Nutritional summary

Function; Copper is essential for energy metabolism (cellular respiration), brain function (neurotransmitter regulation), soft tissues and bone (collagen synthesis), for nutrient metabolism (especially iron), and for antioxidant defense against free radicals (free radicals increase the risk of cancer and cardiovascular disease).

Requirements: Adults should get 0.9mg day (Food and Nutrition Board, Institute of Medicine, 2(H)!), Smoking, strenuous exercise, heat, infections, and injuries each may increase needs by 50% or more.

Food sources: The best food sources of copper include liver, shellfish, nuts, and seeds. Most other foods provide smaller amounts that in combination usually are enough to meet normal needs. People who follow the food guide pyramid recommendations ensure their adequate copper intake.

Deficiency: Deficiency is very unlikely to occur except in people with very rare genetic disorders or during prolonged starvation. Symptoms include anemia, low white cell count, accelerated bone mineral loss, and increased blood pressure and cholesterol levels. If intakes are low, stores last only a few weeks.

Excessive intake: Daily doses in excess of 10 mg (typically from supplements or from contaminated stored or well water) can cause nausea, vomiting, abdominal cramps, diarrhea, and liver damage (especially in infants). Higher doses may lead to coma and death.

Dietary sources

Exceptionally rich sources of copper include liver (45 mg/kg), kidney (35 50 mg/kg), oysters (7.4 mg/kg), walnuts (16mg/kg) and other nuts and seeds. Copper-lined pipes or vessels do not increase copper content of their contents significantly unless exposed to acids. Average daily intake of American adults is about 1.6 mg in males and 1.2 mg in females (Food and Nutrition Board Institute of Medicine. 2001).

Digestion and absorption

Copper absorption occurs in stomach and small intestine by saturable active transport. Bile adds about 5 mg per day to the ingested amount. More than half of a small oral dose (less than I mg) is usually absorbed. Fractional absorption decreases to about 25% w ith a dose of 3 4 mg. and to less than 15% at intakes above 6 -7mg (Wapnir. 199H). Copper absorption is decreased by phytate and inositol pentaphosphate in the same meal, but the decrease is less than for iron and zinc (Lonnerdal ct al., 1999), Excessive zinc intake decreases copper absorption slightly. Ascorbate decreases copper bioavailability by reducing Cu: *" to the poorly absorbed Cu*. Ceruloplasmin in human milk enhances copper absorption in the small intestine of infants.

Copper is taken up through the proton-coupled divalent metal transporter (DMTI, SLC11A2). which also binds iron, zinc and other divalent metal cations. Metallo-thioneins. a family of small cationic metal-binding proteins, sequester excess copper, and limit absorption thereby.

Export across the basolateral membrane depends on the copper-t ran sporting ATPase 7A (Menkes protein, ATP7A, EC3.6.3,4: Kodama et al.. 1999). Transport is linked to the hydrolysis of ATP and is therefore magnesium-dependent.

Transport and cellular uptake

Blood circulation: Newly absorbed copper, which is mainly bound to albumin, is rapidly cleared from blood circulation by the liver, to a lesser extent by the kidneys.

Brush border membrane

Cir' attjumin

Capillary lumen

Brush border membrane

Basolateral Capillary membrane endothelium

Figur* Irue&iinal capper absorption

When copper is secreted from the liver again. it is in association with ceruloplasmin, metallothionein, and other copper-containing proteins. Because of this most of the copper in blood is bound to ceruloplasmin (65-90%) and albumin (5-10%). A much smaller amount is unspccilicatly bound to histidine. The role of transcuprein, metal-lothionein and other copper-binding proteins in humans remains to be fully explored. The different copper carriers can substitute for each other, as shown by the fact that copper delivery to cells is not disrupted even in the absence of ceruloplasmin (Meyer a al.. 2001), Total copper concentration in blood of healthy adults is typically between 75 and 130 p./I. Copper-binding capacity in blood normally exceeds total copper concentration by 5 orders of magnitude (Under eial., 1999). infection, tumors, pregnancy and hormonal contraception increase the concentration of ceruloplasmin in blood since this is an acute-phase protein.

Copper separates front the various carrier systems and enters by itself. An exception arc liver cells that lake up ceruloplasmin through the asialoglycdprotein receptor after ceruloplasmin deglycosylatton at the plasma membrane lllarris. 2000). Uptake into other cells depends on the high-affinity copper transporters CTRl (SLC3IAI; Lee Cttil.. 2002) and CTR2 (SLC31A2). Multiple distinct transcripts of both transporters occur in most tissues. I'he Cu2' form in plasma has to be reduced at the plasma membrane by as yet incompletely characterized N ADII oxidases, before it can be imported through CV-specific CTRl (McArdle et al., 1999).

