Copper

Last Updated: September 28 2022

Copper is an essential mineral for antioxidative enzymes in the human body. While vital, it appears to be sufficient in the human diet and water supply with little evidence concerning its usefulness as a supplement. Excess copper is involved in some cases of Alzheimer's.

Copper is most often used for




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    1.

    Sources and Composition

    1.1

    Sources and Composition

    Copper is an essential mineral found ubiquitously in the food supply[1] and in drinking water[2]. Similar to many other essential minerals in the diet it serves as a cofactor for certain enzymes, enabling these enzymes to catalyze biochemical reactions that play a role in a number of metabolic pathways.[3]

    The EPA allows up to 1.3ppm copper in human drinking water.[4]

    1.2

    Biological Significance

    Copper's primary role in the body is as a cofactor for enzymes with a mineral component, known as metalloenzymes. In the case of copper-containing metalloenzymes, the copper cofactor cycles between the +1 and +2 oxidation state to catalyze important reduction and oxidation (REDOX) reactions.[5] The use of copper as an enzyme cofactor for redox chemistry is ancient, and well-conserved throughout all domains of life; there are at least 10 distinct copper-containing proteins across prokaryotes[6] including proteins such as NADH dehydrogenase-2, Cu,Zn-superoxide dismutase (SOD1), Cu amine oxidase, and most commonly cytochrome c oxidase.[6]

    Copper is most well known for being a vital component of the antioxidant enzyme superoxide dismutase (SOD), the major isoform being fully known as copper, zinc superoxide dismutase due to dependency on these two minerals.[7] The major function of SOD is dismutating the toxic superoxide anion (O2-) into either oxygen or hydrogen peroxide.[8][9] However, SOD also has non-specific CO2-dependent peroxidase activity, ultimately producing SOD-Cu(II)OH which then oxidizes CO2 to CO3- [7] [10] which can then act as an oxidizing intermediate in cellular metabolism.[11][12]

    There is also another variant of this enzyme which uses manganese as its functional group (known as MnSOD) rather than copper and zinc-SOD.[13] MnSOD has similar functions,[14] however, the main difference being where in the body each enzyme is expressed.

    Copper is an important cofactor for a number of enzymes in the body that catalyze redox reactions. The most important enzyme in so far as health claims and the effects of copper in humans is the antioxidant enzyme known as copper, zinc superoxide dismutase (Cu,Zn-SOD) where copper works in concert with zinc to transform toxic superoxide molecules into peroxide.

    Copper as a free ion rather than a component of enzymes has a stimulatory role in immune cells, where a deficiency tends to lead to a suppressed response to antigens[15][16] and may also suppress innate immunity,[17] manifesting as neutropenia (a lack of neutrophils).[18]

    Beyond its role as an enzyme cofactor, copper ions appear to have a stimulatory role in the immune system. It is important to emphasize, however, that copper is an essential_trace mineral; relatively low levels are required for optimal health and copper is inherently toxic high at high concentrations.

    1.4

    Deficiency

    The human body is somewhat resilient to copper deficiency due to the intestines increasing absorption of copper when bodily stores of copper drop,[23] and copper absorption becoming more efficient with reduced dietary copper intake.[22]

    Gastric bypass surgery is thought to be a risk factor for copper deficiency,[24] as are other gastric stressors such as gastrointestinal surgeries.[25] Usage of proton pump inhibitors (PPIs) may also contribute to copper deficiency[26] by reducing the ability of the body to absorb dietary copper.

    Copper deficiency is relatively rare, and not a major concern for the general population. Although rare, copper deficiencies have been noted under conditions that may reduce copper absorption, such as previous gastric bypass surgery or concurrent use of proton pump inhibitors.

    Some rodent studies have assessed the effects of a 'marginally' copper-deficient diet, which tends to be defined as providing approximately 25-50% of required dietary copper. For the rat, this equates to 1.5-3.0mg/kg copper, compared to 6.0-6.2mg/kg in the standard rat diet.[27][28]

    This low dose of copper appears to be associated with increased inflammation following an inflammatory stressor[27] and altered cardiovascular function ranging from altered mitochondrial structure and impaired cardiac function (seen at 50% of the standard copper level) to signs of cardiomyopathy (25% of the standard copper level).[29][28] There also appear to be alterations in blood flow[30] and increases in bleeding with reduced copper intake in rats.[31] One study also noted an upregulation of the pro-inflammatory enzyme COX-2 in rats with low copper intake.[32]

    These studies on reduced intake have noted effects that are similar to but less severe than models of true copper deficiency in rodents, where instances of substantially increased inflammation[33][34] and congestive heart failure have been reported.[35] Alterations in cardiac function prior to cardiomyopathy[36] and cardiac hypertrophy secondary to more drastic copper deficiencies[37] appear to be reversible following copper repletion.

    In rodents given a 'marginal' copper deficiency, (50% of the standard copper intake or less) there are negative changes in immune and cardiovascular function. These changes can be normalized when copper is introduced back into the diet at sufficient levels.

    True copper deficiency may result in myelopathy,[38][39] which has been noted in instances following gastrointestinal surgery.[25] Such myelopathy is known to occur in ruminants, where it is known as 'swayback'[25] and presents in both ruminants and humans as gait ataxia and sensory symptoms.[38][39] As assessed by MRI, copper deficiency myelopathy appears similar to subacute degeneration of the dorsal column in cases of Vitamin B12 deficiency.[38][39][40]

    True copper deficiency results in a neurological condition that is, to a degree, clinically similar to Vitamin B12 deficiency. This has only been noted in situations following gastrointestinal surgeries where copper absorption has been significantly impaired, however.

    1.5

    Sufficiency and Excess

    The copper intrauterine device (copper IUD) is a birth control device which, due to using copper in its actions, causes a small increase in serum copper concentrations in women who use the device.[41] The 6% increase in copper noted after three months using the copper IUD was not associated with toxicity.[41] Moreover, copper IUDs in lactating women a failed to increase copper concentrations in breast milk after six weeks.[42]

    2.

