Copper occurs in the environment in three oxidation states. Copper (0) metal is used widely in the building industry (e.g., water pipes, electrical wires) because of its properties of malleability, ductibility, and high thermal and electrical conductivity. Brass, an alloy of copper and zinc, is used for cooking utensils and musical instruments, and bronze, an alloy of copper and tin, has been used in castings since early times. Copper-based alloys and amalgams are used in dental bridges and crowns, and copper is a constituent of intrauterine contraceptive devices. Copper com-pounds are widely used in the environment as fertil-izers and nutritional supplements and, because of their microbicidal properties, as fungicides, algicides, insecticides, and wood preservatives. Other industrial uses include dye manufacturing, petroleum refining, water treatment, and metal finishing. Copper com-pounds in the cuprous (1) state are easily oxidized to the more stable cupric (2) state, which is found most often in biological systems.
The most important copper ores are chalco-cite (Cu2S), chalcopyrite (CuFeS2), and malachite [CuCO3 ⋅ Cu(OH)2]. Copper concentrations in soil vary from 5 to 50 mg Cu/kg and in natural water from 4 to 10 μg Cu/l. Concentrations of copper in water, however, depend on acidity, softness, and the extent of copper pipes, and municipal water supplies can contain appreciably higher concentrations. The taste threshold of copper ranges from 1 to 5 mg Cu/l, pro-ducing a slight blue–green color at concentrations >5 mg/l copper. Acute copper toxicity symptoms, mainly nausea and gastrointestinal irritation, can occur at concentrations of >4 mg/l copper.
About 50–75% of dietary copper is absorbed, mostly via the intestinal mucosa, from a typical diet. The amount of dietary copper appears to be the primary factor influencing absorption, with decreases in the percentage absorption as the amount of copper ingested increases. High intakes of several nutrients can also influence copper bioavailability. These include antagonistic effects of zinc, iron, molybde-num, ascorbic acid, sucrose, and fructose, although evidence for some of these is mainly from animal studies. Drugs and medication, such as penicillamine and thiomolybdates, restrict copper accumulation in the body and excessive use of antacids can inhibit copper absorption. Although high intakes of sulfur amino acids can limit copper absorption, absorption of copper is promoted from high-protein diets.
Ionic copper can be released from partially digested food particles in the stomach, but immediately forms complexes with amino acids, organic acids, or other chelators. Soluble complexes of these and other highly soluble species of the metal, such as the sulfate or nitrate, are readily absorbed. Regulation of absorp-tion at low levels of copper intake is probably by a saturable active transport mechanism, while passive diffusion plays a role at high levels of copper intake. Regulation of copper absorption is also effected via metallothionein, a metal-binding protein found in the intestine and other tissues. Metallothionein-bound copper in mucosal cells will be lost when these cells are removed by intestinal flow. The major regula-tor of copper elimination from the body, however, is biliary excretion. Most biliary copper is not reab-sorbed and is eliminated in the feces. The overall effect of these regulatory mechanisms is a tight homeostasis of body copper status. Little copper is lost from the urine, skin, nails, and hair.
After absorption from the intestinal tract, ionic copper (2) is transported tightly bound to albumin and transcuprein to the liver via the portal blood- stream, with some going directly to other tissues, especially the kidney. Hepatic copper is mostly incor-porated into ceruloplasmin, which is then released into the blood and delivered to other tissues. Uptake of copper by tissues can occur from various sources, including ceruloplasmin, albumin, transcuprein, and low molecular weight copper compounds. Chaperone proteins are then thought to bind the copper and transfer bound copper across the cell membrane to the intracellular target proteins, for example cyto-chrome c oxidase. The ATPase proteins may form part of the transfer process.
The body of a healthy 70 kg adult contains a little over 0.1 g of copper, with the highest concentrations found in the liver, brain, heart, bone, hair, and nails. Over 25% of body copper resides in the muscle, which forms a large part of the total body tissue. Much of the copper in the body is functional. Storage of copper, however, is very important to the neonate. At birth, infant liver concentrations are some five to 10 times the adult concentration and these stores are used during early life when copper intakes from milk are low.
Copper is a component of several enzymes, cofactors, and proteins in the body. These enzymes and proteins have important functions in processes fundamental to human health (Table 9.15). These include a require-ment for copper in the proper functioning of the immune, nervous and cardiovascular systems, for bone health, for iron metabolism and formation of red blood cells, and in the regulation of mitochon-drial and other gene expression. In particular, copper functions as an electron transfer intermediate in redox reactions and as a cofactor in several copper-containing metalloenzymes. As well as a direct role in maintaining cuproenzyme activity, changes in copper status may have indirect effects on other enzyme systems that do not contain copper.
Owing to remarkable homeostatic mechanisms, clini-cal symptoms of copper deficiency occur in humans only under exceptional circumstances. Infants are more susceptible to overt symptoms of copper defi-ciency than are any other population group. Among the predisposing factors of copper deficiency are prematurity, low birth weight, and malnutrition, especially when combined with feeding practices such as cow’s milk or total parenteral nutrition.
The most frequent symptoms of copper deficiency are anemia, neutropenia, and bone fractures, while less frequent symptoms are hypopigmentation, impaired growth, increased incidence of infections, and abnormalities of glucose and cholesterol metabolism and of electro-cardiograms. Various attempts have been made to relate these symptoms to alterations in copper metal-loenzymes (see Table 9.15) and noncopper enzymes that may be copper responsive, and to identify the role of copper as an antioxidant, in carbohydrate metabo-lism, immune function, bone health, and cardiovas-cular mechanisms. Notwithstanding the rarity of frank copper deficiency in human populations, some have speculated that suboptimal copper intakes over long periods may be involved in the precipitation of chronic diseases, such as cardiovascular disease and osteoporosis. The pathological significance of subtle changes, in the longer term, in those systems that respond to copper deficiency have yet to be defined for humans.
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