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    J Clinic Toxicol Heavy Metal Toxicity ISSN: 2161-0495 JCT, an open access journal

    Research Article Open Access

    Osredkar and Sustar, J Clinic Toxicol 2011, S:3

    http://dx.doi.org/10.4172/2161-0495.S3-001

    Review Article Open Access

    Clinical Toxicology

    Copper and Zinc, Biological Role and Significance of Copper/Zinc

    ImbalanceJosko Osredkar*1and Natasa Sustar2

    1University Medical Centre Ljubljana, Zaloska cesta 2, 1000 Ljubljana, Slovenia2General Hospital Izola, Polje 40, 6310 Izola, S lovenia

    Introduction

    Te human body has an elaborate system or managing andregulating the amount o key trace metals circulating in blood and

    stored in cells. Nutrient metals rom our diet are incorporated intoblood i blood levels are depleted, transported into cells i cellularlevels are inadequate, or excreted i blood and cell levels are sufficient

    or overloaded. When this system ails to unction properly, abnormal

    levels and ratios o trace metals can develop. One o the most commontrace-metal imbalances is elevated copper and depressed zinc. Te ratio

    o copper to zinc is clinically more important than the concentration oeither o these trace metals [1].

    Tere are 2-4 grams o Zn distributed throughout the human body[2]. Most zinc is in the brain, muscle, bones, kidney and liver, with the

    highest concentrations in the prostate and parts o the eye [3]. It is thesecond most abundant transition metal in organisms afer iron and it isthe only metal which appears in all enzyme classes[2,4].

    Copper is also a vital dietary nutrient, although only small amountso the metal are needed or well-being [5]. Although copper is the third

    most abundant trace metal in the body [behind iron and zinc], the totalamount o copper in the body is only 75-100 milligrams [6]. Copper ispresent in every tissue o the body, but is stored primarily in the liver,

    with ewer amounts ound in the brain, heart, kidney, and muscles [7].

    Te Path and the Role of Zinc [Zn] in Organisms

    Biological role of Zn

    Zinc is involved in numerous aspects o cellular metabolism [8].

    It was estimated that about 10% o human proteins potentially bind

    zinc, in addition to hundreds which transport and traffic zinc . It is

    required or the catalytic activity o more than 200 enzymes [9,10] and

    it plays a role in immune unction [10,11], wound healing [10], protein

    synthesis, DNA synthesis and cell division [12]. Zinc is required or

    proper sense o taste and smell [13,14] and supports normal growth

    and development during pregnancy, childhood, and adolescence [15-18]. It is believed to possess antioxidantproperties, which may protect

    against accelerated aging and helps speed up the healing process afer

    an injury; however, studies differ as to its effectiveness [16,19]. Zinc

    ions are effective antimicrobial agents even at low concentrations.

    Gastroenteritis is strongly attenuated by ingestion o zinc and this

    effect could be due to direct antimicrobial action o the zinc ions in

    the gastrointestinal tract, or to the absorption o the zinc and re-release

    rom immune cells [all granulocytessecrete zinc], or both [20,21,22].

    Cells in the salivary gland, prostate, immune system and intestine

    use Zn signaling as one way to communicate with other cells [23]. In

    the brain, zinc is stored in specific synaptic vesiclesby glutamatergic

    neurons and can modulate brain excitability [24]. It plays a key role

    in synaptic plasticity and so in learning [24-26]. It also can be aneurotoxin, suggesting zinc homeostasisplays a critical role in normal

    unctioning o the brain and central nervous system[24].

    *Corresponding author: Josko Osredkar, University Medical Centre Ljubljana,

    Zaloska cesta 2, 1000 Ljubljana, Slovenia, E-mail:[email protected]

    ReceivedOctober 19, 2011; AcceptedDecember 06, 2011; PublishedDecember

    10, 2011

    Citation: Osredkar J, Sustar N (2011) Copper and Zinc, Biological Role and

    Signicance of Copper/Zinc Imbalance. J Clinic Toxicol S3:001. doi:10.4172/2161-

    0495.S3-001

    Copyright: 2011 Osredkar J, et al. This is an open-access article distributedunder the terms of the Creative Commons Attribution License, which permits

    unrestricted use, distribution, and reproduction in any medium, provided the

    original author and source are credited.

    Zn metabolism

    In blood plasma, Zn is bound to and transported by albumin(60%, low-affinity) and transerrin (10%) [27]. Since transerrinalso transports iron, excessive iron can reduce zinc absorption, and

    vice-versa [28]. Te concentration o zinc in blood plasma staysrelatively constant regardless o zinc intake [29]. Zinc may be held inmetallothionein reserves and also transerred in metal transporters

    o ZIP and Zn amily transporter proteins [30]. Metallothioneinsin intestinal cells are capable o adjusting absorption o zinc by 1540% [31]. Excess zinc particularly impairs copper absorption becausemetallothioneins absorb both metals [32].

    Zn enzymes

    wo examples o zinc-containing enzymes are carbonic anhydraseand carboxypeptidase, which are vital to the processes o carbondioxide (CO

    2)regulation and digestion o proteins, respectively

    [33,34]. In vertebrate blood, carbonic anhydrase (Figure 1) convertsCO

    2into bicarbonate and the same enzyme transorms the bicarbonate

    back into CO2 or exhalation through the lungs [35]. Without this

    enzyme, this conversion would occur about one million times slowerat the normal blood pHo 7 or would require a pH o 10 or more [36].

    Carboxypeptidase cleaves peptide linkages during digestion o proteins.A coordinate covalent bondis ormed between the terminal peptideand a C=O group attached to zinc, which gives the carbon a positivecharge. Tis helps to create a hydrophobicpocket on the enzyme nearthe Zn, which attracts the non-polar part o the protein being digested[34].

    Zn serves a purely structural role in zinc fingers(Figure 2) [37].Zinc fingers orm parts o some transcription actors, which areproteins that recognize DNA base sequencesduring the replication andtranscription o DNA. Each o the nine or ten Zn2+ions in a zinc fingerhelps maintain the fingers structure by coordinately binding to ouramino acidsin the transcription actor [38]. Te transcription actorwraps around the DNA helix and uses its fingers to accurately bindto the DNA sequence [39,40]. Zn ions are coordinated to the amino

    acid side chains o aspartic acid, glutamic acid, cysteine and histidine[41].Te metal also has a flexible coordination geometry, which allowsproteins using it to rapidly shif conormationsto perorm biologicalreactions [42].

    http://en.wikipedia.org/wiki/Enzyme#Naming_conventionshttp://en.wikipedia.org/wiki/Antioxidanthttp://en.wikipedia.org/wiki/Antimicrobial_agenthttp://en.wikipedia.org/wiki/Gastroenteritishttp://en.wikipedia.org/wiki/Gastrointestinal_tracthttp://en.wikipedia.org/wiki/Granulocytehttp://en.wikipedia.org/wiki/Synaptic_vesicleshttp://en.wikipedia.org/wiki/Glutamatergichttp://en.wikipedia.org/wiki/Synaptic_plasticityhttp://en.wikipedia.org/wiki/Neurotoxinhttp://en.wikipedia.org/wiki/Homeostasishttp://en.wikipedia.org/wiki/Central_nervous_systemhttp://dx.doi.org/10.4172/2161-0495.S3-001http://dx.doi.org/10.4172/2161-0495.S3-001http://en.wikipedia.org/wiki/Blood_plasmahttp://en.wikipedia.org/wiki/Albuminhttp://en.wikipedia.org/wiki/Transferrinhttp://en.wikipedia.org/wiki/Metallothioneinhttp://en.wikipedia.org/wiki/Carbonic_anhydrasehttp://en.wikipedia.org/wiki/Carboxypeptidasehttp://en.wikipedia.org/wiki/Carbon_dioxidehttp://en.wikipedia.org/wiki/Carbon_dioxidehttp://en.wikipedia.org/wiki/PHhttp://en.wikipedia.org/wiki/Coordinate_covalent_bondhttp://en.wikipedia.org/wiki/Hydrophobichttp://en.wikipedia.org/wiki/Zinc_fingerhttp://en.wikipedia.org/wiki/Transcription_factorhttp://en.wikipedia.org/wiki/DNA_sequencehttp://en.wikipedia.org/wiki/DNAhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Coordination_geometryhttp://en.wikipedia.org/wiki/Protein_structurehttp://en.wikipedia.org/wiki/Protein_structurehttp://en.wikipedia.org/wiki/Coordination_geometryhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/DNAhttp://en.wikipedia.org/wiki/DNA_sequencehttp://en.wikipedia.org/wiki/Transcription_factorhttp://en.wikipedia.org/wiki/Zinc_fingerhttp://en.wikipedia.org/wiki/Hydrophobichttp://en.wikipedia.org/wiki/Coordinate_covalent_bondhttp://en.wikipedia.org/wiki/PHhttp://en.wikipedia.org/wiki/Carbon_dioxidehttp://en.wikipedia.org/wiki/Carbon_dioxidehttp://en.wikipedia.org/wiki/Carboxypeptidasehttp://en.wikipedia.org/wiki/Carbonic_anhydrasehttp://en.wikipedia.org/wiki/Metallothioneinhttp://en.wikipedia.org/wiki/Transferrinhttp://en.wikipedia.org/wiki/Albuminhttp://en.wikipedia.org/wiki/Blood_plasmahttp://dx.doi.org/10.4172/2161-0495.S3-001http://dx.doi.org/10.4172/2161-0495.S3-001http://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Homeostasishttp://en.wikipedia.org/wiki/Neurotoxinhttp://en.wikipedia.org/wiki/Synaptic_plasticityhttp://en.wikipedia.org/wiki/Glutamatergichttp://en.wikipedia.org/wiki/Synaptic_vesicleshttp://en.wikipedia.org/wiki/Granulocytehttp://en.wikipedia.org/wiki/Gastrointestinal_tracthttp://en.wikipedia.org/wiki/Gastroenteritishttp://en.wikipedia.org/wiki/Antimicrobial_agenthttp://en.wikipedia.org/wiki/Antioxidanthttp://en.wikipedia.org/wiki/Enzyme#Naming_conventions
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    Citation: Osredkar J, Sustar N (2011) Copper and Zinc, Biological Role and Signicance of Copper/Zinc Imbalance. J Clinic Toxicol S3:001.