    Pharmacology

    2.1

    Absorption

    Dietary copper tends to be bound a bound form in food products, and the acidic environment of the stomach works to free the copper from these complexes.[43] Copper can be absorbed through stomach tissue[44] although when fed to rats via gastric intubation it has failed to appreciably be absorbed via the stomach wall.[45]

    It has been argued[46] that food-bound copper is processed differently than copper in the water supply or via dietary supplements; copper can appear rapidly in the blood as free copper (see distribution section) bypassing oral metabolism when not in foodbound form,[47] while acid-mediated digestion of copper from food products allows it to be processed by the liver.

    The acidity of the stomach plays a role in extracting dietary copper sources from foodstuffs so that free copper can be absorbed in the intestines.

    Copper is absorbed in the intestines from the same transporter as zinc, known as zinc transporters (ZnTs),[48][49] as well as a common bivalent cation transporter known as DMT1[50] that also mediates absorption of other minerals.[51] Copper also has its own transporter known as the copper transporter 1 (CRT1) which can also mediate zinc and iron transportation.[51] When copper is complexed with amino acids, amino acid transporters may also play a role in copper absorption.[52]

    The overall absorption of copper from the diet tends to be approximately 30-40%[53] although it is estimated to range between 12-67% reflecting dietary copper levels (better absorption with low intake, worse absorption with progressively higher intakes of copper[22][54]). Copper absorption also tends to vary from person to person, as differences have been noted among individuals even with the same amount of copper in the diet.[54]

    Copper can be absorbed from the intestines using a variety of different transporters, with the three groups of transporters (zinc transports, copper transports, and generalized bivalent cation transporters) also mediating iron and zinc absorption.

    High levels of zinc in the intestines can promote the synthesis of a binding protein known as metallothionein[55][56] which also binds to copper; this mechanism leads to high doses of zinc reducing copper absorption.[55][56] Copper also has the potential to induce metallothionein proteins,[57] in a process known as mutual antagonism.[58] Because copper intake is much lower relative to zinc, copper is typically not taken in amounts that would interfere with zinc absorption, however.

    The induction (responsive production) of the protein metallothionein is a protective mechanism that attenuates absorption of zinc or copper at high concentrations, reducing the risk of harm from mineral overdoses. High concentrations of either mineral can induce this protein, raising the potential for one mineral to cause deficiencies of the other by preventing absorption. On a practical level, copper-induced zinc deficiencies have not been reported due to the low amount of copper present in the diet relative to zinc. Excessive zinc intake is a well-known cause of copper deficiency, however.

    The addition of phytate to the diet has failed to influence copper absoprtion in man[54] although high levels of phytate in the rat show the expected reduction in bodily retention of copper over a prolonged period of time.[59]

    When looking at how other dietary components can influence absorption of copper in both rodents and humans,[53] it seems that high protein diets increase copper absorption in both rodents and humans (150g protein compared to 50g[60]) resulting in lower copper requirements with higher protein intakes.[61] Composition of the protein sources may also be relevant, as raw meat products have been noted to induce copper deficiency in rats whereas cooked meats have not been shown to have this effect.[62] The general idea of increased dietary protein promoting greater retention of copper may also be a more general mechanism that applies to other dietary minerals as well.[53]

    In regard to dietary factors that can interact with copper absorption, high protein diets tend to promote copper absorption while higher than normal intakes of phytic acid may reduce absorption. These alterations in absorption are similar for most other divalent cations including calcium and magnesium.

    2.2

    Peripheral Distribution

    When present in the blood, around 85-95% of copper is bound to the main transportation protein known as ceruloplasmin where it is referred to as 'bound' copper. In contrast, the remaining 5-15% of copper is more loosely bound to albumin and is termed 'free copper'.[46] Free copper levels are more biologically relevant since they can dissociate easier and act in nearby tissues. Diseases associated with high copper accumulation in tissue (ex. Wilson's Disease[63]) are at times due to reduced ceruloplasmin levels, causing an increase in free copper[64] (this is not the only explanation, however[65]). Outside of Wilson’s disease, more moderate increases in free copper are still thought to be harmful and a potential cause of toxicity.[66][46]

    The majority of copper found in circulation is tightly bound to the primary binding protein known as ceruloplasmin, with the remaining amount of copper, known as free copper, more loosely associated with albumin. Significant increases in free copper are considered a risk factor for toxicity.

    The overall copper content of an average human body (70kg body weight; approximately 110mg copper) tends to be 6% total copper circulating in the blood and another 9% within the brain, with the remaining 85% being stored in peripheral tissue. Among the peripheral tissues, 47% of total body copper is located in bone and connective tissue while 27% is in skeletal muscle and the remaining copper is stored in the liver.[67][68]

    3.

    Neurology

    3.1

    Anxiety and Stress

    Copper can contribute to oxidative stress, which may play a role in the development of anxiety disorders.[69] Furthermore, copper is known to inhibit the GABAA receptor[70][71], and GABAergic transmission is known to play a role in anxiety and depression.[72]

    Copper levels have been found to be significantly higher in a sample of Bangladeshi patients with generalized anxiety disorder (GAD) than healthy controls.[73] Those with GAD had similar socioeconomic characteristics to the controls, which may suggest that nutritional differences may not explain the differences in copper levels.[73] Higher levels of copper in those with anxiety compared to controls were found in a second study.[74] These patients were then treated with antioxidant therapy for a minimum of 8 weeks, along with zinc and magnesium and manganese if warranted, which reduced anxiety although it did not have a significant effect on serum copper levels.[74]

    3.2

    Depression

    Serum copper levels are consistently higher in patients with unipolar depression, even after successful treatment, thus suggesting that serum copper levels may be a "trait marker" for depression.[75] Copper levels have also been shown to correlate with depression levels in shift nurses[76] and post-partum depression.[77]

    Another study found that patients with depression had higher levels of serum copper compared to controls which was treated with a combination of antioxidant therapy and zinc for 8 weeks; depression did not respond to this treatment, nor did copper serum levels did not change post-treatment.[78]

    4.

    Cardiovascular Health

    4.1

    Cardiac Tissue

    The heart tissue of people who have died of ischemic heart disease tend to be low in copper.[79] Furthermore, enzymes which play a role in cardiovascular health through the rebuilding and maintenance of cardiovascular tissue, such as lysyl oxidase which helps crosslink arterial collagen and elastin, depend on copper.[79] Another copper-dependent enzyme, copper-zinc superoxide dismutase, plays a role in the antioxidant capacity of tissues throughout the body and has also been suggested to play a role in a cardiovascular health.[80] These facts together provide an observational and mechanistic rationale for a possible role of copper supplementation in cardiovascular health.

