Copper is one of the essential (vital) trace elements and is a soft, ductile transition metal – heavy metal/semi-metal. It is in the 11th group of the periodic table, has the symbol Cu, atomic number 29, and an atomic mass of 63.546.Copper occurs in the oxidation states Cu+, Cu2+, and Cu3+, and is found in nature primarily as Cu+ and Cu2+. In biological systems, the 2-valent oxidation state – Cu2+ predominates.The Latin name “cuprum” is derived from aes cyprium ” ore from the island of Cyprus“, where copper was extracted in ancient times. In the soil, the trace element is present mostly in the form of sulfide, arsenate, chloride and carbonate.Because of its excellent thermal and electrical conductivity, copper is used in engineering more than 50% in plumbing and heating. From a chemical point of view, it is used as a catalyst (accelerator of chemical reactions).According to EU directives, only copper carbonate, citrate, gluconate, sulfate and copper lysine complex may be used for nutritional purposes. In addition, certain copper compounds are permitted as additives according to the rule “as much as necessary, as little as possible” – lat. : quantum satis, qs – for example, according to the colorants directive as food colorant E 141 Copper-containing complexes of chlorophylls and chlorophyllins.
Bioavailability
Various dietary components are able to influence copper metabolism by causing changes in the rate of absorption, excretion, and distribution of Cu in the body.For example, the simultaneous intake of vitamin C (ascorbic acid), some amino acids, glucose polymers, proteins, fumaric acid – fumarate -,oxalic acid – oxalate -, and other organic acids, such as citrate, malate, and lactate, promotes copper absorption. Ascorbic acid is able to reduce Cu2+ to Cu+ and thus increase Cu absorption.Excessive concentrations of dietary fiber, calcium, phosphate, zinc, iron, molybdenum, cadmium, sulfide, and phytates or phytic acid, on the other hand, reduce the absorption of copper. The effects are very pronounced for iron and zinc. The latter trace element can lead, on the one hand, to inhibition of Cu transport into the enterocytes – cells of the small intestinal mucosa or mucosa – and, on the other hand, to intracellular binding to the storage protein metallothionein during mucosal passage. This prevents Cu overload of the cell on the one hand, and Cu transport to the basolateral enterocyte membrane and thus Cu uptake into the bloodstream on the other.Similarly, high-dose administration of antacids or penicillamine can have a negative effect on copper supply.
Absorption
Copper is present in food and in the organism in bound form rather than as a free ion. The reason for this is its special electron configuration, which allows it to form complex bonds with biochemically important compounds, such as proteins.Copper is largely absorbed from the stomach and upper small intestine (duodenum). Since the absorption rate depends strongly on the food composition, it varies between 35 and 70%. Other authors state it to be between 20 and over 50 %, depending on the copper content of the diet. From breast milk, 75% of copper is absorbed, whereas from cow’s milk, only about 23% is absorbed. This is because the Cu in cow’s milk is bound to casein, a coarse coagulating protein that is difficult to digest. As a rule, women’s milk, at 0.3 mg/l, contains far more copper than cow’s milk, which has a copper content of only 0.09 mg/l.Copper levels in the body are regulated by adjusting intestinal absorption and excretion. Thus, in copper deficiency, the rate of absorption is increased, whereas in increased copper, zinc, or iron supply, further Cu uptake or excretion is reduced or blocked, respectively.Copper absorption can be explained on the basis of dual kinetics. At low concentrations, copper is absorbed into the enterocytes of the brush border membrane of the small intestine by an active, i.e., energy-dependent, saturable transport mechanism.At higher concentrations, passive diffusion dominates, i.e. transport through the enterocyte membrane in the direction of the concentration gradient without any supply of energy as well as membrane transport proteins.The mechanism of copper uptake by membrane transport proteins – carrier-mediated transport – has not yet been precisely clarified. However, it is clear that the membrane transport protein DCT-1, which is involved in zinc and iron absorption, is also important for intestinal copper absorption. The fact that DCT-1 is used by zinc and iron as well as copper and other metals explains the antagonism of these ions under extreme conditions.When the supply is permanently high, part of the copper in the mucosa cells of the small intestine is bound to metallothionein, which is localized in the cytoplasm. This protein stores the absorbed copper and releases it into the blood only when needed. In addition, it can detoxify excess copper, which would otherwise be able to catalyze the formation of oxygen radicals.The MNK-ATPase, a saturable carrier system, is responsible for Cu transfer from the basolateral enterocyte membrane into the bloodstream.In infants, however, copper is absorbed by diffusion and in a barely saturable cotransport with water.