    doi:10.4172/2161-0495.S3-001

    J Clinic Toxicol Heavy Metal Toxicity ISSN: 2161-0495 JCT, an open access journal

    Zn transport system

    Zinc unctions in biology are numerous, but can be separatedinto three main categories: catalytic, regulatory, and structuralroles [42]. Greater than ten percent o the human genome codes orzinc-containing proteins [43]. Zn homeostasis is controlled by thecoordinated actions o Zn transporters, which are responsible or Zninflux and efflux, and regulate the intracellular and extracellular Znconcentration and distribution. Zn transporters contribute to cellular

    events at the molecular, biochemical, and genetic level, with recentprogress uncovering the roles o Zn transporters in physiology andpathogenesis [42,43].

    ight-control o cellular zinc homeostasis is maintained by proteinsthat can affect the amount o available zinc. Metal transporters o ZIPamily and zinc transporters o Zn amily, as well as zinc-bindingby metallothioneins; maintain control o intracellular zinc levels.Currently, 10 Zn and 14 ZIP transporters have been identified. TeZn proteins unction in cellular zinc efflux or vesicular storage. Zn1was the first zinc transporter to be characterized, and is expressed inall tissues, localizing to the plasma membrane o cells [43]. Subsequentstudies revealed zinc-regulated expression o Zn1, and that zincregulates expression o Zn1 through activation o the metal response

    element metal binding transcription actor MF-1. Already knownmetal-inducible genes regulated by MF-1 include the metallothioneins,glutamatecysteine ligase heavy chain (which codes or an oxidativestress-related protein), and already mentioned Zn1. MF-1 responds

    to changes in intracellular zinc and other heavy-metals (cadmium andcopper), where upon metal-occupancy there is translocation o MF-1rom the cytosol to the nucleus. Subsequently this transcription actor

    binds to metal response elements located in the proximal promoters ometal responsive genes, resulting in an increased rate o transcription[43].Te importance o MF-1 to zinc homeostasis and mammalianphysiology is accentuated by the act that ablation o the gene leads tosevere liver degeneration and embryonic lethality in mice. Subsequentinvestigation o a liver-specific conditional knockout o the MF-1gene in mice revealed another MF-1 regulated zinc transporter gene ZIP10: Te experiment on isolated mice hepatocytes showed that MF-1 is an integral part o ZIP10 related cellular zinc homeostasis in theliver both during zinc restriction and zinc excess. Te results showedthat MF-1 has physiologic significance and can act as a repressor oZIP10 under normal cellular levels o zinc. Upon reducing cellularzinc, repression is lost and MF-1 is not translocated to the nucleus,allowing enhanced ZIP10 transcriptional activation. Te results alsoshow that ZIP10 is a new target to investigate dietary influences on zincmetabolism by the liver and within specific regions o the brain. Zincis believed to have second messenger unctions in brain and the ZIPtransporters are believed to be a key to cellular Zn homeostasis [43].

    Te Path and the Role of Copper [Cu] in Organisms

    Biological role of Cu

    Copper plays an important role in our metabolism, largely becauseit allows many critical enzymes to unction properly [44]. Copperis essential or maintaining the strength o the skin, blood vessels,epithelial and connective tissue throughout the body. Cu plays a rolein the production o hemoglobin, myelin, melanin and it also keeps

    thyroid gland unctioning normally [7,44,45].

    Copper can act as bothan antioxidant and a pro-oxidant. Free radicals occur naturally in thebody and can damage cell walls, interact with genetic material, andcontribute to the development o a number o health problems anddiseases. As an antioxidant, Cu scavenges or neutralize ree radicals andmay reduce or help prevent some o the damage they cause [5,46-48].When copper acts as a pro-oxidant at times, it promotes ree radicaldamage and may contribute to the development o Alzheimers disease[49,50]. Maintaining the proper dietary balance o Cu, along with otherminerals such as zinc and manganese, is important [5].

    Cu metabolism

    Copper is absorbed in the gut and transported to the liver boundto albumin. It enters the bloodstream via the plasma protein called

    ceruloplasmin, where its metabolism is controlled, and is excretedin bile [51]. A transporter protein on the cells o the small bowel,copper membrane transporter 1 - CM1, carries copper inside thecells, where some is bound to metallothioneins and part is carried bycopper transport protein - AOX1 (copper chaperone or AP7Aand AP7B) to the trans-Golgi network. Here, in response to risingconcentrations o copper, an enzyme called AP7A releases copperinto theportal veinto the liver. Liver cells also carry the CM1 protein,and metallothioneins and AOX1 bind Cu inside the liver cells, buthere it is AP7B that links copper to ceruloplasminand releases it intothe bloodstream, as well as removing excess copper by secreting it intobile[52].Approximately 90% o the copper in the blood is incorporatedinto ceruloplasmin, which is responsible or carrying copper to tissuesthat need the mineral [44,45]. Since excretion o copper is so slow (10%in 72 hours) an excessive dose o Cu is a lingering problem [51]. Properabsorption and metabolism o copper requires an appropriate balancewith the minerals zinc and manganese. Because zinccan compete with

    Figure 1:Diagramof human carbonic anhydrase, with Zn atom visible in

    the center.

    Figure 2:The Zn ion (green), coordinated by two histidine side chains in

    Zn ngers.

    http://dx.doi.org/10.4172/2161-0495.S3-001http://en.wikipedia.org/wiki/Serum_albuminhttp://en.wikipedia.org/wiki/Plasma_proteinhttp://en.wikipedia.org/wiki/Ceruloplasminhttp://en.wikipedia.org/wiki/Bilehttp://en.wikipedia.org/wiki/Enterocytehttp://en.wikipedia.org/wiki/SLC31A1http://en.wikipedia.org/wiki/Metallothioneinhttp://en.wikipedia.org/wiki/ATOX1http://en.wikipedia.org/wiki/Golgi_apparatushttp://en.wikipedia.org/wiki/ATP7Ahttp://en.wikipedia.org/wiki/Portal_veinhttp://en.wikipedia.org/wiki/Ceruloplasminhttp://en.wikipedia.org/wiki/Bilehttp://www.whfoods.com/genpage.php?tname=nutrient&dbid=115http://en.wikipedia.org/wiki/Ribbon_diagramhttp://en.wikipedia.org/wiki/Carbonic_anhydrasehttp://en.wikipedia.org/wiki/Carbonic_anhydrasehttp://en.wikipedia.org/wiki/Ribbon_diagramhttp://www.whfoods.com/genpage.php?tname=nutrient&dbid=115http://en.wikipedia.org/wiki/Bilehttp://en.wikipedia.org/wiki/Ceruloplasminhttp://en.wikipedia.org/wiki/Portal_veinhttp://en.wikipedia.org/wiki/ATP7Ahttp://en.wikipedia.org/wiki/Golgi_apparatushttp://en.wikipedia.org/wiki/ATOX1http://en.wikipedia.org/wiki/Metallothioneinhttp://en.wikipedia.org/wiki/SLC31A1http://en.wikipedia.org/wiki/Enterocytehttp://en.wikipedia.org/wiki/Bilehttp://en.wikipedia.org/wiki/Ceruloplasminhttp://en.wikipedia.org/wiki/Plasma_proteinhttp://en.wikipedia.org/wiki/Serum_albuminhttp://dx.doi.org/10.4172/2161-0495.S3-001
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    Citation: Osredkar J, Sustar N (2011) Copper and Zinc, Biological Role and Signicance of Copper/Zinc Imbalance. J Clinic Toxicol S3:001.

