762: 7760: 7758: 7754: 7752: 7750: 7746: 7744: 7742: 7738: 7736: 7734: 7730: 7728: 7726: 7722: 7721: 7719: 7716: 7712: 7706: 7703: 7701: 7698: 7696: 7693: 7691: 7688: 7686: 7683: 7681: 7678: 7676: 7673: 7671: 7668: 7666: 7663: 7661: 7658: 7656: 7653: 7651: 7648: 7646: 7643: 7641: 7638: 7637: 7635: 7631: 7622: 7617: 7615: 7610: 7608: 7603: 7602: 7599: 7583: 7580: 7578: 7575: 7574: 7572: 7570: 7566: 7560: 7557: 7556: 7554: 7552: 7548: 7542: 7539: 7538: 7536: 7534: 7530: 7524: 7521: 7520: 7518: 7516: 7512: 7509: 7507: 7503: 7493: 7490: 7488: 7485: 7483: 7480: 7478: 7475: 7474: 7472: 7470: 7466: 7460: 7457: 7455: 7452: 7450: 7449:Ceruloplasmin 7447: 7445: 7442: 7440: 7437: 7436: 7434: 7432: 7428: 7414: 7411: 7409: 7406: 7404: 7401: 7399: 7398:Ceruloplasmin 7396: 7392: 7389: 7388: 7387: 7384: 7382: 7379: 7377: 7373: 7370: 7369: 7366: 7360: 7357: 7356: 7354: 7351: 7347: 7344: 7340: 7330: 7327: 7325: 7322: 7320: 7317: 7315: 7312: 7311: 7309: 7306: 7302: 7294: 7291: 7289: 7286: 7285: 7284: 7280: 7277: 7275: 7271: 7268: 7266: 7263: 7261: 7258: 7257: 7255: 7252: 7248: 7245: 7243: 7240:Absorption in 7237: 7234: 7232: 7228: 7225: 7223: 7219: 7215: 7211: 7204: 7199: 7197: 7192: 7190: 7185: 7184: 7181: 7171: 7165: 7161: 7154: 7151: 7140:on 2011-02-27 7139: 7135: 7129: 7126: 7121: 7117: 7113: 7109: 7104: 7099: 7095: 7091: 7087: 7080: 7077: 7072: 7068: 7064: 7060: 7056: 7052: 7044: 7041: 7036: 7032: 7028: 7024: 7020: 7016: 7008: 7005: 7000: 6996: 6992: 6988: 6984: 6980: 6972: 6969: 6964: 6960: 6956: 6952: 6948: 6944: 6940: 6936: 6929: 6926: 6921: 6917: 6913: 6909: 6905: 6901: 6893: 6891: 6887: 6882: 6878: 6874: 6870: 6866: 6862: 6854: 6852: 6848: 6843: 6839: 6835: 6831: 6823: 6821: 6817: 6812: 6808: 6804: 6800: 6796: 6792: 6785: 6782: 6777: 6773: 6768: 6763: 6759: 6755: 6751: 6747: 6743: 6739: 6735: 6728: 6725: 6720: 6716: 6711: 6706: 6701: 6696: 6692: 6688: 6684: 6677: 6674: 6663:on 2016-02-01 6662: 6658: 6654: 6650: 6646: 6642: 6635: 6632: 6627: 6623: 6619: 6615: 6611: 6607: 6600: 6597: 6592: 6588: 6584: 6580: 6576: 6572: 6568: 6564: 6557: 6554: 6549: 6545: 6541: 6537: 6533: 6529: 6526:(7): 665–73. 6525: 6521: 6517: 6510: 6507: 6502: 6498: 6494: 6490: 6486: 6482: 6474: 6471: 6466: 6462: 6458: 6454: 6449: 6444: 6441:(4): 327–37. 6440: 6436: 6432: 6425: 6422: 6417: 6413: 6408: 6403: 6399: 6395: 6391: 6384: 6381: 6376: 6372: 6367: 6362: 6358: 6354: 6351:(2): 159–65. 6350: 6346: 6342: 6335: 6332: 6327: 6323: 6319: 6315: 6311: 6307: 6306: 6298: 6295: 6290: 6286: 6283:(6): 233–42. 6282: 6278: 6271: 6268: 6263: 6259: 6254: 6249: 6245: 6241: 6237: 6230: 6228: 6226: 6222: 6217: 6213: 6209: 6205: 6200: 6195: 6191: 6187: 6183: 6176: 6173: 6168: 6164: 6160: 6156: 6151: 6146: 6143:(6): 616–23. 