Erythrocytes may also take up C'u complexod with chloride and hydroxyl ions through the chloride'bicarbonate-exchanger (band 3 ofthe red cell membrane. SLC4A1; Bogdanova et al.. 2002).

Blood bruin barrier Movement of copper into and out ofthe brain of adults is very limited (Stuerenbuig, 2000). The Menkes protein (ATP7A, EC3.6.3.4) operates m brain capillary epithelial cells (Qian et al.. 1998). Choroid plexus epithelial cells express Ctrl (Km el at., 2001).

Maternofetal transfer: The transfer of copper across the placenta is very limited (Krachler et al., 1999). The Menkes protein (ATP7A) is present in placenta, but the overall mechanism remains unresolved.

Metabolism

Various copper binders keep the intracellular concentration of free copper so low (<ll) l8mol/l) that individual cells contain less than one atom on average (O'Halloran and Culotta, 2000). Reduced glutathione (GSII) avidly binds Cu and facilitates its association with the metal-storage protein metallothionein. GSII is also important for the targeted intracellular transport copper in conjunction with specific copper-binding proteins (metallochaperones). Several of these metallochaperones direct copper to specific targets (Harris, 20(H)). CCS (copper chaperone for superoxide dismutase, homologue of yeast LYS7) directs copper toward newly synthesized superoxide dismutase (EC 1.15.1.1 ). COX 17 serves as a mitochondrial shuttle that delivers copper to the cytochrome oxidase c complex. Cu*-binding proteins in the inner mitochondrial membrane, homologs of SCO 1 and SC02 in yeast, probably act as intermediaries. ATOX1 (antioxidant 1. formerly HAHl) moves copper to the copper-Iran sporting ATPase 7B (ATP7B. Wilson protein, EC3.6.3.4). S-adenosyl homocysteine hydrolase (EC 3.3,1.1) may participate in this transport sequence by temporarily binding Cu:* (Bethin crul., 1995). The Wilson protein (ATP7B) resides mainly in theGolgi apparatus of liver cells and enables copper secretion into bile in an incompletely understood fashion (Harris. 2000). Alternative splicing ofthe Wilson gene product generates a truncated cytosolic form of unclear function. The closely related Menkes protein (ATP7A) is essential in most other tissues for delivery ofcopper to newly synthesized enzymes, such as monophenol monooxygenase (tyrosinase. EC 1.14.18.1). in secretory vesicles and for copper export. This copper pump is also closely associated with the trans-Golgi netw ork. ATP7A-containing secretory vesicles cycle move rapidly to the plasma membrane, where they help to remove excess copper from the cell (Paris et al.. 2000).

Storage

Considerable amounts of copper (50 120 tug) are bound to metallothioneins in liver and kidney: much smaller amounts are stored in other organs/tissues. The metallothioneins are small proteins that bind 7 12 atoms of copper, zinc or cadmium. There are at least 10 genetically distinct metallothionein genes with differing lissue expression patterns and metal-binding properties.

Cu2*- ceruloplasmm Cu2' aïwmir Cu2' malaiiotriionBin Cu2' histidine Cua" iTanscuprein

Hepatocyte

Capillary lumen

Capillary endothelium

Hepatocyte

Bile canaliculus

Figure 11.10 Intracellular copper disposition

It has been suggested that S-adenosyl homocysteine hydrolase (IEC3.3.M) is a bi functional protein that provides additional copper-binding capacity in liver (Bet h m étal., 1995).

Excretion

Less than 10" <> of total losses are with skin, urine, and other secretions; the remainder (>9()'(u) is eliminated with feces. The copper-transporting ATPase 7li (Wilson protein. EC3.6.3.4) pumps about 5 mg per day into bile. Much of this is reabsorbed from the small intestine (hepatobiliary cycling), unless concurrent dietary intakes are very high or total body stores are already full

Regulation

Storage as a complex w ith metallothionein and excretion into bile are the central events for maintenance of copper homeostasis. Metallothionein transcription is induced by glucocorticoids, interlcukin 6, copper, zinc, and cadmium. The metal-regulatory transcription factor 1. which appears to be induced by zinc, binds to and activates metal-responsive promoter elements of metallothionein genes. Copper also induces expression of the copper-transporting ATPase in liver (ATP7B. Wilson protein). A much more rapid copper-dependent regulatory event is the phosphorylation of ATP7B, which increases its redistribution to the cell membrane (Vandcrwerf el til.. 2001).

Intracellular distribution of the Menkes protein (ATP7A) similarly helps maintain copper balance in most other tissues. As the intracellular copper concentration rises more ATP7A moves to the plasma membrane and pumps copper out of the cell (Petris et al, 2000).

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