Analyzing Copper As An Essential Trace Element Biology Essay


Copper (Cu) is an essential trace element for humans and animals. In the body, copper shifts between the cuprous (Cu1+) and the cupric (Cu2+) forms, though the majority of the body's copper is in the Cu2+ form. The ability of copper to easily accept and donate electrons explains its important role in oxidation-reduction (redox) reactions and the scavenging of free radicals [49].

Copper is a critical functional component of a number of essential enzymes, known as cuproenzymes. The copper-dependent enzyme, cytochrome C oxidase, plays a critical role in cellular energy production. By catalyzing the reduction of molecular oxygen (O2) to water (H2O), cytochrome C oxidase generates an electrical gradient used by the mitochondria to create the vital energy-storing molecule, ATP [50]. Another cuproenzyme, lysyl oxidase, is required for the cross-linking of collagen and elastin, which are essential for the formation of strong and flexible connective tissue. The action of lysyl oxidase is to help to maintain the integrity of connective tissue in the heart and blood vessels to play a role in bone formation [51].

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Two copper-containing enzymes, ceruloplasmin (ferroxidase I) and ferroxidase II have the capacity to oxidize ferrous (Fe2+) to ferric (Fe3+). As the ferric form of iron can be loaded onto the protein transferrin for transport to the site of red blood cell formation. Although the ferroxidase activity of these two cuproenzymes has not yet been proven to be physiologically significant, the fact that iron mobilization from storage sites is impaired in copper deficiency supports their role in iron metabolism [51,52].

A number of reactions essential for normal function of the brain and nervous system are catalyzed by cuproenzymes. Dopamine-β-monooxygenase catalyzes the conversion of dopamine to the neurotransmitter norepinephrine [52]. Monoamine oxidase (MAO) plays a role in the metabolism of the neurotransmitters norepinephrine, epinephrine, and dopamine. MAO also functions in the degradation of the neurotransmitter serotonin, which is the basis for the use of MAO inhibitors as antidepressants [53].

The myelin sheath is made of phospholipids whose synthesis depends on cytochrome C oxidase activity. The cuproenzyme, tyrosinase, is also required for the formation of the pigment melanin. Melanin is formed in cells called melanocytes and plays a role in the pigmentation of the hair, skin, and eyes [51]. Superoxide dismutase (SOD) functions as an antioxidant by catalyzing the conversion of superoxide radicals (free radicals or ROS) to hydrogen peroxide, which can subsequently be reduced to water by other antioxidant enzymes [54]. Two forms of SOD contain copper: 1) copper/zinc SOD is found within most cells of the body, including red blood cells, and 2) extracellular SOD is a copper containing enzyme found in high levels in the lungs and low levels in blood plasma.

Free copper and iron ions are powerful catalysts of free radical damage. By binding copper, ceruloplasmin prevents free copper ions from catalyzing oxidative damage. The ferroxidase activity of ceruloplasmin (oxidation of ferrous iron) facilitates iron loading onto its transport protein, transferrin, and may prevent free ferrous ions (Fe2+) from participating in harmful free radical generating reactions.

Copper-dependent transcription factors regulate transcription of specific genes. Thus, cellular copper levels may affect the synthesis of proteins by enhancing or inhibiting the transcription of specific genes. Genes regulated by copper-dependent transcription factors include genes for copper/zinc superoxide dismutase (Cu/Zn SOD), catalase (another antioxidant enzyme), and proteins related to the cellular storage of copper [50]. 

1.4.1 Disorders of copper metabolism

Clinically evident or frank copper deficiency is relatively not very common. Serum copper levels and ceruloplasmin levels may fall to 30% of normal in cases of severe copper deficiency. One of the most common clinical signs of copper deficiency is an anemia that is unresponsive to iron therapy but corrected by copper supplementation. The anemia is thought to result from defective iron mobilization due to decreased ceruloplasmin activity. Another copper deficiency 'neutropenia' causes increased susceptibility to infections. Infants with Menkes disease, a genetic disorder that results in severe copper deficiency, suffer from frequent and severe infections [55, 56].

