Department of Chemistry and Biochemistry, California State University, Fullerton 92634, USA.

In this review, our basic and most recent understanding of copper biochemistry and molecular biology for mammals (including humans) is described. Information is provided on the nutritional biochemistry of copper, including food sources, intestinal absorption, transport, tissue distribution, and excretion, along with descriptions of copper-binding proteins and other factors involved and their roles in these processes. The metabolism of copper and its importance for the functions of a roster of vital enzymes is detailed. Its potential toxicology is also addressed. Alterations in copper metabolism associated with genetic and nongenetic diseases are summarized, including potential connections to inflammation, cancer, atherosclerosis, and anemia, and the effects of genetic copper deficiency (Menkes syndrome) and copper overload (Wilson disease). Understanding these diseases suggests new ways of viewing the normal functions of copper and provides new insights into the details of copper transport and distribution in mammals.

Food Science and Human Nutrition Department, University of Florida, Gainesville 32611, USA.

The immune system requires copper to perform several functions, of which little is known about the direct mechanism of action. Animal models and cells in culture have been used to assess copper’s role in the immune response. Some of the recent research showed that interleukin 2 is reduced in copper deficiency and is likely the mechanism by which T cell proliferation is reduced. These results were extended to show that even in marginal deficiency when common indexes of copper are not affected by the diet, the proliferative response and interleukin concentrations are reduced.

The number of neutrophils in human peripheral blood is reduced in cases of severe copper deficiency. Not only are they reduced in number, but their ability to generate superoxide anion and kill ingested microorganisms is also reduced in both overt and marginal copper deficiency. This mechanism is not yet understood. Neutrophil-like HL-60 cells accumulate copper as they differentiate into a more mature cell population and this accumulation is not reflected by increases in Cu/Zn superoxide dismutase or cytochrome-c oxidase activities.

The identity of copper-binding proteins in this cell type may be useful in learning new functions of copper or assessing copper status. Neutrophils, because they are short-lived and homogeneous cell populations, are predicted to be an effective and valuable tool for assessing nutrient status in human populations. – the #1 resource for technical and professional information regarding copper and copper alloys.

Based on an abundance of historical data such as the foregoing, many researchers anticipate that copper will become an increasingly important component of tomorrow’s medical treatments.

Skin Biology, Research & Development Department, 4122 Factoria Boulevard SE, Suite No. 200, Bellevue, WA 98006, USA

During human aging, there is an increase in the activity of inflammatory, cancer-promoting, and tissue destructive genes plus a decrease in the activity of regenerative and reparative genes. The human blood tripeptide GHK possesses many positive effects but declines with age. It improves wound healing and tissue regeneration (skin, hair follicles, stomach, and intestinal linings, and boney tissue), increases collagen and glycosaminoglycans, stimulates the synthesis of decorin, increases angiogenesis, and nerve outgrowth, possesses antioxidant and anti-inflammatory effects, and increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells.

Recently, GHK has been found to reset genes of diseased cells from patients with cancer or COPD to a more healthy state. Cancer cells reset their programmed cell death system while COPD patients’ cells shut down tissue destructive genes and stimulate repair and remodeling activities.

In this paper, we discuss GHK’s effect on genes that suppress fibrinogen synthesis, the insulin/insulin-like system, and cancer growth plus activation of genes that increase the ubiquitin-proteasome system, DNA repair, antioxidant systems, and healing by the TGF beta superfamily. A variety of methods and dosages to effectively use GHK to reset genes to a healthier state are also discussed.

Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.

The essentiality and redox-activity of copper make it indispensable in the mammalian system. However, a comprehensive understanding of copper metabolism and function has not been achieved. Copper chelators have been used as an approach to provide insights into copper acquisition, distribution, and disposition at both the cellular and organism level. Unfortunately, the understanding of effective copper chelators is predominantly based upon their chemical structures and their reactions with copper. The understanding of the efficacy of copper chelators in the biological system has been equivocal, thereby leading to under -or misleading- utilization of these agents in clinical and experimental approaches.

The current use of copper chelators in vivo almost exclusively either limits the availability or focuses on the removal of copper in the mammalian organ system. There are at least two aspects of copper chelators that are yet to be explored. First, copper chelators preferentially bind either cuprous or cupric. As a result, they potentially modulate copper redox-activity without removing copper from the system.

Second, copper chelators are characterized as either membrane-permeable or -impermeable, thus would serve as an organ-selective copper delivery or deprivation system to manipulate the biological function of copper. Here we review clinically relevant copper chelators that have been experimentally or clinically studied for their role in the manipulation of copper metabolism and function, paying critical attention to potentially more valuable usage of these agents.

The mechanisms of antibacterial action of copper are antimicrobial effects as shown by ions of copper and zinc. The oligodynamic effect was discovered in 1893 as a toxic effect of metal ions on living cells, algae, molds, spores, fungi, viruses, prokaryotic and eukaryotic microorganisms, even in relatively low concentrations.

Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.

Copper deficiency alters cell bioenergetics and induces mitochondrial fusion through the up-regulation of MFN2 and OPA1 in erythropoietic cells.

Copper is essential in cell physiology, participating in numerous enzyme reactions. In mitochondria, copper is a cofactor for respiratory complex IV, the cytochrome c oxidase. Low copper content is associated with anemia and the appearance of enlarged mitochondria in erythropoietic cells. These findings suggest a connection between copper metabolism and bioenergetics, mitochondrial dynamics, and erythropoiesis, which has not been explored so far. Here, we describe that bathocuproine disulfonate-induced copper deficiency does not alter erythropoietic cell proliferation nor induce apoptosis.