    doi:10.4172/2161-0495.S3-001

    J Clinic Toxicol Heavy Metal Toxicity ISSN: 2161-0495 JCT, an open access journal

    mediated knockdown o COMMD1 expression results in a significantinduction o SOD1 activity and a consequent decrease in superoxideanion concentrations, whereas overexpression o COMMD1 exerts

    exactly the opposite effects. COMMD1 is a novel protein regulatingSOD1 activation and associate COMMD1 unction with the productiono ree radicals [70,71].

    Cu chaperones

    Te intracellular trafficking o Cu to copper-dependent proteins isundamental to normal cellular metabolism. Te copper chaperonesperorm the dual unctions o trafficking and the prevention ocytoplasmic exposure to copper ions in transit. Only a small numbero copper chaperones have been identified at this time but theirconservation across plant, bacterial and animal species suggests thatthe majority o living systems utilise these proteins or copper routing[72].Te available data suggest that each copper-dependent protein in

    the cell is served by a specific copper chaperone. Specificity or a givencopper-dependent protein appears to be mediated by the residuessurrounding the copper-binding moti [73].

    Copper is needed within mitochondria to supply the Cu proteinsand intramembrane Cu sites o cytochrome oxidase, within the trans-Golgi network to supply secreted cuproproteins and within the cytosolto supply Cu/Zn superoxide dismutase1 (SOD1). Subpopulations ocopper-zinc superoxide dismutase also localize to mitochondria, thesecretory system and the nucleus [74]. Copper metallochaperonesassist copper in reaching vital destinations without inflicting damage orbecoming trapped in adventitious binding sites [72]. Copper ions arespecifically released rom copper metallochaperones upon contact withtheir cognate cuproproteins, so metal transer is thought to proceed byligand substitution [73].

    Copper chaperone or SOD1 specifically delivers copper to SOD1in cytoplasm o mammalian cells. In the present study, small intereringRNA targeting copper chaperone or SOD1 (CCS) was introduced intometallothionein-knockout mouse fibroblasts (M-KO cells) and theirwild type cells (M-W cells) to reveal the interactive role o CCS withother Cu-regulating proteins. CCS knockdown significantly decreasedthe level o Cu influx transporter (Ctr1). On the other hand, mRNAexpression or a Cu efflux transporter (AP7A) was increased andwas 3.0 - 2.5 times higher than those o the control. Te experimentalso showed that the AP7A knockdown significantly increased theintracellular Cu concentration. Te activity o SOD1 were maintainedin both M-W and M-KO cells even when copper chaperone orSOD1 protein expression was reduced to 0.30-0.35 o control. Tis

    suggests that the amount o CCS protein exceeds that required tosupply Cu to SOD1 in the cells. Further, the CCS knockdown inducesCu accumulation in cells. Te results showed that Cu accumulationis ameliorated by the metallothionein induction, the decrease o Ctr1expression and the increase o AP7A expression to maintain Cuhomeostasis [76].

    Sources of Copper and Zinc and Dietary Intakes

    Food sources

    A daily intakes o Cu and Zn is required to maintain a steadystate because the body has no specialized storage system o these twoelements [5,12,77].A wide variety o oods contain zinc [18]. Oysterscontain more zinc per serving than any other ood, but red meat,

    especially bee, lamband liverhave some o the highest concentrationso zinc in ood [78]. Other good ood sources include beans, nuts,other types o seaood (such as crab and lobster), whole grains, cereals,

    almonds, pumpkin seeds, sunflower seeds [18,78]. Rich sources ocopper include oysters and other sea ood, bee and organ meats(especially liver), dark green leay vegetables, enriched cereals, nuts

    and sunflower seeds, green olives, avocados, dried legumes, chocolate,cocoa, and black pepper [5,45].

    Dietary supplements

    Supplements contain several orms o zinc, including zinc gluconate,zinc sulate, and zinc acetate. Te percentage o elemental zinc variesby orm o supplement [79].Scientists has not determined whetherdifferences exist among orms o zinc in absorption, bioavailability, ortolerability [17].

    Multivitamins that include minerals generally provide copper. It isalso available as an individual oral supplement. Cu supplements shouldnot be given to children, at children it should be obtained rom ood[5,7].

    Recommended intakes for Zn

    Intake recommendations or Zn are provided in the DietaryReerence Intakes developed by the Food and Nutrition Board (FNB)at the Institute o Medicine o the National Academies. Te currentRecommended Dietary Allowances [RDA] or zinc is listed in able1 [18]. For inants aged 0-6 months, the FNB established an AdequateIntake * or Zn (= intake o Zn in breasted inants) [80,81]. U.S.National Research Council set a olerable Upper Intake or adults o40 mg/day [82,83].

    Recommended intakes for Cu

    Te 10th edition o Recommended Dietary Allowances (RDA) did

    not include an RDA or copper; rather a sae and adequate daily intakewas suggested. Some nutritionists think, committees that establishRDAs should return to the traditions o the first nine editions andmake recommendations that meet unctional needs, because lack oa recommended dietary allowance or copper may be hazardous tohealth [81,84]. Te ollowing able 2 provide the Recommended dailydietary intake (RDI) o copper or children and adults and olerableupper intake levels or copper [83,85].

    Interactions of Cu and Zn with micronutrients

    Fortification o oods with iron in iron-deficiency anemia does notsignificantly affect zinc absorption. But large amounts o supplementaliron, greater than 25 mg, might decrease zinc absorption [86,87] .aking iron supplements between meals helps decrease its effect on

    zinc absorption [87].Several laboratory and human studies have oundthat high levels o supplemental zinc taken over extended periods otime may result in decreased copper absorption in the intestine, andcopper deficiency with associated anemia [88]. But some studiesin humans suggest that high dietary Zn may not interere with theactual tissue or plasma concentrations o Cu [7]. Some experts believethat elevated copper levels, especially when zinc levels are also low,

    Age Male [mg] Female [mg] Pregnancy [mg] Lactation [mg]

    06 months 2 * 2 *

    712 months 3 3

    13 years 3 3

    48 years 5 5

    913 years 8 8

    1418 years 11 9 12 13

    19+ years 11 8 11 12

    Table 1:Recommended Dietary Allowances [RDAs] for Zn /per day.

    http://dx.doi.org/10.4172/2161-0495.S3-001http://en.wikipedia.org/wiki/Beefhttp://en.wikipedia.org/wiki/Lamb_and_muttonhttp://en.wikipedia.org/wiki/Liver#As_foodhttp://en.wikipedia.org/wiki/Pumpkin_seedhttp://en.wikipedia.org/wiki/Sunflower_seedhttp://en.wikipedia.org/wiki/Sunflower_seedhttp://en.wikipedia.org/wiki/Pumpkin_seedhttp://en.wikipedia.org/wiki/Liver#As_foodhttp://en.wikipedia.org/wiki/Lamb_and_muttonhttp://en.wikipedia.org/wiki/Beefhttp://dx.doi.org/10.4172/2161-0495.S3-001
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    Citation: Osredkar J, Sustar N (2011) Copper and Zinc, Biological Role and Signicance of Copper/Zinc Imbalance. J Clinic Toxicol S3:001.

    doi:10.4172/2161-0495.S3-001

    J Clinic Toxicol Heavy Metal Toxicity ISSN: 2161-0495 JCT, an open access journal

    may be a contributing actor in many medical conditions including

    schizophrenia, hypertension, autism, atigue, muscle and joint pain,

    headaches, childhood hyperactivity, depression, insomnia, senility,

    and premenstrual syndrome [1]. Adults taking copper supplementsshould also take zinc supplements (8 - 15 mg o zinc or every 1 mg o

    copper), because o an imbalance o these two minerals [89,90]. Copper

    is known to react with a variety o nutrients, including iron, zinc,

    molybdenum, sulur, selenium and vitamin C [5]. Teres also some

    evidence, not conclusive, that high supplemental doses o vitamin C

    in a range approaching 1 gram or more-may decrease Cu availability

    [91].Tere is also some evidence that in the ormula eeding o inants,

    too much iron in a ormula can lower absorption o copper rom that

    ormula [45,92].