    However, several observational studies have noted that blood copper levels may actually be associated with cardiovascular disease. One cohort study found that increased ceruloplasmin levels (which is a major protein which carries copper in the blood) was correlated with an increased risk of heart attack.[81] An analysis of the Second National Health and Nutrition Examination Survey which directly measured serum copper also found that increased serum copper was associated with an increased risk for cardiovascular disease.[82]

    The heart tissue of people with heart disease tends to be low in copper. However, people with heart disease also tend to have higher levels of copper in the blood.

    There have been a few clinical trials to date specifically looking at how copper affects heart tissue and markers of cardiovascular disease.

    One study found that administering a copper chelator, which would be expected to bind copper in the blood, decreased hypertrophy of the left ventrical in patients with type 2 diabetes; urinary copper excretion due to chelation was found to be associated with better outcomes.[83] The phenomenon of high serum copper levels has been noted in an observational study involving elderly patients with left ventricular hypertrophy.[84]

    In terms of copper supplementation, one randomized placebo-controlled trial found no effect on C-reactive protein, homocysteine, and cholesterol when supplementing patients with moderately high blood cholesterol with 2mg copper per day for 8 weeks.[85] A randomized crossover trial in healthy young women treated with 0, 3, or 6mg copper for 4 weeks per period found no effect on several markers for cardiovascular disease except for a 30% reduction in plasminogen activator inhibitor type 1, a risk factor for thrombosis and atherosclerosis,[86] with 6mg of copper.[87]

    A copper chelator has been noted to help mitigate left ventricular hypertrophy in patients with type 2 diabetes. Copper supplementation has not been seen to have much effect on cardiovascular risk markers over the short term in clinical trials.

    4.2

    Atherosclerosis

    Serum copper is elevated in those with atherosclerosis, and there seems to be a dose-response relationship: higher serum copper levels correlate with more severe coronary artery disease.[88] Higher copper levels in the arterial wall of those with atherosclerosis has also been observed.[89]

    A randomized crossover trial in healthy young women treated with 0, 3, or 6mg copper for 4 weeks per period found that 6mg of copper for 4 weeks led to a 30% reduction in plasminogen activator inhibitor type 1,[87] which is a risk factor for atherosclerosis.[86]

    4.3

    Blood Pressure

    People newly-diagnosed with essential hypertension had lower plasma copper levels compared to people with normal blood pressure who were matched for age.[90]

    4.4

    Platelets and Viscosity

    A randomized crossover trial in healthy young women treated with 0, 3, or 6mg copper for 4 weeks per period found a 30% reduction in plasminogen activator inhibitor type 1 with 6mg of copper.[87]

    4.5

    Cholesterol

    One randomized placebo-controlled trial found no effect on total, HDL, or LDL cholesterol when supplementing healthy middle-aged people with moderately high blood cholesterol with 2mg copper per day for 8 weeks.[85] Similar null results on blood cholesterol were found when men with moderately high blood cholesterol were supplemented with 2mg copper per day for 4 weeks in a crossover trial.[91] Another trial in healthy men taking 8mg copper supplementation for 6 months found no effect on plasma lipid profile, either.[92]

    Copper supplementation of up to 6mg per day does not seem to have an effect on the susceptibility of LDL to oxidation in vitro.[93]

    Clinical trial evidence to date suggests that copper supplementation has no effect on plasma lipid profile.

    5.

    Interactions with Glucose Metabolism

    5.1

    Type II Diabetes

    While a deficiency of copper tends to result in impaired glucose metabolism and alterations in lipid metabolism phenotypically similar to that of type II diabetes,[94] serum concentrations of copper are generally unaltered in naturally-occurring type II diabetes when compared to healthy controls[95][96] or slightly increased.[97][98][99] A decrease in red blood cell concentration of copper may occur[100] and due in part due to reductions in serum zinc during the pathogenesis of type II diabetes the copper:zinc ratio is increased.[101]

    6.

    Peripheral Organ Systems

    6.1

    Eyes

    Copper is present in the retina[102] where it functions in REDOX balance as a cofactor for the enzyme copper, zinc-superoxide dismutase. Similar to other minerals involved in the catalytic activity of antioxidative enzymes, copper exerts protective effects by functioning as an enzyme cofactor,[103] but can also induce oxidative toxicity at high doses.[104]

    Copper concentrations in the human retina are generally an order of magnitude lower than zinc concentrations when assessed posthumously, ranging between 0.2-9nM/mg (retina), 0.4-7nM/mg (RPE; retinal pigment epithelium), and 0.6-4.2nM/mg (choroid) dry weight.[102] The changes in copper seem to be similar to changes in zinc, increasing in the choroid during the aging process (with minimal changes in the retina and RPE. There also appears to be some sex differences, with zinc being higher in the male choroid (no difference between zinc and copper in females) and copper higher in the RPE of women.[102] Cadmium, which is not present in this tissue at birth but increases with age[105] seems to also accumulate in the eye alongside copper and zinc with some sex differences.[102]

    Copper is present in all regions of the eye where it works with zinc as a cofactor for the enzyme Cu,Zn-superoxide dismutase.

    Due to the role of other essential minerals that are involved in oxidative processes in the retina (Zinc and Selenium in particular), copper is also thought to play a role in oxidative pathology of the retina, namely age-related macular degeneration.[106] Copper has been added to some compound formulations for age-related macular degeneration (AREDS at 2mg[107][108]) to avoid copper-deficiency, which is thought to be a risk with zinc supplementation.[109] There do not appear to be any studies on copper in isolation, however.

    At this moment in time there is no evidence to assess the role of copper specifically in age-related macular degeneration. It has been included alongside zinc in some formulations for precautionary measures.

    7.

    Inflammation and Immunology

    7.1

    Neutrophils

    Copper is implicated in the function of neutrophils.