6142: 6138: 6134: 6127: 6124: 6119: 6115: 6111: 6107: 6102: 6097: 6093: 6089: 6085: 6078: 6075: 6070: 6066: 6062: 6058: 6054: 6050: 6046: 6042: 6035: 6032: 6027: 6023: 6019: 6015: 6012:(4): 264–78. 6011: 6007: 6000: 5997: 5992: 5988: 5983: 5978: 5973: 5968: 5964: 5960: 5959:Int J Mol Sci 5956: 5949: 5946: 5941: 5937: 5933: 5929: 5925: 5921: 5918:(3): 139–42. 5917: 5913: 5905: 5903: 5899: 5894: 5890: 5885: 5880: 5876: 5872: 5868: 5861: 5858: 5853: 5849: 5844: 5839: 5835: 5831: 5827: 5820: 5817: 5812: 5808: 5804: 5800: 5796: 5792: 5785: 5782: 5771:on 2011-07-08 5770: 5766: 5760: 5758: 5754: 5749: 5745: 5741: 5737: 5733: 5729: 5722: 5719: 5714: 5710: 5706: 5702: 5698: 5694: 5690: 5686: 5679: 5677: 5673: 5668: 5664: 5660: 5656: 5652: 5648: 5644: 5640: 5633: 5631: 5629: 5627: 5623: 5612:on 2011-07-08 5611: 5607: 5601: 5598: 5593: 5589: 5584: 5579: 5575: 5571: 5567: 5560: 5557: 5552: 5548: 5544: 5540: 5535: 5530: 5526: 5522: 5518: 5511: 5508: 5503: 5499: 5495: 5491: 5487: 5483: 5475: 5472: 5467: 5463: 5458: 5453: 5449: 5445: 5441: 5434: 5431: 5426: 5422: 5418: 5414: 5410: 5406: 5402: 5398: 5390: 5387: 5382: 5378: 5373: 5368: 5365:(3): 646–50. 5364: 5360: 5356: 5349: 5346: 5341: 5337: 5333: 5329: 5326:(4): 256–61. 5325: 5321: 5314: 5311: 5306: 5302: 5298: 5294: 5287: 5284: 5279: 5275: 5270: 5265: 5261: 5257: 5253: 5246: 5243: 5238: 5234: 5229: 5224: 5220: 5216: 5212: 5205: 5202: 5197: 5193: 5188: 5183: 5179: 5175: 5172:(2): 117–21. 5171: 5167: 5163: 5156: 5153: 5148: 5144: 5140: 5136: 5132: 5128: 5124: 5120: 5113: 5110: 5105: 5101: 5097: 5093: 5090:(3): 389–99. 5089: 5085: 5077: 5074: 5069: 5065: 5061: 5057: 5054:(2): 137–45. 5053: 5049: 5041: 5038: 5032: 5031:2027.42/35050 5027: 5023: 5019: 5016:(3): 249–54. 5015: 5011: 5004: 5001: 4996: 4992: 4988: 4984: 4980: 4976: 4972: 4968: 4967: 4959: 4956: 4951: 4947: 4943: 4939: 4934: 4929: 4925: 4921: 4917: 4909: 4906: 4901: 4897: 4892: 4887: 4883: 4879: 4876:(8): 1181–7. 4875: 4871: 4867: 4860: 4857: 4852: 4848: 4843: 4838: 4833: 4828: 4824: 4820: 4816: 4809: 4806: 4801: 4795: 4792: 4787: 4783: 4779: 4775: 4771: 4767: 4762: 4757: 4753: 4749: 4745: 4738: 4735: 4730: 4726: 4721: 4716: 4711: 4706: 4702: 4698: 4694: 4690: 4686: 4678: 4675: 4671:. 2003-08-12. 4670: 4669:New Scientist 4666: 4660: 4657: 4652: 4648: 4644: 4640: 4637:(4): 259–70. 4636: 4632: 4625: 4623: 4621: 4619: 4615: 4610: 4606: 4602: 4598: 4594: 4590: 4587:(4): 459–60. 4586: 4582: 4575: 4572: 4561:on 2012-03-11 4560: 4556: 4550: 4547: 4542: 4538: 4533: 4528: 4524: 4520: 4517:(6): 857–67. 4516: 4512: 4508: 4500: 4497: 4492: 4488: 4484: 4480: 4476: 4472: 4468: 4461: 4458: 4453: 4449: 4444: 4439: 4435: 4431: 4427: 4420: 4417: 4410: 4408: 4406: 4402: 4397: 4393: 4390:(10): 983–6. 