Herbfacts

Copper

The essential role of copper in humans was first reported in 1956 in a paper on malnourished children presenting with anaemia refractory to iron therapy  (1). Further studies allowed a clear definition of the pathological observations related to copper deficiency, particularly in newborns (2). Copper is utilized by a large number of enzymes, probably more than 300 in humans, involved in oxidative reactions.

Copper is an essential trace element for living organisms, taking part in all aspects of metabolism, including mitochondrial oxidative phosphorylation, free radical detoxification, neurotransmitter synthesis and denaturation, pigment formation, connective tissue synthesis and iron metabolism. In the human body, copper is found in relatively high amounts: a healthy 70 kg adult contains about 110mg of copper, the major part (46 mg) in skeleton and bone marrow, 26mg in skeletal muscles, 10mg in liver, 8.8mg in brain and 6mg in blood  (3). The greater part of copper in the human body, in physiological conditions, is probably functional, being copper atoms involved as cofactor of different redox enzymes. The best known among these are: ceruloplasmin ; cytochrome c oxidase, the terminal enzyme of electron transport and oxidative phosphorylation; superoxide dismutase, an antioxidant enzyme able to remove superoxide radicals from tissues; lysyl oxidase, essential for cross-linking of collagen and elastic fibres; monophenol mono-oxygenase, involved in the synthesis of melanin; dopaminebeta- mono-oxygenase, required for the synthesis of dopamine; and peptide-alpha-amidating mono-oxygenase, essential for the synthesis of pituitary hormones. Copper plays further additional non-enzymatic functions in angiogenesis, nerve myelination and activity of endorphin; it also plays an essential role in brain development, shown by the presence of demyelination and by neurodegeneration in patients affected by Menkes disease, the best documented congenital copper deficiency in humans. Copper is essential for reproduction, regulation of gene expression, and for normal growth and development.

Wilson’s Disease

Wilson’s disease (WD), also known as hepatolenticular degeneration, is a disorder of copper metabolism characterized by its accumulation in different organs, leading to liver cirrhosis, neurological disturbances and to a complexity of symptoms related to the disarrangement of copper transport and distribution in the whole body. Low serum levels of ceruloplasmin, frequently found in patients affected by WD, have been considered for many years the main cause of the modifications in copper metabolism: ceruloplasmin was considered until 20 years ago the principal copper transporter in the human body, and its deficiency was considered the cause of the block of copper excretion and, accordingly, of its accumulation in different organs, mainly in the liver and central nervous system (CNS) (4). Ceruloplasmin belongs to the family of multinuclear copper oxidases, which has a ferroxidase activity with a relevant role in iron metabolism;  it is not only a copper transporter, but a copper enzyme which utilizes copper atoms as an electron donator/acceptor in oxidative reactions. The ferroxidase activity of plasma ceruloplasmin can be considered as one of the most important mechanisms of its antioxidant properties, since by clearing Fe(II) from plasma, the production of reactive oxygen species (ROS) generated in the non-catalyzed autoxidation of Fe(II) is avoided. Ceruloplasmin plays an essential role in mobilization of iron stores, determining the rate of iron efflux from cells.

In 1993, the gene responsible for the disease ATP7B was identified (5,6). A mutation in the WD gene may reduce the functionality of ATP7B, leading to a block in copper excretion into the bile and therefore to hepatic copper accumulation, chronic hepatitis, and cirrhosis. As a consequence, copper serum levels may rise, leading to copper accumulation in the central nervous system,  in the cornea, in the kidney and in other organs. The loss of functional ATP7B protein may cause failure in the incorporation of copper atoms in the apoceruloplasmin, resulting in the decreased ceruloplasmin blood levels found in the majority of WD patients.

Wilson’s disease was a fatal disease until treatments for halting copper storage were developed in the fifties. Wilson’s disease was the first chronic liver disease for which an effective pharmacologic treatment was discovered. In 1951 2,3-dimercaptopropanol, also known as BAL, was introduced (7), and succeeded by penicillamine (8).

Sources of Copper

Pipe water, for the widespread use of copper pipes in household plumbing, can be an important dietary source of copper, differently from unpolluted fresh water that contains no or very little copper. The guideline value for copper in water for human use is 2mg/L (WHO Directives). The principal dietary sources of copper are chocolate, animal liver, crustaceans, shellfish, green vegetables, dried fruits and nuts; it is much more bio available from meat than vegetables. Copper concentration in these foods ranges from 20 up to 50 mg/kg, about 500 times higher than in human milk, one of the poorest dietary sources. The copper content in human milk largely decreases (50%) from the fourth month of lactation, so that a prolonged breast feeding could lead to copper deficiency. Several studies underlined the risk of copper deficiency and the relevance of the intestinal mucosa in maintaining a normal copper status (9). Copper bioavailability depends on three main factors: absorption from the gastrointestinal tract, transport in blood, and extraction by hepatocytes from the portal blood supply. A variety of factors may alter copper bioavailability: aging, that decreasing the efficiency of copper homeostasis results in higher serum copper concentrations in elderly population, sex, i.e. higher mean serum copper levels are detected in females, and hormonal factors – women on contraceptive pill have increased serum copper levels with respect to control women .