    Marginal copper deficiency (25% of the copper-sufficient diet) appears to promote neutrophil accumulation in liver tissue following an inflammatory response in rats,[27] whereas more extensive deficiency has been shown to activate neutrophils.[110][111] Both neutrophil accumulation and activation contribute to the development of inflammation.

    7.2

    Macrophages

    Copper is known to play an important role in several cell signaling pathways important for the immunological function of macrophages.[17] In macrophages that have been activated by inflammatory cytokines, copper levels tend to increase,[112] while copper deficiency has been shown to impair their immunological function.[113] Moreover, copper deficiency in animals has been correlated with increased susceptibility to bacterial infections.[114]

    The mechanism by which copper enhances the macrophage immune-response has only recently been uncovered. As part of the innate immune response, activated macrophages (and neutrophils) engulf invading pathogens such as bacteria into membrane-bound phagosomes in a process called phagocytosis. The respiratory burst reaction inside phagosomes generates toxic reactive oxygen species (ROS) to kill invading pathogens while protecting the rest of the cell from damage. Copper has recently been found to play an important role in this process, where elevated intracellular copper levels in macrophages causes the copper transporter protein ATP7A to relocate to phagosomes, delivering additional copper ions that are thought to enhance the ROS-generating ability of the respiratory burst reaction.[115][116]

    By increasing ROS production within phagosomes, copper plays an important role in the ability of macrophages and neutrophils to kill invading pathogens.

    8.

    Interactions with Aesthetics

    8.1

    Hair

    Copper is known to play a role in differentiation and proliferation of dermal papilla cells (DPCs), a special type of fibroblast cell that is involved in hair growth.[117] In vitro administration of a tripeptide containing copper (at 1µM) appears to promote DPC proliferation, while promoting the growth and elongation of human hair follicles.[117]

    In subjects with hair loss, although Zinc seems to be lower relative to controls with no hair loss, serum concentrations of copper are unaltered.[118][119] The lone study assessing copper levels in hair itself (in men with androgenic alopecia) noted reduced concentrations relative to those without hair loss.[120]

    9.

    Sexuality and Pregnancy

    9.1

    Copper IUD

    The copper intrauterine device (IUD) is an implantable device in women which utilizes copper to exert an antifertility effect either acutely as emergency contraceptive[121] or for more prolonged periods of time with efficacy.[122][123]

    Women who use a copper IUD may experience bleeding irregularities within the first six months of usage[124] that may promote discontinuation of the IUD;[125] these irregularities may be treated by the likes of NSAIDs and other drugs.[126] Usage of the contraceptive may increase serum copper levels slightly (up to 6%), which is not thought to be toxic.[41] Use of a copper IUD has not been shown to affect copper concentrations in breast milk.[42]

    Copper IUDs may increase serum copper concentrations, but it is to a small degree and currently not thought be a significant health factor.

    10.

    Interactions with Medical Conditions

    10.1

    Alzheimer's Disease

    Copper is thought to contribute to Alzheimer's Disease (AD) since alterations in copper levels tend to precede symptoms of AD in some, but not all patients.[127] Generally subjects with AD have higher serum but not cerebrospinal fluid (CSF) copper concentrations than otherwise healthy controls[128] and copper is implicated in the disease mostly due to its correlation with the time-course of Alzheimer's (prevalence increasing in the last half decade) in developed nations using copper plumbing.[129] Increased free copper levels, while sometimes elevated only slightly, are prevalent enough in those with AD relative to healthy controls that this has been termed the "copper phenotype".[67]

    Although copper concentrations tend to be increased in the brain during the normal aging process in both serum[130] and the brain,[131] preexisting symptoms of AD can be exacerbated by long-term dietary copper exposure,[132] and copper chelators that decrease free copper levels can be therapeutic in mouse models.[133] Given the plausible role for copper in the pathology of AD, and plenty of aforementioned “circumstantial” evidence, it has been recommended that the elderly avoid multivitamins containing added copper[21] and also consider diets with lower copper levels.[20]

    Although copper concentrations in the body naturally become elevated during the aging process, levels tend to be higher in subjects with symptoms of Alzheimer's disease. Copper seems to be associated with worsening of symptoms and may have a causative role, suggesting that the elderly may benefit from reducing copper intake from food and supplements.

    When looking at in vitro evidence, it seems that copper itself can induce oxidative stress in neurons in a manner modulated by amyloid precursor proteins (APPs).[134][135] A prevailing theory is that by binding to amyloid beta (Aβ), a peptide derived from from APP, copper to undergoes redox cycling that produces peroxide, a possible driver of the oxidative-stress associated with AD pathology.[136][137][138][139][140][141]

    ATP7B is a gene that controls 'free' copper levels (copper in the body that is not bound to the primary copper-binding protein ceruloplasmin) and its dysfunction explains Wilson's disease. Thus, it was hypothesized that variations in ATP7B activity could also partially explain AD occurrence.[142] Supporting this idea, it has been reported that ATP7B SNPs that affect the affinity of ceruloplasmin for copper differ between AD patients and age-matched healthy controls.[143]

    The presence of certain mutations (SNPs) in ATP7B can increase free copper levels by reducing the binding affinity of ceruloplasmin. Certain ATP7B SNPs have recently been found to be more prevalent in those with Alzheimer’s disease (AD), suggesting that changes in genes that affect copper handling may confer a genetic susceptibility to AD.

    11.

    Nutrient-Nutrient Interactions

    11.1

    Zinc

    Zinc is a dietary mineral with shared metabolism and regulation with copper. Proteins known as metallothioneins exist which serve to sequester minerals and limit their activity through binding to them. These proteins are so important for metal ion regulation that they are expressed in almost all forms of life, from bacteria and fungi to plants and eukaryotes.[144] The major site of metallothionein biosynthesis is in the liver and kidneys,[145] where they are are normally expressed at low levels, which limits their activity, but are increased in response to elevated concentrations of zinc[146] or copper.[57] By binding to and regulating the concentration of essential minerals such as zinc and copper, metallothioneins limit cellular toxicity and regulate a number of metal ion-dependent physiological processes including transcription, metabolism, and the control of protein synthesis.[145]

    Metallothionein gene expression is regulated by the transcription factor metal-regulatory transcription factor 1 (MTF-1),[146][147] which is activated by zinc or copper as well as toxic heavy metals including cadmium[148][148] and mercury.[149] By binding to and sequestering heavy metals, metallothioneins also play an important role in limiting heavy metal toxicity.