    Zinc deficiency

    Nearly two billion people in the developing world are deficient

    in zinc [93]. Zinc deficiency is characterized by growth retardation,loss o appetite, and impaired immune unction [94,95,96]. In more

    severe cases, zinc deficiency causes hair loss, diarrhea, delayed sexual

    maturation, impotence, hypogonadism in males, and eye and skin

    lesions. Weight loss and impaired appetite, delayed healing o wounds,

    taste abnormalities, and altered cognition can also occur [13,17,94,97-

    99]. When zinc deficiency does occur, it is usually due to inadequate

    zinc intake or absorption, increased losses o zinc rom the body, or

    increased requirements or zinc [94,98]. It can be associated with

    malabsorption, acrodermatitis enteropathica, chronic liver disease,

    chronic renal disease, sickle cell disease, diabetes, malignancy, and

    other chronic illnesses [97-102]. In children it causes an increase in

    inection and diarrhea, contributing to the death o about 800,000

    children worldwide per year [94,101]. Te WHO advocates zincsupplementation or severe malnutrition and diarrhea [103].

    Severe Zn deficiency depresses immune unction [104],and even

    mild to moderate degrees o zinc deficiency can impair macrophage

    and neutrophil unctions, natural killer cell activity, and complement

    activity [105,106]. Te body requires zinc to develop and activate

    -lymphocytes [107]. Individuals with low zinc levels have shown

    reduced lymphocyte prolieration response to mitogens and other

    adverse alterations in immunity that can be corrected by zinc

    supplementation [104,108]. Tese alterations in immune unction

    might explain why low zinc status has been associated with increased

    susceptibility to pneumonia and other inections in children in

    developing countries and the elderly [94, 109-111]. However, zinc

    supplements should not be administered alone, since many in the

    developing world have several deficiencies, and zinc also interacts with

    other micronutrients [112].

    Groups at risk of Zn inadequacy

    Pregnant and lactating women: Pregnant women, particularly

    those starting their pregnancy with marginal zinc status, are atincreased risk o becoming zinc insufficient due, in part, to high etalrequirements or zinc [113]. Lactation can also deplete maternal zincstores [114]. For these reasons, the RDA or zinc is higher or pregnantand lactating women than or other women [80]. Te ollowing studywas perormed, to analyse the inter-relationship among trace elements:iron, copper and zinc o blood sample in pregnant women. Te levelo copper was ound to be significantly higher in iron deficiencyanaemia, when compared to non-iron deficiency anaemia [p

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    Citation: Osredkar J, Sustar N (2011) Copper and Zinc, Biological Role and Signicance of Copper/Zinc Imbalance. J Clinic Toxicol S3:001.

    doi:10.4172/2161-0495.S3-001

    J Clinic Toxicol Heavy Metal Toxicity ISSN: 2161-0495 JCT, an open access journal

    diarrhea in children with adequate zinc status, such as most children,are not clear. Te WHO and UNICEF now recommend short-term zincsupplementation (20 mg o zinc per day, or 10 mg or inants under 6

    months, or 1014 days) to treat acute childhood diarrhea [103].

    Alcoholics: Approximately 30%50% o alcoholics have low zincstatus because ethanol consumption decreases intestinal absorption ozinc and increases urinary zinc excretion [127].In addition, the varietyand amount o ood consumed by many alcoholics is limited, leadingto inadequate zinc intake [128,129].

    Acrodermatitis enteropathica

    Zinc supplementation is an effective treatment or acrodermatitisenteropathica, an inborn error o zinc metabolism that is inheritedas an autosomal recessive disorder. Te lack o zinc presents,characteristically, as: pustular dermatitis, diarrhea, and nail dystrophy.Irritability and emotional disturbances are due to atrophy o the braincortex. Te severity o the disease is proportional to the zinc level.Beore zinc supplementations acrodermatitis enteropathicawas atal tobabies born with it [97,98].

    Cooper Deficiency

    Because copper is involved in many unctions o the body,copper deficiency can produce an extensive range o symptoms [130].Deficiencies o copper can result in hernias, aneurysms, blood vesselbreakage maniesting as bruising or nosebleeds [5], iron deficiencyanemia [45], osteoporosis and joint problems [131], brain disturbances[54], abnormalities in glucose and cholesterol metabolism [132],increased susceptibility to inections due to poor immune unction[neutropenia] [133], loss o pigment, weakness, atigue, skin sores,

    poor thyroid unction [5], irregular heart beat [134] and low bodytemperature [46]. I copper is important in cellular membranestructure, then a copper deficiency could seriously alter the movemento nutrients through cell walls [5].

    Groups at risk of Cu inadequacy

    Despite the act that most people consume less than recommendedamounts o copper in their diet, these symptoms o copper deficiencyare relatively rare [5]. However, certain medical conditions includingchronic diarrhea, celiac sprue, Crohns disease and GI surgery result indecreased absorption o copper and may increase the risk o developinga copper deficiency. Inflammatory bowel disease (IBD) may be relatedto oxidation or damage caused by ree radicals. In act, copper levels maybe low in the inflamed tissue o those with IBD, particularly Crohnsdisease. When treating IBD, clinicians ofen recommend multivitamincontaining essential minerals [135]. In addition, copper requiressufficient stomach acid or absorption, so people who consume antacidsregularly may increase the risk o developing a copper deficiency [7].Inadequate copper status is also observed in children with low proteinintake and in inants ed only cows milk without supplemental copper(they might have poor eeding habits and lack o proper gowth) [5,45].

    Menkes disease

    Menkes disease is an X-linked recessive disorder characterizedby copper deficiency resulting in a diminished unction o copper-dependent enzymes. A diversity o mutations in the gene encodingo the copper-transporting APase, AP7A (located on chromosome

    Xq12-q13), underlies Menkes disease [68]. Signs and symptoms o thisdisorder include weak muscle tone, sagging acial eatures, seizures,mental retardation, developmental delay and kinky, colorless hair.Tere can be an extensive neurodegeneration in the gray matter o the

    brain. Arteries in the brain can also be twisted with split inner walls.Tis can lead to rupture or blockage o the arteries. O steoporosismayresult in ractures. Most patients die in early childhood, although mild

    orms have also been described [53,54].

    Diagnosis of Copper and Zinc Deficiency

    Te diagnosis o Cu and Zn deficiency is based on our maincriteria, namely anamnesis, symptomatology, belonging to well-definedrisk groups and the determination o biomarkers [5,7,8]. Te optimalplasma or serum ratio between these two elements is 0.70 - 1.00 [1].

    Diagnosing zinc deficiency is a persistent challenge. Zincnutritional status is difficult to measure adequately using laboratorytests due to its distribution throughout the body as a component o

    various proteins and nucleic acids [18,136]. Plasma or serum zinc levelsare the most commonly used indices or evaluating zinc deficiency, butplasma zinc, has poor sensitivity and specificity- these levels do not

    necessarily reflect cellular zinc status due to tight homeostatic controlmechanisms. So clinical effects o zinc deficiency can be present in theabsence o abnormal laboratory indices [17,25,47].

    Severe Cu deficiency can be ound by testing or low plasmaor serum copper levels, low ceruloplasmin, and low red blood cellsuperoxide dismutase levels; but these are not sensitive at a state omarginal copper status [46,137]. Te cytochrome c oxidase activity oleucocytes and platelets has been stated as another actor in deficiency,but in the studies this hypotesis has not been confirmed yet [138].