4389: 4385: 4378: 4375: 4370: 4366: 4361: 4356: 4352: 4348: 4344: 4337: 4334: 4329: 4325: 4321: 4317: 4313: 4309: 4302: 4299: 4294: 4290: 4286: 4282: 4278: 4274: 4267: 4264: 4259: 4255: 4251: 4247: 4242: 4237: 4234:(3): 583–98. 4233: 4229: 4225: 4218: 4215: 4210: 4206: 4202: 4198: 4191: 4188: 4183: 4179: 4175: 4171: 4167: 4163: 4156: 4154: 4150: 4145: 4138: 4135: 4130: 4126: 4121: 4116: 4112: 4108: 4104: 4097: 4094: 4089: 4085: 4081: 4077: 4073: 4069: 4065: 4061: 4054: 4051: 4046: 4042: 4038: 4034: 4030: 4026: 4023:(8): 1012–7. 4022: 4018: 4011: 4008: 4004: 4000: 3997: 3992: 3989: 3984: 3980: 3976: 3972: 3967: 3962: 3958: 3954: 3950: 3943: 3940: 3929:on 2010-10-01 3928: 3924: 3923:"Quick Facts" 3918: 3916: 3912: 3907: 3903: 3899: 3895: 3891: 3887: 3883: 3879: 3872: 3869: 3865: 3859: 3856: 3851: 3844: 3841: 3836: 3830: 3826: 3819: 3817: 3815: 3813: 3811: 3809: 3807: 3805: 3801: 3796: 3789: 3786: 3780: 3777: 3772: 3768: 3764: 3760: 3756: 3752: 3748: 3744: 3737: 3735: 3731: 3726: 3722: 3718: 3714: 3710: 3706: 3702: 3698: 3695:(4): 341–94. 3694: 3690: 3683: 3680: 3672: 3666: 3663: 3655: 3654: 3647: 3644: 3639: 3635: 3631: 3627: 3623: 3617: 3613: 3609: 3605: 3601: 3594: 3592: 3590: 3588: 3584: 3581: 3577: 3576: 3570: 3567: 3561: 3558: 3553: 3549: 3545: 3541: 3534: 3531: 3526: 3522: 3517: 3512: 3508: 3504: 3500: 3493: 3490: 3485: 3481: 3477: 3475:9780123649317 3471: 3467: 3463: 3459: 3455: 3448: 3445: 3440: 3436: 3432: 3428: 3424: 3420: 3413: 3410: 3405: 3401: 3396: 3391: 3387: 3383: 3379: 3372: 3369: 3364: 3360: 3356: 3352: 3348: 3344: 3340: 3333: 3330: 3325: 3321: 3317: 3313: 3310:(2): 137–45. 3309: 3305: 3298: 3295: 3290: 3286: 3282: 3278: 3275:(2): 377–83. 3274: 3270: 3263: 3260: 3255: 3251: 3247: 3243: 3238: 3233: 3229: 3225: 3221: 3214: 3211: 3206: 3202: 3198: 3194: 3191:(7): 237–41. 3190: 3186: 3179: 3176: 3171: 3167: 3163: 3159: 3155: 3151: 3144: 3141: 3128: 3124: 3118: 3116: 3112: 3107: 3101: 3098: 3093: 3089: 3084: 3079: 3075: 3071: 3067: 3060: 3058: 3054: 3049: 3045: 3041: 3037: 3033: 3029: 3025: 3018: 3015: 3010: 3006: 3002: 2998: 2995:(2): 200–10. 2994: 2990: 2983: 2980: 2975: 2971: 2964: 2962: 2958: 2953: 2949: 2945: 2941: 2938:(2): 159–66. 2937: 2933: 2926: 2923: 2918: 2914: 2910: 2906: 2902: 2898: 2891: 2888: 2883: 2879: 2875: 2871: 2867: 2863: 2856: 2853: 2848: 2844: 2840: 2836: 2831: 2826: 2822: 2818: 2814: 2807: 2804: 2799: 2795: 2790: 2785: 2781: 2777: 2773: 2766: 2763: 2758: 2754: 2749: 2744: 2740: 2736: 2732: 2725: 2722: 2717: 2713: 2709: 2705: 2702:(5): 605–15. 2701: 2697: 2690: 2687: 2682: 2678: 2674: 2670: 2667:(5): 617–25. 2666: 2662: 2655: 2652: 2647: 2643: 2640:(4): 623–31. 