    Metallothioneins can be found in the intestines, where high oral doses of zinc (600mg or greater[150]) increase their expression, which appears to be a protective response to limit zinc toxicity. Because metallothioneins bind minerals indiscriminately, this can cause reduced absorption of other minerals such as copper and is known to induce copper deficiencies,[151][152] a potential cause of CNS demyelination[153] [154] and/or death.[151]

    High doses of zinc are known to induce metallothioneins which can bind to copper and prevent its absorption. At the extreme, this could potentially cause copper deficiencies resulting in cognitive impairments and potentially death. It is unlikely that standard supplemental doses of zinc (15-50mg) are sufficient to cause such symptoms, however, as all known cases of zinc-induced copper deficiency were the result of accidental zinc overdoses or 500mg or greater.

    11.2

    Amino Acids

    High dietary protein intake (150g in an adult male[60]) has been shown to increase copper retention, although individual amino acids can have positive or negative effects in isolation. L-histidine has shown an inhibitory effect on copper retention[155] while other amino acids like Glycine, L-tryptophan, and L-methionine have been shown to promote it.[52] The ability of protein to affect copper levels is thought to be related to the affinity of individual amino acids for copper ions, which can function as ligands to transport copper across cellular membranes for absorption.[53] L-cysteine can reduce copper absorption by reducing divalent copper to a less absorbed, monovalent state,[156] a mechanism similar to Vitamin C-mediated suppression of copper absorption.[157] Binding of divalent copper to amino acid ligands attenuates the inhibitory effect of cysteine or vitamin C on absorption.[158]

    Copper is known to have a variety of interactions at the level of the intestines with amino acids that can affect absorption in a positive and negative manner. From a practical standpoint, the effects of increased dietary protein consumption (from food) seem to cause the pro-absorptive mechanisms to win out; increased protein intake has been shown to promote copper absorption.