    Copper and Zinc oxicity

    Health risks from excessive zinc

    Although zinc is an essential requirement or good health, excesszinc can be harmul [9]. Excessive absorption o zinc suppresses copperand iron absorption [32]. Acute adverse effects o high zinc intakeinclude nausea, vomiting, loss o appetite, abdominal cramps, diarrhea,and headaches [9]. One case report cited severe nausea and vomitingwithin 30 minutes o ingesting 4 g o zinc gluconate [139] .Intakes o150450 mg o zinc per day have been associated with such chroniceffects as low copper status, altered iron unction, reduced immuneunction, and reduced levels o high-density lipoproteins. Reductionsin the superoxide dismutase levels, a marker o copper status, havebeen reported with even moderately high zinc intakes o approximately60 mg/day or up to 10 weeks [140,141].

    Zn poisoning

    In 1982, pennieswere made primarily o zinc covered with copper.With the new zinc pennies, there was the potential or zinc toxicosis,which can be atal. One reported case o ingestion o 425 pennies (over1 kg o zinc) resulted in death due to gastrointestinal bacterial andungal sepsis, while another patient, who ingested 12 grams o zinc,showed lethargyand ataxia [142,143].

    Copper toxicity

    Excessive copper intake can cause nausea, vomiting, abdominalpain and cramps, headache, dizziness, weakness, diarrhea, and ametallic taste in the mouth (assosiated with water containing copperconcentrations greater than 6 mg/L) [5]. Chronic copper toxicitydoes not normally occur in humans because o transport systems that

    regulate absorption and excretion [144]. Since excess copper is excretedthrough bile, copper toxicity is most likely to occur in individuals withliver disease or other medical conditions in which the excretion o bileis compromised [5]. Whether copper is carcinogenic has not been

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    doi:10.4172/2161-0495.S3-001

    J Clinic Toxicol Heavy Metal Toxicity ISSN: 2161-0495 JCT, an open access journal

    determined yet [145-147]. Postpartum depression has also been linkedto high levels o copper. Tis is because copper concentrations increasethroughout pregnancy to approximately twice normal values, and it

    may take up to three months afer delivery or copper concentrations tonormalize [148]. Tere are scientific articles that indicate a link betweenlong-term exposure to high concentrations o copper and a decline inintelligence with young adolescents [149]. Whether this should be oconcern is a topic or urther investigation.

    Cu poisoning

    In recent years, nutritionists have been more concerned aboutcopper toxicity than copper deficiency. One explanation or this wasthe increase in the amount o copper ound in drinking water due tothe switch in some areas rom galvanized water pipes to copper waterpipes. Cooking with copper cookware can also increase the coppercontent o oods. Industrial exposure to copper umes, dusts or mists

    may result in metal ume ever with atrophic changes in nasal mucousmembranes [5]. Intentionally high uptakes o copper may cause liverand kidney damage and even death. Gram quantities o various coppersalts have been taken in suicide attempts and produced copper toxicityin humans, possibly due to redox cycling and the generation o reactiveoxygen species that damage DNA[150].Corresponding amounts ocopper salts (30 mg/kg) are toxic in animals [151].

    Wilsons disease or hepatolenticular degeneration

    Wilsons disease is a rare, progressive, autosomal recessive disordercharacterised by impaired transport and excessive accumulation ocopper in the liver, brain, and other tissues [152].Te condition is dueto mutations in the Wilson disease protein o AP7B gene (locatedon chromosome13q14.3) [68], by impaired copper incorporation to

    ceruloplasmin and biliary copper excretion. It is characterisied by ahepatic cirrhosis, neurological maniestations (dystonia, dysarthria,muscle weakness, vertigo), psychiatric maniestations, renal disease,and copper deposition in the cornea Kayser-Fleischer ring (Figure5) [53,54,152]. Te treatment o Wilsons disease involves avoidance ooods rich in copper and any supplements containing copper and drugtreatment with chelating agents that remove the excess copper rom thebody (D-penicillamine, Zn acetate)[153].

    In the study o copper toxicosic in humans, lipid peroxidationand copper content were significantly increased (P < 0.05) in hepaticmitochondria rom patients with Wilsons disease. More modestincreases in lipid peroxidation were present in microsomes rompatients with Wilsons disease. Mitochondrial copper concentrations

    correlated strongly with the severity o mitochondrial lipidperoxidation. Tese data suggest that the hepatic mitochondria are animportant target in hepatic copper toxicity and that oxidant damage tothe liver may be involved in the pathogenesis o copper-induced injury.A significant decrease (37%) in the vitamin E/lipid ratio was alsodetectable in patients with Wilsons disease showing high ree serum

    copper (>10 micrograms/dl). Te data support a role or ree radicals inthe pathogenesis o active liver diseases [154].Another study revealedthat impaired conversion o 25(OH)D to 1,25(OH)2D occurs in copper

    intoxication and suggests that altered vitamin D metabolism is apotential actor in the development o bone and mineral abnormalitiesin Wilsons disease [155].

    Te Studies about the Role of Copper and Zinc in

    Diseases

    Immunological disorders

    Te common cold: Researchers have hypothesized that zinccould reduce the severity and duration o cold symptoms by directlyinhibiting rhinovirus binding and replication in the nasal mucosaand suppressing inflammation [156]. Although studies examiningthe effect o zinc treatment on cold symptoms have had somewhatconflicting results, overall zinc appears to be beneficial under certaincircumstances. In a randomized, double-blind, placebo-controlledclinical trial, 50 subjects (within 24 hours o developing the commoncold) took a zinc acetate lozenge (13.3 mg zinc) or placebo every 23wakeul hours. Compared with placebo, zinc lozenges significantlyreduced the duration o cold symptoms (cough, nasal discharge, andmuscle aches) [157]. In another clinical trial involving 273 participantswith experimentally induced colds, zinc gluconate lozenges significantlyreduced the duration o illness compared with placebo but had no effecton symptom severity [158]. In 2007, Caruso and colleagues published astructured review o the effects o zinc lozenges, nasal sprays, and nasalgels on the common cold. O the 14 randomized, placebo-controlledstudies included, 7 showed that the zinc treatment had a beneficialeffect and 7 showed no effect [159]. A Cochrane review concluded

    that zinc (lozenges or syrup) is beneficial in reducing the duration andseverity o the common cold in healthy people, when taken within 24hours o onset o symptoms [160].Recently (in August 2011), in themeta-analysis all o the identified placebo-controlled trials, includedin MEDLINE, Scopus, and Cochrane Central Register o Controlledrials (CENRAL) databases, were analysed together. Te study showsstrong evidence that the zinc lozenge effect on common cold durationis heterogeneous so that benefit is observed with high doses o zinc butnot with low doses: a total daily zinc dose o less than 75 mg ound noeffect on common cold duration, whereas using zinc acetate in dailydoses exceeding 75 mg showed a 42% reduction in the duration o coldsand using zinc salts other than acetate in daily doses exceeding 75 mgshowed a 20% reduction in the duration o colds. Te effects o zinclozenges should be urther studied to determine the optimal lozenge

    compositions and treatment strategies [161]. Numerous case reports oanosmia, in some cases long-lasting or permanent, rom the use o zinc-containing nasal gels or sprays (but only in these orms) raise questionsabout the saety o intranasal zinc [162, 163]. In June 2009, the FDAwarned consumers to stop using three zinc-containing intranasalproducts because they might cause anosmia [164].On the basis o thelong-term studies with high zinc doses, mentioned beore, there doesnot seem to be any basis or assuming that treating the common coldor a week with high doses o zinc in the orm o lozenges would causeunanticipated harm. A patient suffering rom acute adverse effects suchas bad taste can simply stop taking the lozenges [161].

    Arterial and venous leg ulcers: Zinc helps maintain the integrityo skin and mucosal membranes [105]. Patients with chronic leg ulcers

    have abnormal zinc metabolism and low serum zinc levels [165].Clinicians requently treat skin ulcers with zinc supplements [166].Te authors o a systematic review concluded that zinc sulate mightbe effective or treating leg ulcers in some patients who have low serum

    Figure 5:Kayser-Fleischers ring (the deposition of copper on Descemets

    membrane and the anterior and posterior lens capsule).

    http://dx.doi.org/10.4172/2161-0495.S3-001http://en.wikipedia.org/wiki/Reactive_oxygen_specieshttp://en.wikipedia.org/wiki/Reactive_oxygen_specieshttp://en.wikipedia.org/wiki/DNAhttp://en.wikipedia.org/wiki/Mutationhttp://en.wikipedia.org/wiki/Wilson_disease_proteinhttp://en.wikipedia.org/wiki/Genehttp://en.wikipedia.org/wiki/Chromosomehttp://en.wikipedia.org/wiki/Chromosomehttp://en.wikipedia.org/wiki/Genehttp://en.wikipedia.org/wiki/Wilson_disease_proteinhttp://en.wikipedia.org/wiki/Mutationhttp://en.wikipedia.org/wiki/DNAhttp://en.wikipedia.org/wiki/Reactive_oxygen_specieshttp://en.wikipedia.org/wiki/Reactive_oxygen_specieshttp://dx.doi.org/10.4172/2161-0495.S3-001
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    doi:10.4172/2161-0495.S3-001

    J Clinic Toxicol Heavy Metal Toxicity ISSN: 2161-0495 JCT, an open access journal

    zinc level, but it is not effective in the general use in patients withchronic leg ulcers, arterial or venous ulcers [167,168].