However, it does impair erythroid differentiation, which is associated with a metabolic switch between the two main energy-generating pathways. That is, from mitochondrial function to glycolysis. Switching off mitochondria implies a reduction in oxygen consumption and ROS generation along with an increase in mitochondrial membrane potential. Mitochondrial fusion proteins MFN2 and OPA1 were up-regulated along with the ability of mitochondria to fuse. Morphometric analysis of mitochondria did not show changes in total mitochondrial biomass but rather bigger mitochondria because of increased fusion.

Similar results were also obtained with human CD34+, which were induced to differentiate into red blood cells. In all, we have shown that adequate copper levels are important for maintaining proper mitochondrial function and for erythroid differentiation where the energy metabolic switch plus the up-regulation of fusion proteins define an adaptive response to copper deprivation to keep cells alive.

Department of Biochemistry and Molecular Biology, University of Minnesota Medical School, Duluth, MN 55812, USA.

Copper is an essential trace element whose recommended intake is met by most North American diets. However, the incidence of new cases of secondary copper deficiency is rising due to complications of gastric bypass surgery and high zinc exposure. Patients frequently are ataxic and anemic. Anemia of copper deficiency was first described in the 19th century, but the underlying biochemistry remains unknown. Approximately one dozen cuproenzymes have been characterized in mammals. Four of these are referred to as multicopper oxidases (MCO) due to their copper-binding geometries. They have iron oxidase activity (ferroxidase).

These include the hepatic secreted protein ceruloplasmin representing ∼90% of plasma copper, a splice-variant of ceruloplasmin originally characterized in the brain linked by a glycosylphosphatidylinositol (GPI) to membranes, an intestinal enriched MCO named hephaestin, and newly described MCO in the placenta called zyklopen.

Limitation in available copper appears to limit the function of the MCO group exhibited as impaired iron flux due to the copper requirement of MCO for their ferroxidase activity.

Dietary copper deficiency is associated with lower levels of ceruloplasmin, GPI-ceruloplasmin, and hephaestin. Limitation of copper does not appear to limit the synthesis of MCO but rather their stability and turnover. However, there appears to be a disconnect between the limitation in MCO function and anemia, because humans and mice missing ceruloplasmin are not anemic despite hepatic iron overload and hypoferremia. Furthermore, anemic copper-deficient mammals are not improved by iron replacement. This suggests that the anemia of copper deficiency is not caused by iron limitation but rather impairment in iron utilization.

United States Department of Agriculture, Grand Forks Human Nutrition Research Center, North Dakota 58202-9034, USA.

The 10th edition of Recommended Dietary Allowances (RDA) did not include an RDA for copper; rather a safe and adequate daily intake was suggested. Criteria, history, and uses of RDAs were summarized along with data on dietary intakes, balance and depletion experiments, low (fats and oils, skim milk and yogurt), and high (legumes, mushrooms, nuts, and seeds) copper foods and hazards of zinc supplements. Bone disease and cardiovascular disease from diets-low in copper have been studied in animals for decades. Men and women fed diets close to 1 mg of copper per day, amounts quite frequent in the US, responded similarly to deficient animals with reversible, potentially harmful changes in blood pressure control, cholesterol, and glucose metabolism, and electrocardiograms. Women supplemented with trace elements including copper experienced beneficial effects on bone density.

These data exceed similar data on magnesium, selenium, and zinc and are sufficient for establishing an RDA. Ischemic heart disease and osteoporosis are likely consequences of diets low in copper. Numerous anatomical, chemical, and physiological similarities between animals deficient in copper and people with ischemic heart disease have been noticed. Association between osteoporosis and low copper status deserves further inquiry. Augmenting low copper diets with high copper foods may be beneficial. Committees that establish RDAs should return to the traditions of the first nine editions and make recommendations that promote health and nutritional welfare, meet functional needs, prevent disease, and promote public welfare.

[Code of Federal Regulations] [Title 21, Volume 3] [Revised as of April 1, 2014] [CITE: 21CFR184.1261] TITLE 21–FOOD AND DRUGS CHAPTER I–FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER B–FOOD FOR HUMAN CONSUMPTION (CONTINUED) PART 184 — DIRECT FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED AS SAFE Subpart B–Listing of Specific Substances Affirmed as GRAS Sec. 184.1261 Copper sulfate. (a) Copper sulfate (cupric sulfate, CuSO4.5 H2O, CAS Reg. No. 7758-99-8) usually is used in the pentahydrate form. This form occurs as large, deep blue or ultramarine, triclinic crystals; as blue granules, or as a light blue powder. The ingredient is prepared by the reaction of sulfuric acid with cupric oxide or with copper metal. (b) The ingredient must be of a purity suitable for its intended use. (c) In accordance with 184.1(b)(1), the ingredient is used in food with no limitation other than current good manufacturing practice. The affirmation of this ingredient as generally recognized as safe (GRAS) as a direct human food ingredient is based upon the following current good manufacturing practice conditions of use: (1) The ingredient is used as a nutrient supplement as defined in 170.3(o)(20) of this chapter and as a processing aid as defined in 170.3(o)(24) of this chapter. (2) The ingredient is used in food at levels not to exceed current good manufacturing practice. Copper sulfate may be used in infant formula in accordance with section 412(g) of the Federal Food, Drug, and Cosmetic Act (the Act) or with regulations promulgated under section 412(a)(2) of the Act. (d) Prior sanctions for this ingredient different from the uses established in this section do not exist or have been waived. [49 FR 24119, June 12, 1984, as amended at 73 FR 8607, Feb. 14, 2008; 76 FR 59249, Sept. 26, 2011]

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