    References
    1.^Subar AF1, Krebs-Smith SM, Cook A, Kahle LLDietary sources of nutrients among US adults, 1989 to 1991J Am Diet Assoc.(1998 May)
    7.^Liochev SI1, Fridovich IMechanism of the peroxidase activity of Cu, Zn superoxide dismutaseFree Radic Biol Med.(2010 Jun 15)
    8.^Tainer JA, Getzoff ED, Richardson JS, Richardson DCStructure and mechanism of copper, zinc superoxide dismutaseNature.(1983 Nov 17-23)
    9.^Getzoff ED, Tainer JA, Weiner PK, Kollman PA, Richardson JS, Richardson DCElectrostatic recognition between superoxide and copper, zinc superoxide dismutaseNature.(1983 Nov 17-23)
    10.^Liochev SI1, Fridovich ICO2, not HCO3-, facilitates oxidations by Cu,Zn superoxide dismutase plus H2O2Proc Natl Acad Sci U S A.(2004 Jan 20)
    12.^Medinas DB1, Cerchiaro G, Trindade DF, Augusto OThe carbonate radical and related oxidants derived from bicarbonate bufferIUBMB Life.(2007 Apr-May)
    15.^Blakley BR, Hamilton DLThe effect of copper deficiency on the immune response in miceDrug Nutr Interact.(1987)
    16.^Koller LD, Mulhern SA, Frankel NC, Steven MG, Williams JRImmune dysfunction in rats fed a diet deficient in copperAm J Clin Nutr.(1987 May)
    17.^Percival SS1Copper and immunityAm J Clin Nutr.(1998 May)
    18.^Williams DMCopper deficiency in humansSemin Hematol.(1983 Apr)
    20.^Squitti R1, Siotto M2, Polimanti R3Low-copper diet as a preventive strategy for Alzheimer's diseaseNeurobiol Aging.(2014 Sep)
    21.^Barnard ND1, Bush AI2, Ceccarelli A3, Cooper J4, de Jager CA5, Erickson KI6, Fraser G7, Kesler S8, Levin SM9, Lucey B10, Morris MC11, Squitti R12Dietary and lifestyle guidelines for the prevention of Alzheimer's diseaseNeurobiol Aging.(2014 Sep)
    24.^Saltzman E1, Karl JPNutrient deficiencies after gastric bypass surgeryAnnu Rev Nutr.(2013)
    25.^Kumar N1, McEvoy KM, Ahlskog JEMyelopathy due to copper deficiency following gastrointestinal surgeryArch Neurol.(2003 Dec)
    26.^Plantone D1, Renna R2, Primiano G3, Shukralla A4, Koudriavtseva T2PPIs as possible risk factor for copper deficiency myelopathyJ Neurol Sci.(2015 Jan 12)
    27.^Sakai N1, Shin T, Schuster R, Blanchard J, Lentsch AB, Johnson WT, Schuschke DAMarginal copper deficiency increases liver neutrophil accumulation after ischemia/reperfusion in ratsBiol Trace Elem Res.(2011 Jul)
    28.^Li Y1, Wang L, Schuschke DA, Zhou Z, Saari JT, Kang YJMarginal dietary copper restriction induces cardiomyopathy in ratsJ Nutr.(2005 Sep)
    29.^Wildman RE1, Hopkins R, Failla ML, Medeiros DMMarginal copper-restricted diets produce altered cardiac ultrastructure in the ratProc Soc Exp Biol Med.(1995 Oct)
    31.^Schuschke LA1, Saari JT, Miller FN, Schuschke DAHemostatic mechanisms in marginally copper-deficient ratsJ Lab Clin Med.(1995 Jun)
    32.^Schuschke DA1, Adeagbo AS, Patibandla PK, Egbuhuzo U, Fernandez-Botran R, Johnson WTCyclooxygenase-2 is upregulated in copper-deficient ratsInflammation.(2009 Oct)
    33.^Lentsch AB1, Kato A, Saari JT, Schuschke DAAugmented metalloproteinase activity and acute lung injury in copper-deficient ratsAm J Physiol Lung Cell Mol Physiol.(2001 Aug)
    34.^Schuschke DA1, Percival SS, Lominadze D, Saari JT, Lentsch ABTissue-specific ICAM-1 expression and neutrophil transmigration in the copper-deficient ratInflammation.(2002 Dec)
    35.^Elsherif L1, Ortines RV, Saari JT, Kang YJCongestive heart failure in copper-deficient miceExp Biol Med (Maywood).(2003 Jul)
    38.^Plantone D, Primiano G, Renna R, Restuccia D, Iorio R, Patanella KA, Ferilli MN, Servidei SCopper deficiency myelopathy: A report of two casesJ Spinal Cord Med.(2014 Oct 24)
    40.^Kumar N1, Ahlskog JE, Klein CJ, Port JDImaging features of copper deficiency myelopathy: a study of 25 casesNeuroradiology.(2006 Feb)
    41.^Imani S1, Moghaddam-Banaem L, Roudbar-Mohammadi S, Asghari-Jafarabadi MChanges in copper and zinc serum levels in women wearing a copper TCu-380A intrauterine deviceEur J Contracept Reprod Health Care.(2014 Feb)
    42.^Rodrigues da Cunha AC1, Dorea JG, Cantuaria AAIntrauterine device and maternal copper metabolism during lactationContraception.(2001 Jan)
    45.^Fields M, Craft N, Lewis C, Holbrook J, Rose A, Reiser S, Smith JCContrasting effects of the stomach and small intestine of rats on copper absorptionJ Nutr.(1986 Nov)
    46.^Brewer GJRisks of copper and iron toxicity during aging in humansChem Res Toxicol.(2010 Feb 15)
    47.^Hill GM, Brewer GJ, Juni JE, Prasad AS, Dick RDTreatment of Wilson's disease with zinc. II. Validation of oral 64copper with copper balanceAm J Med Sci.(1986 Dec)
    48.^Murgia C1, Vespignani I, Cerase J, Nobili F, Perozzi GCloning, expression, and vesicular localization of zinc transporter Dri 27/ZnT4 in intestinal tissue and cellsAm J Physiol.(1999 Dec)
    50.^Arredondo M1, Muñoz P, Mura CV, Nùñez MTDMT1, a physiologically relevant apical Cu1+ transporter of intestinal cellsAm J Physiol Cell Physiol.(2003 Jun)
    51.^Espinoza A1, Le Blanc S, Olivares M, Pizarro F, Ruz M, Arredondo MIron, copper, and zinc transport: inhibition of divalent metal transporter 1 (DMT1) and human copper transporter 1 (hCTR1) by shRNABiol Trace Elem Res.(2012 May)
    52.^Gao S1, Yin T2, Xu B2, Ma Y2, Hu M2Amino acid facilitates absorption of copper in the Caco-2 cell culture modelLife Sci.(2014 Jul 25)
    53.^Wapnir RACopper absorption and bioavailabilityAm J Clin Nutr.(1998 May)
    54.^Turnlund JR, King JC, Gong B, Keyes WR, Michel MCA stable isotope study of copper absorption in young men: effect of phytate and alpha-celluloseAm J Clin Nutr.(1985 Jul)
    56.^Fischer PW, Giroux A, L'Abbé MRThe effect of dietary zinc on intestinal copper absorptionAm J Clin Nutr.(1981 Sep)
    57.^Kumar KS1, Dayananda S, Subramanyam CCopper alone, but not oxidative stress, induces copper-metallothionein gene in Neurospora crassaFEMS Microbiol Lett.(2005 Jan 1)
    61.^Sandstead HHCopper bioavailability and requirementsAm J Clin Nutr.(1982 Apr)