Transport and storage
Absorbed copper is bound in the blood to the plasma proteins albumin and transcuprein and to low-molecular-weight ligands, such as the amino acid histidine. Transcuprein represents a specificCu transport protein and has a higher affinity for copper than albumin.Plasma Cu levels are about 0.5-1.5 µg/ml under normal conditions and are 10% higher in women than in men. Neither food intake nor fasting affects plasma Cu levels. For reasons that are still unclear, plasma Cu levels are nearly doubled to tripled at the end of pregnancy or after taking contraceptives (birth control pills). Serum copper levels remain elevated in:
- Infections
- Glomerulonephritis – an inflammation, usually autoimmune, of the renal corpuscles (glomeruli) as a major cause of chronic renal failure requiring dialysis
- Myocardial infarction (heart attack)
- Thyrotoxicosis – crisis exacerbation of hyperthyroidism (hyperthyroidism), which is acutely life-threatening due to its symptoms.
- Lupus erythematosus – systemic autoimmune disease from the group of collagenoses.
- Biliary cirrhosis – chronic liver disease leading to slow progressive destruction of the small bile ducts in the liver and eventually to cirrhosis.
- Acute leukemia – tumor disease of the blood cells, in which there is an unchecked multiplication of leukocytes (white blood cells).
- Aplastic anemia – special form of anemia (anemia), where there is a reduction in the number of all blood cells due to an acquired bone marrow aplasia.
- Administration of estrogens
Decreased Cu plasma levels are found, for example, in the disease Kwashiorkor, a form of protein malnutrition. Due to undersupply of certain essential amino acids, there is a decrease in albumins (hypoalbuminemia) in the blood and thus a drop in colloid osmotic pressure. As a result, tissue fluid – especially in the abdominal region – cannot be reabsorbed into the venous capillaries.Transcuprein, albumin, and histidine transport copper via the portal vein (vena portae) to the liver, which takes it up via the hCtr1 carrier. The liver is the central organ of copper metabolism and the most important copper store of the organism. In hepatocytes (liver cells), copper is partially stored, directed to specific subcellular compartments by cytosolic transport proteins called chaperones, and incorporated into copper-dependent enzymes, such as caeruloplasmin, cytochrome c oxidase, or superoxide dismutase.Of particular importance is the plasma protein caeruloplasmin. This exhibits both an enzyme function and a specific binding and transport function for copper. As ferroxidase I, the enzyme is essential for the oxidation of divalent to trivalent iron on the one hand and for the binding of iron to plasma transferrin on the other.Part of the copper is incorporated into the enzyme during caeruloplasmin synthesis via a copper-binding ATPase localized in the Golgi apparatus and is released again into the blood by the liver in the form of Cu-caeruloplasmin.The copper remaining in the hepatocytes is stored in metallothionein.The copper bound to caeruloplasmin in plasma is distributed to various organs and tissues in the organism as required. Cellular uptake occurs through membrane-bound Cu receptors.Copper is the third most abundant trace metal in the organism after iron and zinc, with a body content of 80-100 mg. The highest concentrations of copper are found mainly in liver (15%) and brain (10%), followed by heart and kidneys. Muscle (40%) and skeleton (20%) account for about half of the total content. Only 6% of the total copper content is found in serum. Of this, about 80 to 95 % is in the form of Cu caeruloplasmin.Cu distribution in fetuses and infants differs from that in adults. At birth, the liver and spleen account for half of the body inventory. Finally, the liver of newborns has a 3-10-fold higher Cu concentration than that of adults. These liver reserves are physiologically normal and appear to protect the infant from copper deficiency during the first few months.
Excretion
In addition to absorption, excretion is one of the most important regulatory variables for Cu homeostasis, or the maintenance of Cu balance in the body.About 80% of excess copper is excreted in the bile with the feces. For this purpose, the trace element is released by a lysosomal degradation from the compound Cu-metallothionein as well as Cu-caeruloplasmin in hepatocytes and plasma, respectively, and bound at their canalicular membrane to a Cu-binding ATPase or in parallel with glutathione (GSH) to a GSH-dependent transporter. In this way, copper is released into the bile and excreted in the stool in association with proteins, bile acids, and amino acids.15% of the excess copper is secreted across the intestinal wall into the lumen and also eliminated in the stool. Only 2-4% is excreted renally in the urine. In tubular defects, losses via the kidneys with urine can increase significantly. Losses of copper via the skin are variable and are estimated to average 0.34 mg/d. A very small amount of copper returns to the organism from the intestine via the enterohepatic circulation or is reabsorbed.
