Selected Physiologic Roles of Copper

Antioxidant action Bone mineralization Catecholamine metabolism Collagen cross-linking Elastin

Erythropoiesis Iron turnover Leukopoiesis Melanin formation copper-induced oxidative damage has been implicated in disorders associated with abnormal copper metabolism and neurodegenerative changes. Interestingly, a deficiency in dietary copper also increases cellular susceptibility to oxidative damage. A number of nutrients have been shown to interact with copper and alter its cellular effects. Vitamin E is generally protective against copper-induced oxidative damage. Although most in vitro or cell culture studies show that ascorbic acid aggravates copper-induced oxidative damage, results obtained from available animal studies suggest that the compound is protective. High intakes of ascorbic acid and zinc may provide protection against copper toxicity by preventing excess copper uptake. Zinc also removes copper from its binding site, where it may cause free radical formation.

P-Carotene, a-lipoic acid, and polyphenols have also been shown to attenuate copper-induced oxidative damage.80

Copper status is assessed using serum, plasma, erythrocyte, leukocyte, serum ceruloplasmin, serum amine oxidase, hemoglobin, and urinary concentrations.

Microcytic hypochromic anemia (similar to iron deficiency) and neutropenia are the most common hematological manifestations of copper deficiency. Hair depig-mentation, demineralization of skeleton, and central nervous system anomalies may also be found with deficiency.

Kinky hair disease, first described in 1962, is a sex-linked disorder, with its gene located on the long arm of the X chromosome close to the centromere. The condition is marked by intellectual deterioration, seizures, and poorly pigmented, friable hair. Bony changes resembling scurvy, tortuosities of the cerebral and systemic vascula-ture, and diverticuli of the bladder are also seen. Biochemically, the most diagnostic alteration is a marked reduction in blood copper and ceruloplasmin levels. Even though parenteral copper administration will correct the biochemical abnormalities, such treatment will not arrest cerebral deterioration.81 In central nervous system demyelination, hematologic recovery followed copper supplementation, both initially and after relapse off copper therapy, while serum zinc levels remained high, and the neurologic abnormalities only stabilized.82

Copper toxicity includes nausea, vomiting, bloody diarrhea, hypotension, hemolytic anemia, uremia, and cardiovascular collapse. Chronic exposure symptoms include sporadic fever, vomiting, epigastric pain, diarrhea, and jaundice. Renal failure and death can occur with ingestion of as little as 1 g of copper sulfate.83

Angiogenesis plays a central role in wound healing. Among many known growth factors, vascular endothelial growth factor (VEGF) is believed to be the most prevalent, efficacious, and long-term signal that is known to stimulate angiogenesis in wounds. Whereas a direct role of copper in facilitating angiogenesis was evident two decades ago, the specific targets of copper action remained unclear. This report presents the first evidence showing that inducible VEGF expression is sensitive to copper and that the angiogenic potential of copper may be harnessed to accelerate dermal wound contraction and closure. At physiologically relevant concentrations, copper sulfate induced VEGF expression in primary as well as transformed human keratinocytes. Copper shared some of the pathways utilized by hypoxia to regulate VEGF expression. Topical copper sulfate accelerated the closure of an excisional murine dermal wound allowed to heal by secondary intention. Copper-sensitive pathways regulate key mediators of wound healing, such as angiogenesis and extracellular matrix remodeling. The use of copper-based therapeutics represents a feasible approach to promote dermal wound healing.84

Copper is a required cofactor for cytochrome oxidase and the cytosolic antioxidant superoxide dismutase. Lysyl oxidase is a key copper enzyme used in the development of connective tissue, where it catalyzes the cross-linking of collagen and strengthens the collagen framework. Experimentally, impaired healing has been noted secondary to decreased copper stores in patients with Wilson's disease and in animal models after the administration of penicillamine.85

Copper ions can adopt distinct redox states, oxidized Cu(II) or reduced (I), allowing the metal to play a pivotal role in cell physiology as a catalytic cofactor in the redox chemistry of enzymes, mitochondrial respiration, iron absorption, free radical scavenging, and elastin cross-linking. If present in excess, free copper ions can cause damage to cellular components, and a delicate balance between the uptake and efflux of copper ions determines the amount of cellular copper. In biological systems, copper homeostasis has been characterized at the molecular level. It is coordinated by several proteins, such as glutathione, metallothionein, Cu-transporting P-type ATPases, Menkes and Wilson proteins, and cytoplasmic transport proteins called copper chaperones to ensure that it is delivered to specific subcellular compartments and thereby to copper-requiring proteins.

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