    Wound healing: Copper plays a major role in wound healing.Scientists think that introducing copper into wound dressings wouldnot only reduce the risk o wound and dressing contamination, but alsostimulate aster healing. Releasing copper rom the dressings directlyonto the wound promotes skin regeneration [169].

    Burns: When skin is burned, a substantial percentage omicronutrients, such as copper, selenium, and zinc may be lost. Tisincreases the risk or inection, slows the healing process, prolongs thehospital stay, and even increases the risk o death. However, peoplewith major burns tend to lose copper more rapidly than other minerals.Although it is unclear which micronutrients are most beneficial orpeople with burns, many clinical studies suggest that a multivitaminincluding copper and other minerals may aid in the recovery process[170].

    Immunological disorders on animal models: Another studyshows that copper deficiency in mice impairs immune system unction.Dietary copper was restricted in mice during five discrete intervalsover a 9 week period o perinatal development: gestation only (G),lactation only (L), 3 week postlactation (PL), 1 week afer birth throughpostlactation (2/3L + PL), and lactation plus postlactation (L + PL).Signs o severe copper deficiency, such as low liver copper levels,and significant reductions in activity o plasma ceruloplasmin andsplenocyte Cu/Zn superoxide dismutase were most evident in 6-week-old mice rom two groups, -Cu 2/3L + PL and -Cu L + PL. Mice inthese groups were anemic and had small thymuses and enlargedspleens compared to controls receiving +Cu treatment. Te -Cu micedemonstrated impaired antibody - plaque-orming cells response (PFC)

    to sheep erythrocytes, and the attenuation was proportional to copperdeficiency, as judged by liver copper levels. otal plasma IgM levelswere not greatly altered by -Cu treatment except in model L + PL. otalIgG levels were markedly reduced in this group and in the Cu 2/3L +PL group. Te PFC response o mice in the -Cu PL group was normaleven though signs o copper deficiency were evident; however, the PFCresponse was reduced when -Cu treatment was extended to 5 weeks,and was reversible by switching to +Cu treatment. It is evident thatseverity o copper deficiency in mice is related to degree o impairedimmunity. Furthermore, severity o copper deficiency is dependent onduration and time o initiation o dietary copper restriction [171].

    In the next study, the effects o severe, moderate, and mild copperdeficiencies on cellular and humoral immunity o fify male rats were

    studied. All rats were immunized once with sheep red blood cells.Mean plasma-copper concentration reflected the dietary levels ocopper, and ceruloplasmin activity correlated highly to plasma copper.Rats consuming suboptimal levels o copper responded differently tothe deficiencies, so copper status varied among those animals. Afer8 weeks, cell prolieration, when stimulated by phytohemagglutinin,was dependent on the copper status o the animal. Severely deficientrats had consistently lower lymphocyte stimulation indexes orphytohemagglutinin, but specific antibody response was not reduced.ImmunoglobulinG concentrations were variable or all rats, andimmunoglobulin M concentrations were lower or the severelydeficient rats [172].

    Te role of Cu/ZnSOD1 in oxidative stress

    Detailed studies in the past two decades have shown that redoxactive metals like iron, copper, chromium, cobalt and other metalsundergo redox cycling reactions and possess the ability to produce

    reactive radicals such as superoxide anion radical and nitric oxide inbiological systems. Disruption o metal ion homeostasis may lead tooxidative stress, a state where increased ormation o reactive oxygen

    species overwhelms body antioxidant protection and subsequentlyinduces DNA damage, lipid peroxidation, protein modification andother effects, all symptomatic or numerous diseases, involving cancer,cardiovascular disease, diabetes, atherosclerosis, neurological disorders,chronic inflammation and others. A special position among metals isoccupied by the redox inert metal zinc. Zn is an essential componento numerous proteins involved in the deense against oxidative stress.It has been shown, that depletion o Zn may enhance DNA damage viaimpairments o DNA repair mechanisms. In addition, Zn has an impacton the immune system and possesses neuroprotective properties. Temechanism o metal-induced ormation o ree radicals is tightlyinfluenced by the action o cellular antioxidants. Besides the encymes(SOD, catalase), many low-molecular weight antioxidants (ascorbic

    acid, alpha-tocopherol, glutathione, carotenoids, flavonoids, andother antioxidants) are capable o chelating metal ions reducing theircatalytic activity to orm reactive oxygen species [173]. In the studydesigned to assess the antioxidant status and erythrocyte oxidativeinjuries in Iranian at-tailed sheep that suffered rom malignanttheileriosis, blood samples were taken and hematological parameters,the activities o antioxidant enzymes including superoxide dismutase(SOD), glutathione peroxidase (GPX) and catalase, erythrocyteosmotic ragility, and serum concentrations o some trace elements(copper, iron, zinc, manganese, and selenium), were measured. As anindex o lipid peroxidation, the level o malondialdehyde (MDA) wasalso determined. According to the results, a significant decrease in redblood cell count, packed cell volume, the activities o SOD, GPX, andcatalase (p

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    doi:10.4172/2161-0495.S3-001

    J Clinic Toxicol Heavy Metal Toxicity ISSN: 2161-0495 JCT, an open access journal

    [NF-B] in rat cortical neurons in animal model o Zn deficiency.A low rate o in vitro tubulin polymerization, an increase in tubulinoligomers, and a higher protein cysteine oxidation were observed in

    the Zn-deficient neuronal cells. In this animal model o Zn deficiencythe conclusion was that a deficit in Zn viability could affect earlybrain development through: an induction o oxidative stress, tubulin

    oxidation, altered tubulin dynamics and deregulation o signals(NF-B) involved in critical developmental events [176]. In anotherstudy, rat embryos were ed with Cu-adequate (8 micrograms Cu/g)

    or Cu-deficient (< 0.5 micrograms Cu/g) diet and were cultured inCu-adequate (16.2 microM) or Cu-deficient (1.0 microM) rat serum.Control embryos cultured in control serum were morphologically

    normal. Cu-deficient embryos developed abnormally when culturedin Cu-deficient serum; the abnormalities included distended hindbrains, blisters, blood pooling, and cardiac deects. Control embryos

    cultured in Cu-deficient serum and Cu-deficient embryos cultured

    in control serum also showed abnormal development, but to a lesserdegree than that o the Cu-deficient embryos cultured in Cu-deficient

    serum. o test the idea that the above abnormalities were due in partto ree radical induced damage occurring secondary to an impairedoxidant deense system, a chemiluminescence assay was used to detect

    superoxide dismutase (SOD) activity in the cultured embryos. SODactivity was lowest in embryos cultured in Cu-deficient serum. Whenthe Cu-deficient serum was supplemented with antioxidants (Cu/

    ZnSOD or glutathione peroxidase), its teratogenicity was reduced.Tese data support the idea that an impaired oxidant deense systemcontributes to the dysmorphology associated with Cu deficiency.

    However, the Cu-deficient embryos also had low cytochrome c oxidaseactivity compared to control embryos - thus, multiple actors are likelycontributing to Cu deficiency induced abnormalities [177].

    Te Studies of Cu/Zn imbalance in neurological disorders

    Te highest levels o zinc are ound in the hippocampus insynaptic vesicles, boutons, and mossy fibers. Zinc is also ound inlarge concentrations in the choroid layer o the retina. Zinc plays animportant role in axonal and synaptic transmission and is necessary ornucleic acid metabolism and brain tubulin growth and phosphorylation.Lack o zinc has been implicated in impaired DNA, RNA, and proteinsynthesis during brain development. For these reasons, deficiency ozinc during pregnancy and lactation has been shown to be related tomany congenital abnormalities o the nervous system. Furthermore, inchildren insufficient levels o zinc have been associated with loweredlearning ability, apathy, lethargy, and mental retardation. Children

    with attention deficit disorder may be deficient in zinc and vitaminB-6 and have an excess o lead and copper. Alcoholism, schizophrenia,Wilsons disease, and Picks disease are brain disorders dynamicallyrelated to zinc levels. Zinc has been employed with success to treatWilsons disease, achrodermatitis enteropathica, and specific types oschizophrenia [3].