    62.^MOORE T, CONSTABLE BJ, DAY KC, IMPEY SG, SYMONDS KRCOPPER DEFICIENCY IN RATS FED UPON RAW MEATBr J Nutr.(1964)
    63.^Ferenci PWilson's diseaseClin Liver Dis.(1998 Feb)
    64.^Brewer GJ1, Askari F, Dick RB, Sitterly J, Fink JK, Carlson M, Kluin KJ, Lorincz MTTreatment of Wilson's disease with tetrathiomolybdate: V. Control of free copper by tetrathiomolybdate and a comparison with trientineTransl Res.(2009 Aug)
    65.^Yüce A1, Koçak N, Ozen H, Gürakan FWilson's disease patients with normal ceruloplasmin levelsTurk J Pediatr.(1999 Jan-Mar)
    66.^Squitti R1, Ghidoni R, Scrascia F, Benussi L, Panetta V, Pasqualetti P, Moffa F, Bernardini S, Ventriglia M, Binetti G, Rossini PMFree copper distinguishes mild cognitive impairment subjects from healthy elderly individualsJ Alzheimers Dis.(2011)
    67.^Squitti R1, Polimanti RCopper phenotype in Alzheimer's disease: dissecting the pathwayAm J Neurodegener Dis.(2013 Jun 21)
    68.^Linder MC1, Hazegh-Azam MCopper biochemistry and molecular biologyAm J Clin Nutr.(1996 May)
    69.^Hassan W1, Silva CE2, Mohammadzai IU3, da Rocha JB4, J LF2Association of oxidative stress to the genesis of anxiety: implications for possible therapeutic interventionsCurr Neuropharmacol.(2014 Mar)
    72.^Kalueff AV1, Nutt DJRole of GABA in anxiety and depressionDepress Anxiety.(2007)
    74.^Russo AJ1Decreased zinc and increased copper in individuals with anxietyNutr Metab Insights.(2011 Feb 7)
    75.^Schlegel-Zawadzka M1, Zieba A, Dudek D, Zak-Knapik J, Nowak GIs serum copper a "trait marker" of unipolar depression? A preliminary clinical studyPol J Pharmacol.(1999 Nov-Dec)
    80.^Allen KG, Klevay LMCopper: an antioxidant nutrient for cardiovascular healthCurr Opin Lipidol.(1994 Feb)
    81.^Reunanen A, Knekt P, Aaran RKSerum ceruloplasmin level and the risk of myocardial infarction and strokeAm J Epidemiol.(1992 Nov 1)
    83.^Cooper GJ, Young AA, Gamble GD, Occleshaw CJ, Dissanayake AM, Cowan BR, Brunton DH, Baker JR, Phillips AR, Frampton CM, Poppitt SD, Doughty RNA copper(II)-selective chelator ameliorates left-ventricular hypertrophy in type 2 diabetic patients: a randomised placebo-controlled studyDiabetologia.(2009 Apr)
    86.^Vaughan DEPAI-1 and atherothrombosisJ Thromb Haemost.(2005 Aug)
    87.^Bügel S, Harper A, Rock E, O'Connor JM, Bonham MP, Strain JJEffect of copper supplementation on indices of copper status and certain CVD risk markers in young healthy womenBr J Nutr.(2005 Aug)
    88.^Bagheri B, Akbari N, Tabiban S, Habibi V, Mokhberi VSerum level of copper in patients with coronary artery diseaseNiger Med J.(2015 Jan-Feb)
    90.^Russo C, Olivieri O, Girelli D, Faccini G, Zenari ML, Lombardi S, Corrocher RAnti-oxidant status and lipid peroxidation in patients with essential hypertensionJ Hypertens.(1998 Sep)
    92.^Rojas-Sobarzo L, Olivares M, Brito A, Suazo M, Araya M, Pizarro FCopper supplementation at 8 mg neither affects circulating lipids nor liver function in apparently healthy Chilean menBiol Trace Elem Res.(2013 Dec)
    93.^Turley E, McKeown A, Bonham MP, O'Connor JM, Chopra M, Harvey LJ, Majsak-Newman G, Fairweather-Tait SJ, Bügel S, Sandström B, Rock E, Mazur A, Rayssiguier Y, Strain JJCopper supplementation in humans does not affect the susceptibility of low density lipoprotein to in vitro induced oxidation (FOODCUE project)Free Radic Biol Med.(2000 Dec)
    94.^Keil HL, Nelson VETHE RÔLE OF COPPER IN CARBOHYDRATE METABOLISMJ Biol Chem.(1934)
    95.^Kazi TG1, Afridi HI, Kazi N, Jamali MK, Arain MB, Jalbani N, Kandhro GACopper, chromium, manganese, iron, nickel, and zinc levels in biological samples of diabetes mellitus patientsBiol Trace Elem Res.(2008 Apr)
    96.^Ekmekcioglu C1, Prohaska C, Pomazal K, Steffan I, Schernthaner G, Marktl WConcentrations of seven trace elements in different hematological matrices in patients with type 2 diabetes as compared to healthy controlsBiol Trace Elem Res.(2001 Mar)
    97.^Walter RM Jr1, Uriu-Hare JY, Olin KL, Oster MH, Anawalt BD, Critchfield JW, Keen CLCopper, zinc, manganese, and magnesium status and complications of diabetes mellitusDiabetes Care.(1991 Nov)
    98.^Savu O1, Ionescu-Tirgoviste C, Atanasiu V, Gaman L, Papacocea R, Stoian IIncrease in total antioxidant capacity of plasma despite high levels of oxidative stress in uncomplicated type 2 diabetes mellitusJ Int Med Res.(2012)
    99.^Aguilar MV1, Saavedra P, Arrieta FJ, Mateos CJ, González MJ, Meseguer I, Martínez-Para MCPlasma mineral content in type-2 diabetic patients and their association with the metabolic syndromeAnn Nutr Metab.(2007)
    100.^Williams NR1, Rajput-Williams J, West JA, Nigdikar SV, Foote JW, Howard ANPlasma, granulocyte and mononuclear cell copper and zinc in patients with diabetes mellitusAnalyst.(1995 Mar)
    102.^Wills NK1, Ramanujam VM, Kalariya N, Lewis JR, van Kuijk FJCopper and zinc distribution in the human retina: relationship to cadmium accumulation, age, and genderExp Eye Res.(2008 Aug)
    103.^Behndig A1, Svensson B, Marklund SL, Karlsson KSuperoxide dismutase isoenzymes in the human eyeInvest Ophthalmol Vis Sci.(1998 Mar)
    104.^Gahlot DK, Ratnakar KSEffect of experimentally induced chronic copper toxicity on retinaIndian J Ophthalmol.(1981 Dec)
    105.^Wills NK1, Ramanujam VM, Chang J, Kalariya N, Lewis JR, Weng TX, van Kuijk FJCadmium accumulation in the human retina: effects of age, gender, and cellular toxicityExp Eye Res.(2008 Jan)
    106.^Zampatti S1, Ricci F2, Cusumano A2, Marsella LT1, Novelli G3, Giardina E4Review of nutrient actions on age-related macular degenerationNutr Res.(2014 Feb)
    107.^Age-Related Eye Disease Study Research GroupThe Age-Related Eye Disease Study (AREDS): design implications. AREDS report no. 1Control Clin Trials.(1999 Dec)
    110.^Gordon SA1, Lominadze D, Saari JT, Lentsch AB, Schuschke DAImpaired deformability of copper-deficient neutrophilsExp Biol Med (Maywood).(2005 Sep)