2639: 2635: 2631: 2624: 2621: 2616: 2612: 2607: 2602: 2598: 2594: 2591:(1): 111–26. 2590: 2586: 2582: 2575: 2572: 2567: 2563: 2558: 2553: 2549: 2545: 2541: 2534: 2531: 2527: 2521: 2518: 2511: 2508: 2503: 2499: 2494: 2489: 2486:(6): 316–22. 2485: 2481: 2477: 2470: 2467: 2462: 2458: 2453: 2448: 2444: 2440: 2436: 2429: 2427: 2423: 2418: 2414: 2410: 2406: 2402: 2398: 2391: 2389: 2387: 2383: 2378: 2374: 2370: 2366: 2363:(2): 225–32. 2362: 2358: 2351: 2349: 2345: 2340: 2336: 2332: 2330:92-4-157200-0 2326: 2322: 2315: 2313: 2311: 2309: 2307: 2305: 2303: 2301: 2299: 2297: 2295: 2291: 2285: 2283: 2281: 2279: 2277: 2273: 2268: 2264: 2260: 2256: 2252: 2248: 2244: 2240: 2237:(2): 114–27. 2236: 2232: 2225: 2223: 2221: 2219: 2217: 2215: 2213: 2209: 2204: 2200: 2196: 2192: 2188: 2184: 2180: 2176: 2172: 2168: 2160: 2158: 2156: 2154: 2152: 2148: 2143: 2139: 2135: 2129: 2125: 2121: 2117: 2110: 2107: 2096: 2092: 2085: 2082: 2076: 2071: 2067: 2063: 2059: 2052: 2049: 2044: 2040: 2035: 2030: 2026: 2022: 2018: 2014: 2007: 2004: 1999: 1995: 1991: 1985: 1981: 1977: 1973: 1969: 1962: 1960: 1956: 1951: 1939: 1931: 1927: 1923: 1917: 1913: 1909: 1905: 1898: 1895: 1890: 1886: 1882: 1876: 1872: 1868: 1864: 1856: 1853: 1848: 1844: 1839: 1834: 1830: 1826: 1822: 1815: 1812: 1808: 1807:0-935702-73-3 1804: 1798: 1796: 1792: 1779: 1775: 1771: 1765: 1762: 1759: 1755: 1751: 1747: 1744: 1740: 1734: 1730: 1726: 1720: 1716: 1712: 1708: 1701: 1698: 1693: 1689: 1683: 1680: 1674: 1670: 1667: 1665: 1662: 1660: 1657: 1655: 1652: 1650: 1647: 1646: 1642: 1640: 1638: 1631:Animal health 1630: 1628: 1626: 1625:Sewage sludge 1621: 1619: 1615: 1611: 1607: 1603: 1598: 1594: 1587: 1585: 1579: 1577: 1575: 1571: 1565: 1561: 1553: 1551: 1547: 1545: 1539: 1535: 1533: 1527: 1525: 1524:kidney cancer 1521: 1517: 1513: 1509: 1504: 1496: 1494: 1490: 1488: 1487:consanguinity 1482: 1480: 1475: 1473: 1469: 1465: 1461: 1453: 1451: 1447: 1444: 1440: 1435: 1433: 1429: 1426: 1422: 1418: 1414: 1409: 1405: 1403: 1399: 1395: 1391: 1387: 1383: 1379: 1375: 1369: 1365: 1363: 1362:chromosome 13 1359: 1355: 1346: 1344: 1339: 1335: 1332: 1331:intrathecally 1328: 1325: 1320: 1318: 1314: 1310: 1309:lysyl oxidase 1304: 1300: 1298: 1294: 1290: 1285: 1278: 1276: 1272: 1269: 1265: 1262: 1261:genetic codes 1258: 1254: 1250: 1246: 1238: 1236: 1234: 1230: 1224: 1217: 1215: 1211: 1208: 1202: 1199: 1194: 1188: 1186: 1182: 1178: 1176: 1172: 1168: 1159: 1157: 1154: 1150: 1146: 1141: 1134: 1132: 1128: 1126: 1122: 1118: 1114: 1108: 1105: 1100: 1098: 1094: 1090: 1086: 1082: 1077: 1075: 1070: 1067: 1060: 1053:Copper excess 1052: 1050: 1047: 1043: 1039: 1035: 1030: 1028: 1024: 1020: 1016: 1011: 1009: 1005: 1000: 993: 