    Also, copper and zinc are regarded as neurotransmitters and arein high concentrations in brain hippocampus. As a result elevatedcopper and depressed zinc have been associated with hyperactivity,attention deficit disorders, behavior disorders, and depression. Also,many o those labeled with autism and paranoid schizophreniahave elevated blood copper levels in addition to other biochemicalimbalances [1]. Elevated copper/zinc ratios can be especially seriousor persons with low blood histamine. Tis combination o imbalanceshas been associated with anxiety, panic disorders, paranoia, and, insevere cases, hallucinations [1]. Low histamine patients are typicallyoverstimulated with thoughts racing through their minds making

    normal ideation difficult. Low histamine children are hyperactive whileofen healthy in other respects. Serum Cu levels in these patients areabnormally high. Since Cu is a brain stimulant and destroys histamine

    (over-methylation), the elevated serum (and presumably brain) Culevel probably accounts or many symptoms, including the low bloodhistamine level. I the laboratory tests showed a high copper: low zincratio and low histamine levels, the treatment should consist o theadministration o zinc, manganese, vitamin C, niacin, vitamin B-12,and olic acid. Folic acid in conjunction with B-12 injections raisesblood histamine while lowering the degree o symptomatology. Znallows or the normal storage o histamine in both the blood cells andthe brain. Zn and Mn increase the urinary excretion o Cu [178].

    On the other hand in the research o Effect o a deficiency oceruloplasmin copper in blood plasma on copper metabolism in theadult rat brain, the copper deficiency in adult rats was induced byaddition o silver chloride to the eed [179]. Te concentrations o

    silver, copper, iron, and zinc and relative activity o genes or coppertransporting proteins and copper enzymes were measured in thecortex, cerebellum, hippocampus, amygdala, pituitary gland, andhypothalamus. Silver was accumulated only in the hypothalamic-pituitary system. Tese changes were accompanied by a decrease inthe concentration o copper and increase in the contents o iron andzinc. Activity o genes or copper transport enzymes (high-affinitycopper transporter; and two copper transport APases, AP7A andAP7B) and copper enzymes that were ormed in the intracellularsecretory pathway did not decrease in the brain o rats with copperdeficiency. Relative activity o genes or intracellular copper enzymes(Cu/Zn superoxide dismutase and subunit IV o cytochrome coxidase), concentration o immunoreactive polypeptides o superoxidedismutase, and enzymatic activity o superoxide dismutase remained

    unchanged under these conditions [179].

    Hippocampal neuronal injury: An experiment was conducted toinvestigate whether intracellular zinc depletion can actually changeexpression o voltage-dependent anion channel VDAC1 and VDAC2in cultured hippocampal neurons o rats. Hippocampal neurons wereobtained by primary culture rom hippocampus o newborn rats.Cultured hippocampal neurons were exposed to a cell membranepermeable zinc chelator ethylenediamine. Te results demonstratedthat exposure o hippocampal neurons to chelator or 24 hoursinduced notably neuronal injury, significantly increased the number oapoptotic nuclei, up-regulated the expression o VDAC1 protein leveland down-regulated the expression o VDAC2 protein level. Significantdown-regulation o mRNA levels or both, VDAC1 and VDAC2 were

    observed. Co-addition o zinc almost completely reversed chelatorinduced neuronal injury and above alterations in VDAC1 and VDAC2protein levels and mRNA levels. Present results implicate a possibilitythat up-regulation o VDAC1 and down-regulation o VDAC2 mayparticipate in hippocampal neuron injury induced by zinc deficiency[180].

    raumatic brain injury: Depression, anxiety, and impairmentsin learning and memory are all associated with traumatic braininjury (BI). Because o the strong link between zinc deficiency,depression, and anxiety, in both humans and rodent models, scientistshypothesized that dietary zinc supplementation prior to injury couldprovide behavioral resiliency to lessen the severity o these outcomesafer BI. Rats were ed with marginal zinc deficient, zinc adequate,or zinc supplemented diet or 4weeks ollowed by a moderately-severe BI. While moderate zinc deficiency did not worsen outcomesollowing BI, rats that were ed with the zinc supplemented diet or4weeks showed significantly attenuated increases in adrenal weight

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    (p

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    J Clinic Toxicol Heavy Metal Toxicity ISSN: 2161-0495 JCT, an open access journal

    In another study dyshomeostasis o extracellular zinc and copperhas been implicated in -amyloid aggregation, the major pathologyassociated with Alzheimer disease. Presenilin mediates the proteolytic

    cleavage o the -amyloid precursor protein to release -amyloid,and mutations in presenilin can cause amilial Alzheimer disease.In the recent study there was tested, whether presenilin expressionaffects copper and zinc transport in murine embryonic fibroblastsrom presenilin knock-out mice. Tey observed a marked decreasein saturable uptake o radiolabeled copper and zinc in several tissues,including brain. Copper/zinc superoxide dismutase activity wassignificantly decreased and copper chaperone o SOD1 levels was alsodecreased. Tese data indicate that presenilins are important or cellularcopper and zinc turnover, influencing SOD1 activity, and having thepotential to indirectly impact -amyloid aggregation through metal ionclearance [195].

    Despite the crucial role o redox active metals like copper and iron

    in central biological reactions, their elevated levels are involved in thepathogenesis o Alzheimers disease. Similarly reactive oxygen/nitrogenspecies (ROS/RNS) produced during normal metabolic activities,specifically oxidative phosphorylation o the cell, are scavenged bysuperoxide dismutase, catalase, but impaired metabolic pathwaystend to generate elevated levels o these ROS/RNS. Alterations intrace elements as iron, copper, and zinc may intensiy this process andcontribute or the pathogenesis o Alzheimers disease [196].

    Te aim o the present study was to evaluate the status o plasmaessential trace elements magnesium, copper, zinc, iron and seleniumconcentrations and their some related antioxidant enzyme activities,erythrocyte glutathione peroxidase (GPX), superoxide dismutase, andcatalase activities in patients with Alzheimers disease. Fify patients

    with AD and fify healthy control subjects were included in this study.Plasma Cu and Zn concentrations by atomic absorption spectrometry(AAS), plasma Mg and Fe concentrations by spectrophotometricmethods and plasma Se concentrations by graphite urnace AASwere determined. Erythrocyte GPX, SOD and catalase activities weremeasured by spectrophotometric methods. Plasma Mg, Cu, Zn, Fe andSe levels and erythrocyte GPX, SOD and catalase activities were oundto be significantly lower in patients with AD compared with controls.Tese results suggest that alterations in essential trace elements andtheir related enzymes may play a role in the etiopathogenesis o AD.Also, there is a deect in the antioxidant deense system, which may leadto oxidative damage in patients with AD. Te changes in antioxidantenzyme activities may be secondary to the alterations in their coactorconcentrations [197].

    Parkinsonism: Te biometals iron, manganese and copper havebeen associated to Parkinsons disease and Parkinsonism. In recentwork, it was reported or the first time that acute or chronic Fe, Mnand Cu exposure significantly reduced lie span and locomotor activityin Drosophila melanogaster. It was shown that the concentration othose biometals dramatically increase in Drosophilas brain acutely orchronically ed with metal, and that the metal accumulation in the flyshead is associated with the neurodegeneration o several dopaminergicneuronal clusters. Furthermore, they ound that the chelatordeseroxamine, ethylenediaminetetraacetic acid, and D-penicillaminewere able to protect but not rescue D. melanogaster against metalintoxication. aken together these data suggest that iron, manganeseand copper are capable to destroy dopaminergic neurons in the flys

    brain, thereby impairing their movement capabilities [198].