The chemical speciation of copper contained in vegetables or in animal foodstuffs represents a key factor in copper absorption; Copper salts (carbonate, acetate, sulphate and chloride) are well absorbed, but a much lower ability to cross the intestinal barrier is shown by copper oxide. Food treatments also affect copper absorption: salts for food preservation may modify the solubility of copper bound to proteins and its bioavailability. Intestinal pH is probably the most important physiological factor affecting copper absorption since an acid environment is essential for freeing copper ions from complexes formed in foods and in mucosal secretions, setting the conditions for their absorption. The presence in the diet of chelating agents as citric acid, in large amounts in fruits, and lactic acid, favours copper absorption. The capacity of zinc to halt copper absorption was first described in rats and subsequently confirmed in humans: 3mg of zinc added to the diet cause copper deficiency, leading to severe anaemia and leucopoenia (10). Zinc interferes with copper metabolism, acting at different sites: displaces copper from the specific carrier on the intestinal cells and increases metallothionein content in the intestinal epithelium that blocks copper trafficking and favours its loss in faeces through apoptosis of intestinal cells.

Copper in health and disease

Pregnancy

Copper has a significant influence in maintaining normal female reproduction and foetal development (11). The placenta may be considered a key organ in copper supply to the foetus during pregnancy, being one of the few organs in the human body which expresses both ATP7A and ATP7B that have distinct functions in copper transport. In human placenta,

Mammary glands demonstrate a marked avidity for copper, enhanced during lactation, when most of the absorbed copper is diverted from liver and kidney to mammary glands (12).

Cognitive function 

Copper is essential for brain metabolism, serving as a cofactor to superoxide dismutase, dopamine-beta-hydroxylase, amyloid precursor protein, ceruloplasmin and other metalloproteins essential for normal brain function. ATP7A and ATP7B play a central role in distribution of copper in the various compartments of the central nervous system. The study of many researchers in the next future will be focused on copper trafficking in the adult human brain, due to the mounting evidence that if copper homeostasis is disturbed in patients affected by Alzheimer disease, this leads to oxidative stress and neurodegeneration (13). Two proteins related to neurodegeneration, the amyloid precursor protein (APP) and the Prion protein are copper-binding proteins and, at the same time, they are the major regulators of neuronal homeostasis.

New functions of ceruloplasmin have been recently proposed in the central nervous system, where it could play an important role in neuropathological conditions by stimulating various neurotoxic molecules, including nitric oxide (NO) in microglial cells (14).

Eye Health

Both copper ATPases have been localized in the human retina, in pigment epithelial cells. ATP7A was also detected in the neurosensory retina (15). Retinopathy in Wilson disease, generally related to the abnormal systemic copper deposition, could result from loss of retinal ATP7A and ATP7B, and to the consequent dysregulation of copper levels in the different retinal compartments

  1. P. Sturgeon, C. Brubaker, Am. J. Dis. Child 92 (1956) 254.
  2. R.A. al-Rashid, J. Spangler, N. Engl. J. Med. 285 (1971) 841
  3. M.C. Linder, M. Hazeg-Azam, Am. J. Clin. Nutr. 63 (1996) 797S.
  4. I.H. Scheimberg, D. Gitlin, Science 116 (1952) 484.
  5. R.E. Tanzi, et al. Nat. Genet. 5 (1993) 344.
  6. P.C. Bull, et al. Nat. Genet. 5 (1993) 327..
  7. J.N. Cumings, Brain 74 (1951) 10.
  8. J.M.Walshe, Lancet (1956) 25.
  9. E. Madsen, J.D. Gitlin, Curr. Opin. Gastroenterol. 23 (2007) 187.
  10. H.N. Hoffman et al.Gastroenterology 94 (1988) 508
  11. Michaluk, K. Kochman, Reprod. Biol. 7 (2007) 193.
  12. S.A. Donley, et al. Am. J. Physiol. Endocrinol. Metab. 283 (2002) E667.
  13. L. Rossi, et al. J. Nutr. Health Aging 11 (2007) 408.
  14. K.H. Lee, S.J. Yun, K.N. Nam, Y.S. Gho, E.H. Lee, Brain Res. 1171 (2007) 1.
  15. P. Krajacic, et al. Inv. Opht. Vis. Sci. 47 (2006) 3129.

Keywords:-copper, wilsons disease, pregnancy, cognitive function, eye health.