Osteoporosis and other abnormalities of bone development related to copper deficiency are most common in copper-deficient low-birth weight infants and young children. Serum copper levels of people with fractures are decrease than the healthy individuals [57]. Orally given copper supplementation may decrease loss of bone mineral density (BMD) from the lumbar spine [58]. A study reported that marginal copper intake of 0.7 mg/day for 6 weeks significantly increased a measurement of bone resorption (breakdown) in healthy adult males [59]. Severe copper deficiency is known to adversely affect bone health, strength and shape [60].

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Less common features of copper deficiency may include loss of pigmentation, neurological symptoms, and impaired growth [50, 51].

Copper toxicity is rare in the general population. Acute copper poisoning has occurred through the contamination of beverages by storage in copper containing containers as well as from contaminated water supplies [61]. Symptoms of acute copper toxicity include abdominal pain, nausea, vomiting, and diarrhea, which help to prevent additional ingestion and absorption of copper. More serious signs of acute copper toxicity include severe liver damage, kidney failure, coma, and death. Of more concern from a nutritional standpoint is the possibility of liver damage resulting from long-term exposure to lower doses of copper. The tolerable upper level of intake (UL) for copper provided by U.S. food and nutrition board (FNB) is 10mg/day from food and supplements [53]. It is important to note that individuals with genetic disorders affecting copper metabolism (Wilson's disease, Indian childhood cirrhosis, and idiopathic copper toxicosis) may be at risk of adverse effects of chronic copper toxicity at significantly lower intake levels.

1.4.2 Interaction of copper with other nutrients

High iron intake may results in low copper absorption, as iron intakes may interfere with copper absorption [53].

High supplemental zinc intakes of 50 mg/day or more for extended periods of time may result in copper deficiency. High dietary zinc increases the synthesis of an intestinal cell protein called metallothionein, which binds certain metals and prevents their absorption by trapping them in intestinal cells. Metallothionein has a stronger affinity for copper than zinc, so high levels of metallothionein induced by excess zinc cause a decrease in intestinal copper absorption. High copper intakes have not been reported to affect zinc nutritional status [51, 53]. Vitamin C supplements may produce copper deficiency [62, 63].  Drug Interactions

Relatively little is reported about the interaction of copper with drugs. Penicillamine is used to bind copper and enhance its elimination in Wilson's disease. Because it dramatically increases the urinary excretion of copper, individuals taking penicillamine for reasons other than copper overload may have an increased requirement for copper. Antacids may interfere with copper absorption when used in very high amounts [51].

1.4.3 Copper relation to cardiovascular diseases

Abnormal concentration of copper in serum is related to the cardiovascular disease, but the role of copper in atherosclerosis is controversial. There are two thoughts about the relation of copper with cardiovascular disease. Some studies suggest that decreased copper concentration in diet may lead to cardiovascular disease. While other studies suggest a positive relation between copper concentration in serum and appearance of cardiovascular disease.

Heart abnormalities and damage may result in some animals due to severe copper deficiency [53]. Some studies favor this thought that copper deficiency causes cardiovascular disease. Low copper concentration in serum can also decrease the amount of copper in heart, and cells, and increase the cholesterol in plasma. People with ischemic heart disease have decreased cardiac and leucocyte copper and decreased activity of some copper dependent enzymes, and also show abnormal electrocardiogram [64].

Studies reported in humans have produced inconsistent results, and their interpretation is hindered by the lack of a reliable marker of copper nutritional status. The people died from cardiovascular disease, the concentration of copper was found on higher side in heart muscles and serum in them.

Outside the body, free copper is known to be a pro-oxidant and is frequently used to produce oxidation of low-density lipoprotein (LDL) in the test tube. Recently, the copper-containing protein ceruloplasmin was found to stimulate LDL oxidation in the test tube. Increased copper levels could increase the risk of atherosclerosis by promoting the oxidation of LDL. However, there is little evidence that copper or ceruloplasmin promotes LDL oxidation in the human body. But in human body cuproenzymes, superoxide dismutase and ceruloplasmin, have antioxidant properties. The association between serum ceruloplasmin levels and inflammatory conditions is not clear.

In humans serum ceruloplasmin levels increase by 50% or more under certain conditions of physical stress, such as trauma, inflammation, or disease. Because over 90% of serum copper is carried in ceruloplasmin, elevated serum copper may simply be a marker of the inflammation that accompanies atherosclerosis [65].