991: 988: 984: 979: 971: 969: 965: 963: 959: 956:, those with 955: 951: 947: 941: 939: 935: 926: 924: 922: 917: 913: 909: 907: 903: 898: 891: 884: 882: 875: 873: 869: 862: 860: 858: 854: 849: 841: 839: 832: 826: 822: 819: 817: 816: 812: 809: 807: 806: 802: 799: 796: 795: 792: 788: 785: 783: 782: 778: 775: 773: 772: 768: 765: 762: 761: 757: 754: 752: 751: 748: 744: 741: 738: 737: 734: 730: 728: 726: 725: 721: 719: 717: 716: 712: 709: 706: 705: 699: 692: 690: 688: 684: 680: 676: 672: 664: 662: 660: 655: 651: 648: 642: 640: 636: 632: 628: 627:copper oxides 624: 620: 616: 612: 608: 604: 599: 596: 594: 589: 580: 578: 576: 572: 568: 564: 563:ceruloplasmin 560: 556: 555:cell membrane 545: 543: 540: 539: 535: 531: 530:extracellular 527: 526:Intracellular 524: 521: 518: 517: 513: 510: 506: 502: 501:neuropeptides 498: 495: 494: 491: 487: 483: 481: 480:Lysyl oxidase 478: 477: 474: 470: 466: 463:Multi-copper 462: 460: 457: 456: 453: 449: 445: 444:catecholamine 441: 439: 436: 435: 431: 429: 426: 425: 421: 418: 414: 413:Ceruloplasmin 411: 410: 406: 402: 400: 397: 396: 392: 389: 388: 382: 380: 376: 372: 368: 364: 359: 356: 348: 346: 343: 339: 334: 332: 327: 323: 320: 315: 313: 309: 305: 301: 297: 293: 286: 284: 282: 277: 275: 271: 263: 261: 258: 254: 250: 245: 243: 242:micronutrient 239: 235: 231: 227: 220: 218: 215: 213: 205: 201: 196: 192: 190: 186: 182: 178: 174: 170: 166: 162: 158: 154: 138: 123: 122: 121: 119: 115: 111: 107: 95: 91: 87: 83: 79: 75: 70: 62: 60: 56: 53: 48: 44: 40: 36: 35:trace element 32: 25: 24:ceruloplasmin 20: 16: 7777:Deficiencies 7764: 7756: 7748: 7740: 7732: 7724: 7674: 7159: 7153: 7142:. Retrieved 7138:the original 7128: 7093: 7089: 7079: 7054: 7050: 7043: 7018: 7014: 7007: 6982: 6978: 6971: 6938: 6934: 6928: 6903: 6899: 6864: 6860: 6833: 6829: 6797:(1): 26–36. 6794: 6790: 6784: 6741: 6737: 6727: 6690: 6686: 6676: 6665:. Retrieved 6661:the original 6648: 6644: 6634: 6612:(4): 230–4. 6609: 6605: 6599: 6566: 6562: 6556: 6523: 6519: 6509: 6484: 6480: 6473: 6438: 6434: 6424: 6397: 6393: 6383: 6348: 6344: 6334: 6312:(7): 543–9. 6309: 6303: 6297: 6280: 6276: 6270: 6243: 6239: 6192:(6): 624–8. 6189: 6185: 6175: 6140: 6136: 6126: 6091: 6087: 6077: 6044: 6040: 6034: 6009: 6005: 5999: 5962: 5958: 5948: 5915: 5911: 5874: 5870: 5860: 5833: 5829: 5819: 5794: 5790: 5784: 5773:. Retrieved 5769:the original 5731: 5727: 5721: 5688: 5684: 5645:(1): 85–98. 5642: 5638: 5614:. Retrieved 5610:the original 5600: 5573: 5569: 5559: 5527:(3): 251–7. 5524: 5520: 5510: 5485: 5481: 5474: 5450:(4): 681–2. 5447: 5443: 5433: 5403:(5): 201–6. 5400: 5396: 5389: 5362: 5358: 5348: 5323: 5319: 5313: 5296: 5292: 5286: 5259: 5255: 5245: 5218: 5214: 5204: 5169: 5165: 5155: 5125:(4): 231–8. 