    111.^Lominadze D1, Saari JT, Percival SS, Schuschke DAProinflammatory effects of copper deficiency on neutrophils and lung endothelial cellsImmunol Cell Biol.(2004 Jun)
    116.^White C1, Lee J, Kambe T, Fritsche K, Petris MJA role for the ATP7A copper-transporting ATPase in macrophage bactericidal activityJ Biol Chem.(2009 Dec 4)
    117.^Pyo HK1, Yoo HG, Won CH, Lee SH, Kang YJ, Eun HC, Cho KH, Kim KHThe effect of tripeptide-copper complex on human hair growth in vitroArch Pharm Res.(2007 Jul)
    118.^Kil MS, Kim CW, Kim SSAnalysis of serum zinc and copper concentrations in hair lossAnn Dermatol.(2013 Nov)
    119.^Bhat YJ1, Manzoor S, Khan AR, Qayoom STrace element levels in alopecia areataIndian J Dermatol Venereol Leprol.(2009 Jan-Feb)
    120.^Ozturk P1, Kurutas E2, Ataseven A3, Dokur N4, Gumusalan Y5, Gorur A6, Tamer L7, Inaloz S8BMI and levels of zinc, copper in hair, serum and urine of Turkish male patients with androgenetic alopeciaJ Trace Elem Med Biol.(2014 Jul)
    121.^Turok DK1, Jacobson JC2, Dermish AI2, Simonsen SE3, Gurtcheff S4, McFadden M5, Murphy PA6Emergency contraception with a copper IUD or oral levonorgestrel: an observational study of 1-year pregnancy ratesContraception.(2014 Mar)
    125.^Sivin I1, Stern J, Diaz S, Pavéz M, Alvarez F, Brache V, Mishell DR Jr, Lacarra M, McCarthy T, Holma P, et alRates and outcomes of planned pregnancy after use of Norplant capsules, Norplant II rods, or levonorgestrel-releasing or copper TCu 380Ag intrauterine contraceptive devicesAm J Obstet Gynecol.(1992 Apr)
    126.^Godfrey EM1, Folger SG, Jeng G, Jamieson DJ, Curtis KMTreatment of bleeding irregularities in women with copper-containing IUDs: a systematic reviewContraception.(2013 May)
    127.^Bush AI1, Tanzi RETherapeutics for Alzheimer's disease based on the metal hypothesisNeurotherapeutics.(2008 Jul)
    128.^Bucossi S1, Ventriglia M, Panetta V, Salustri C, Pasqualetti P, Mariani S, Siotto M, Rossini PM, Squitti RCopper in Alzheimer's disease: a meta-analysis of serum,plasma, and cerebrospinal fluid studiesJ Alzheimers Dis.(2011)
    130.^Madarić A1, Ginter E, Kadrabová JSerum copper, zinc and copper/zinc ratio in males: influence of agingPhysiol Res.(1994)
    131.^Vasudevaraju P1, Bharathi, T J, Shamasundar NM, Subba Rao K, Balaraj BM, Ksj R, T S SRNew evidence on iron, copper accumulation and zinc depletion and its correlation with DNA integrity in aging human brain regionsIndian J Psychiatry.(2010 Apr)
    132.^Mao X1, Ye J, Zhou S, Pi R, Dou J, Zang L, Chen X, Chao X, Li W, Liu M, Liu PThe effects of chronic copper exposure on the amyloid protein metabolisim associated genes' expression in chronic cerebral hypoperfused ratsNeurosci Lett.(2012 Jun 14)
    133.^Ceccom J1, Coslédan F, Halley H, Francès B, Lassalle JM, Meunier BCopper chelator induced efficient episodic memory recovery in a non-transgenic Alzheimer's mouse modelPLoS One.(2012)
    134.^White AR1, Multhaup G, Maher F, Bellingham S, Camakaris J, Zheng H, Bush AI, Beyreuther K, Masters CL, Cappai RThe Alzheimer's disease amyloid precursor protein modulates copper-induced toxicity and oxidative stress in primary neuronal culturesJ Neurosci.(1999 Nov 1)
    136.^Yoshiike Y1, Tanemura K, Murayama O, Akagi T, Murayama M, Sato S, Sun X, Tanaka N, Takashima ANew insights on how metals disrupt amyloid beta-aggregation and their effects on amyloid-beta cytotoxicityJ Biol Chem.(2001 Aug 24)
    137.^Huang X1, Atwood CS, Hartshorn MA, Multhaup G, Goldstein LE, Scarpa RC, Cuajungco MP, Gray DN, Lim J, Moir RD, Tanzi RE, Bush AIThe A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reductionBiochemistry.(1999 Jun 15)
    139.^Huang X1, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LE, Scarpa RC, Saunders AJ, Lim J, Moir RD, Glabe C, Bowden EF, Masters CL, Fairlie DP, Tanzi RE, Bush AICu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reductionJ Biol Chem.(1999 Dec 24)
    140.^Barnham KJ1, Masters CL, Bush AINeurodegenerative diseases and oxidative stressNat Rev Drug Discov.(2004 Mar)
    141.^Dai XL1, Sun YX, Jiang ZFCu(II) potentiation of Alzheimer Abeta1-40 cytotoxicity and transition on its secondary structureActa Biochim Biophys Sin (Shanghai).(2006 Nov)
    143.^Squitti R1, Polimanti R, Bucossi S, Ventriglia M, Mariani S, Manfellotto D, Vernieri F, Cassetta E, Ursini F, Rossini PMLinkage disequilibrium and haplotype analysis of the ATP7B gene in Alzheimer's diseaseRejuvenation Res.(2013 Feb)
    144.^Aschner M1, West AKThe role of MT in neurological disordersJ Alzheimers Dis.(2005 Nov)
    145.^Sharma S1, Ebadi M2Significance of metallothioneins in aging brainNeurochem Int.(2014 Jan)
    147.^Heuchel R1, Radtke F, Georgiev O, Stark G, Aguet M, Schaffner WThe transcription factor MTF-1 is essential for basal and heavy metal-induced metallothionein gene expressionEMBO J.(1994 Jun 15)
    148.^Klaassen CD1, Liu J, Choudhuri SMetallothionein: an intracellular protein to protect against cadmium toxicityAnnu Rev Pharmacol Toxicol.(1999)
    149.^Aschner M1, Syversen T, Souza DO, Rocha JBMetallothioneins: mercury species-specific induction and their potential role in attenuating neurotoxicityExp Biol Med (Maywood).(2006 Oct)
    150.^Willis MS1, Monaghan SA, Miller ML, McKenna RW, Perkins WD, Levinson BS, Bhushan V, Kroft SHZinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examinationAm J Clin Pathol.(2005 Jan)
    152.^Nations SP1, Boyer PJ, Love LA, Burritt MF, Butz JA, Wolfe GI, Hynan LS, Reisch J, Trivedi JRDenture cream: an unusual source of excess zinc, leading to hypocupremia and neurologic diseaseNeurology.(2008 Aug 26)
    153.^Prodan CI1, Holland NR, Wisdom PJ, Burstein SA, Bottomley SSCNS demyelination associated with copper deficiency and hyperzincemiaNeurology.(2002 Nov 12)
    154.^Prodan CI1, Holland NRCNS demyelination from zinc toxicityNeurology.(2000 Apr 25)
    157.^Van Campen D, Gross EInfluence of ascorbic acid on the absorption of copper by ratsJ Nutr.(1968 Aug)