    Malignant glioma: Te scientists assessed relevance o mineraltrace element and heavy metal levels in patients with malignant

    gliomas. In the study, erythrocyte catalase, and carbonic anhydrase,serum copper, zinc, lead, iron, cadmium, cobalt, manganese, andmagnesium levels were measured in plasma o 22 healthy humans and

    22 malignant glioma patients. Te Cd, Fe, Mg, Mn, Pb and Zn levelswere significantly elevated in the patients as a whole compared tocontrols (P

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    Citation: Osredkar J, Sustar N (2011) Copper and Zinc, Biological Role and Signicance of Copper/Zinc Imbalance. J Clinic Toxicol S3:001.

    doi:10.4172/2161-0495.S3-001

    J Clinic Toxicol Heavy Metal Toxicity ISSN: 2161-0495 JCT, an open access journal

    in inerior colliculus and whole brain o copper-deficient rats. Teelevated glutamine could not be related to any change in activity oglutamine synthetase or glutaminase, major enzymes o glutamine

    metabolism. It is speculated that the increase in glutamine might resultrom a net increase in ammonia accumulation in the brains o copper-deficient rats [204].

    Metabolic and endocrinological disorders

    Disorders of thyroid gland: Te aim o the present study wasto investigate the effect o copper deficiency on thyroid hormonemetabolism in rats. Tereore, an experiment with growing male ratswas carried out, consisting o two groups o rats ed either a copper-deficient (0.06 mg Cu/kg) or a copper-adequate diet (16 mg Cu/kg).Copper deficiency decreased the final body weight o the rats by 5%compared to copper-adequate control rats. A severe copper-deficientstate in the rats ed the copper-deficient diet was proved by a large

    decrease o ceruloplasmin activity in serum (by 97%) and hematologicalchanges. Copper-deficient rats had an increased concentration o 3 inserum, whereas the concentrations o total and ree thyroxine were notdifferent compared with copper-adequate control rats [205].

    In the subsequent study the intracellular localization o Cu/Zn- and Mn-superoxide dismutase was studied in the thyroid tissueo various thyroid disorders by an immunohistochemical technique.Te concentrations o both SODs in those tissues were measured alsoby a sandwich enzyme immunoassay technique. Copper/zinc-SODin thyroid tissues was identified by immunocytochemical staining inmost cases o papillary carcinoma and in some cases o other thyroiddisorders. In normal ollicular cells this enzyme is localized in theperinuclear cytoplasm, whereas in thyroid tumor or hyperplasticollicular cells it exists homogeneously in cytoplasm. Manganese-SOD stained strongly in papillary carcinoma and papillary-growingcells in the thyroid tissue o adenoma and Graves disease. Teconcentrations o Cu/Zn-and Mn-SOD in thyroid tumor tissues andhyperplastic ollicular disorders were significantly higher than thosein normal thyroid tissue. In conclusion, SOD seems to be related tocell prolieration and differentiation in the thyroid ollicular cellbecause Cu/Zn-SOD changes its localization in tumor and hyperplasticollicular cells and because the Mn-SOD concentration is increased inpapillary carcinoma or papillary-growing cells [206].

    Diabetes: A laboratory animal study ound that copper-deficientrats tend to have elevated blood sugar levels over time, indicating apossible connection between low copper and diabetes [132]. But aclinical study including people with diabetes, however, ound very

    different results. Copper levels were higher in people with diabetescompared to those without. In act, the higher the copper level, themore likely the person was to have complications rom diabetes,including retinopathy, high blood pressure, or vascular disease [207].

    Digestive system: In the next study, a growing rat model o zincdeficiency was established to investigate the effect o zinc deficiencyon intestinal mucosal morphology and digestive enzyme activity.Symptoms o zinc deficiency, such as anorexia, diarrhea, dermatitis,and growth retardation, were observed. Zinc deficiency can cause losso appetite, weight loss, and decreased activity o peptidase in the jejunalmucosal brush border. Zinc deficiency has little effect on the heightratio o the villus and crypt and lactase activity, thereby indicating thatzinc deficiency may first affect protein digestion and absorption [208].

    Osteoporosis: race elements are essential or normal growth anddevelopment o skeletons in humans and animals. Although they areminor building components in teeth and bone, they play important

    unctional roles in bone metabolism and bone turnover. Zinc regulatessecretion o calcitonin rom thyroid grand and influences on boneturnover. Copper induces low bone turnover by both suppressions o

    osteoblastic and osteoclastic unctions. Among the trace elements inbone and hair, significant differences were ound in the contents ozinc, copper and manganese between normal subjects and osteoporoticpatients. However, exact involvements o the trace elements inosteoporosis have not yet been clarified [209].

    Zinc is implicated as an activator or bone ormation. Te ollowingstudy examined how zinc regulates the bone matrix calcificationin osteoblasts. Te findings suggest that zinc deprivation inhibitsextracellular matrix calcification in osteoblasts by decreasing thesynthesis and activity o matrix proteins, type I collagen and alkalinephosphatase, and decreasing Ca and P accumulation. Tereore zincdeficiency can be considered as risk actor or poor extracellular matrixcalcification [210].

    estosterone deficiency: estosterone deficiency is associatedwith late-onset hypogonadism. Micronutrients including copper andzinc have influence on testosterone synthesis. Te association betweenmicronutrient concentrations in hair tissue and serum testosteronewas studied in Korean men. Subjects with normal testosterone grouphad a significantly higher Zn level compared to low testosterone group(P=0.003). Significant negative correlations were evident between totaltestosterone and Cu level (P=0.022), and the Cu/Zn ratio (P=0.008).Normal testosterone is associated with a higher Zn level. Decreasedserum testosterone is significantly associated with a high level o Cuand elevated Cu/Zn ratio in hair tissue [211].

    Te role of Zn in fertility: Semen is particulary rich in Zn, which isa key actor in prostate gland unction and reproductive organ growth

    [78].In the present study on rats, scientists observed changes in thetestes afer dietary zinc deficiency. Ultrastructural studies revealedseveral apoptotic eatures such as wavy basement membrane, displacednuclei, chromatin condensation, plasma membrane blebbing, nuclearmembrane dissolution, loss o inter-Sertoli cell junctional complexes,and intercellular bridges and deormed mitochondria. Increasedapoptotic degeneration in testes may cause irreversible changes in thegerm cells associated with decreased epididymal sperm concentration,motility, and ertility index which contributes to the low efficiency ospermatogenesis thereby indicating a possible role o zinc in ertility[212].

    Cardiovascular system disorders

    Little is known about the selective toxicity to the heart. Tereore,the ollowing study demonstrated the relationship between theseverity o copper deficiency-induced oxidative damage and thecapacity o antioxidant deense in heart and liver to investigate apossible mechanism or the selective cardiotoxicity in rats. Copperdeficiency induced a 2-old increase in lipid peroxidation in the heart(thiobarbituric assay) but did not alter peroxidation in the liver. Teantioxidant enzymatic activities o superoxide dismutase, catalase, andglutathione peroxidase were, respectively, 3-, 50- and 1.5-old lowerin the heart than in the liver, although these enzymatic activities weredepressed in both organs by copper deficiency. In addition, the activityo glutathione reductase was 4 times lower in the heart than in the liver.Te data suggest that a weak antioxidant deense system in the heartis responsible or the relatively high degree o oxidative damage in

    copper-deficient hearts [213].

    Several research groups have demonstrated that essential traceelements play important roles in states o cardiovascular diseases. Te

    http://dx.doi.org/10.4172/2161-0495.S3-001http://dx.doi.org/10.4172/2161-0495.S3-001
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    Citation: Osredkar J, Sustar N (2011) Copper and Zinc, Biological Role and Signicance of Copper/Zinc Imbalance. J Clinic Toxicol S3:001.

    doi:10.4172/2161-0495.S3-001

    J Clinic Toxicol Heavy Metal Toxicity ISSN: 2161-0495 JCT, an open access journal

    aim was to investigate whether there is a relationship between trace

    elements, Zn and Cu and the degree o atherosclerosis. Te serum

    levels o zinc and copper were ound to be significantly lower in

    patients with atherosclerosis than in the control group, but there wereno significant differences in the serum levels o Cu and Zn between

    severe atherosclerosis and mild atherosclerosis. Te present study

    revealed a relationship between the serum levels o zinc and copper

    and atherosclerosis, but not between these levels and the severity o the

    disease [214].

    o understand the role o Cu and Zn in human blood both in

    controls as well as in cardiovascular (CVD) patients, whole blood

    samples o 181 CVD patients and 185 controls between the ages o

    20-66 years were investigated. Te mean blood-Cu levels (1.50 mg/l)

    were ound as enhanced, whereas Zn levels (5.88 mg/l) were reduced

    in cardiovascular patients group. Cu/Zn ratios or CVD patients are

    also higher than in control subjects. However, when the CVD patientswere checked or their systolic and diastolic pressure it was ound that

    copper concentrations in these patients was significantly increased (p