5122: 5118: 5112: 5087: 5083: 5076: 5051: 5047: 5040: 5013: 5009: 5003: 4970: 4964: 4958: 4923: 4919: 4908: 4873: 4869: 4859: 4822: 4818: 4808: 4794: 4751: 4747: 4737: 4692: 4688: 4677: 4668: 4659: 4634: 4630: 4584: 4580: 4574: 4563:. Retrieved 4559:the original 4549: 4514: 4510: 4499: 4477:(1): 47–53. 4474: 4470: 4460: 4433: 4429: 4419: 4387: 4383: 4377: 4350: 4346: 4336: 4311: 4308:Biochemistry 4307: 4301: 4276: 4272: 4266: 4231: 4227: 4217: 4200: 4196: 4190: 4165: 4161: 4143: 4137: 4113:(7): 943–6. 4110: 4106: 4096: 4066:(5): 524–7. 4063: 4059: 4053: 4020: 4016: 4010: 3991: 3956: 3952: 3942: 3931:. Retrieved 3927:the original 3881: 3877: 3871: 3863: 3858: 3843: 3824: 3788: 3779: 3746: 3742: 3692: 3688: 3682: 3665: 3652: 3646: 3603: 3573: 3569: 3560: 3546:(6): 214–6. 3543: 3539: 3533: 3506: 3502: 3492: 3457: 3453: 3447: 3422: 3418: 3412: 3385: 3381: 3371: 3346: 3342: 3332: 3307: 3303: 3297: 3272: 3268: 3262: 3227: 3223: 3213: 3188: 3184: 3178: 3153: 3150:Biochemistry 3149: 3143: 3131:. Retrieved 3127:the original 3100: 3073: 3069: 3031: 3027: 3017: 2992: 2988: 2982: 2976:(3): 616–20. 2973: 2969: 2935: 2931: 2925: 2900: 2896: 2890: 2865: 2861: 2855: 2823:(1): 58–67. 2820: 2816: 2806: 2779: 2775: 2765: 2741:(5): 870–8. 2738: 2734: 2724: 2699: 2695: 2689: 2664: 2660: 2654: 2637: 2633: 2623: 2588: 2584: 2574: 2550:(2): 120–4. 2547: 2543: 2533: 2525: 2520: 2510: 2483: 2479: 2469: 2445:(9): 281–5. 2442: 2438: 2400: 2396: 2360: 2356: 2320: 2234: 2230: 2170: 2166: 2115: 2109: 2099:, retrieved 2094: 2084: 2065: 2061: 2051: 2016: 2006: 1971: 1903: 1897: 1862: 1855: 1828: 1824: 1814: 1782:. Retrieved 1778:the original 1773: 1764: 1706: 1700: 1691: 1682: 1634: 1622: 1599: 1595: 1591: 1588:Plant health 1583: 1567: 1548: 1544:MOLT-4 cells 1540: 1536: 1531: 1528: 1512:mesothelioma 1503:angiogenesis 1500: 1491: 1483: 1476: 1457: 1448: 1436: 1430: 1410: 1406: 1370: 1366: 1352: 1340: 1336: 1321: 1305: 1301: 1286: 1282: 1273: 1270: 1266: 1242: 1229:erythrocytes 1225: 1221: 1212: 1203: 1195: 1192: 1183: 1179: 1163: 1153:heterozygote 1149:hemodialysis 1142: 1138: 1129: 1113:amyloid beta 1109: 1101: 1089:peroxidation 1078: 1071: 1062: 1031: 1012: 1001: 997: 989: 985: 981: 966: 962:osteoporosis 942: 934:cupric oxide 930: 918: 914: 910: 899: 896: 885:Food sources 879: 870: 866: 845: 836: 824: 790: 746: 732: 696: 683:transcuprein 668: 665:Distribution 656: 652: 643: 600: 597: 584: 551: 442:Involved in 360: 352: 338:malnourished 335: 328: 324: 316: 290: 278: 267: 264:Essentiality 249:microbiology 246: 224: 216: 209: 204:plastocyanin 168: 163:such as the 151:The protein 150: 143:→ Cu-SOD 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