Copper absorption, intestinal

In mammals, cadmium inhibits copper absorption across the intestinal mucosa (Aaseth and Norseth 1986). Intercorrelations of copper with cadmium and zinc in livers of polar bears (Ursus maritimus) are probably mediated by metallothioneins, which may contain all three metals (Braune etal. 1991). In rats, copper protects against nephrotoxicity induced by cadmium, provided that copper is administered 24 h prior to cadmium insult. Specifically, rats given 12.5 mg Cu/kg BW by way of subcutaneous injection 24 h before receiving 0.4 mg Cd/kg BW — when compared to a group receiving Cd alone — did not have excessive calcium in urine and renal cortex or excessive protein in urine. Thus, 2.8 mg Cu/kg BW protects against 0.25 mg Cd/kg BW (Liu et al. 1992). 

In mammals, copper absorption across the intestinal mucosa is inhibited by concomitant high oral intake of zinc (Aaseth and Norseth 1986). In livers from Weddell seals, copper is positively correlated with zinc (Szefer et al. 1994). The addition of zinc to swine diets protects against copper toxicosis caused by eating diets containing 250 mg Cu/kg ration (USEPA 1980). 

Handy, R. D., Musonda, M. M., Phillips, C. and Falla, S. J. (2000). Mechanisms of gastro-intestinal copper absorption in the African Walking Catfish copper dose-effects and a novel anion-dependent pathway in the intestine, J. Exp. Biol.,... 

For patients who are unable to tolerate penicillamine, trientine, another chelating agent, may be used in a daily dose of 1-1.5 g. Trientine appears to have few adverse effects other than mild anemia due to iron deficiency in a few patients. Zinc acetate administered orally increases the fecal excretion of copper and is sometimes used for maintenance therapy. The dose is 50 mg three times a day. Zinc sulfate (200 mg/d orally) has also been used to decrease copper absorption. Zinc blocks copper absorption from the gastrointestinal tract by induction of intestinal cell metallothionein. Its main advantage is its low toxicity compared with that of other anticopper agents, although it may cause gastric irritation when introduced. 

For the most part, adequate copper is received in diet and widespread human deficiencies do not occur, but deficiencies may arise because of antagonists. The metals Cd, Hg, Ag and Zn interfere with copper metabolism, probably by competing for copper-binding sites in proteins. Ascorbic acid depresses intestinal absorption of copper56 (in contrast to iron). Some proteins in the diet adversely affect utilization of copper. The sulfide ion is a well known inhibitor of copper absorption, since it forms copper(II) sulfide which is insoluble.56... 

Copper absorption appears to occur through both a rapid, low-capacity system, and a slower, high-capacity system, which may be similar to the two processes seen with calcium absorption. Inactivating mutations in the gene encoding an intracellular copper ATPase have been shown to be responsible for the failure of intestinal copper absorption in Menkes disease. 

Interactions Overabundance of one trace element can interfere with the metabolic use of another element available at normal levels. For example, addition of large amounts of zinc to a diet interferes with (antagonizes) intestinal copper absorption, resulting in copper deficiency from a diet with adequate copper content. Copper deficiency can provoke iron deficiency and anaemia. Molybdenum deficiency in animals can be induced by co-administration of large amounts of the similar element tungsten. Iron deficiency can also increase retention of cadmium and lead, and selenium has been proposed to protect against cadmium and mercury toxicity. 

The best known of these is the interference of copper absorption caused by zinc due to the induction of intestinal metallothionem this binds to copper and prevents its entry into the bloodstream. The intestinal cells eventually slough, carrying the copper with them. The prolonged intake of zinc necessitates copper supplements except in patients with Wilson s disease. 

Zinc acetate (Galzin, Gate Pharmaceutical Co), developed for the treatment of Wilson s disease (4), has been used in maintenance therapy of adult and pediatric disease, but it also has efficacy in the treatment of pregnant women and presymptomatic patients from the start. It also has value as adjunctive therapy for the initial treatment of symptomatic patients. Its mechanism of action involves induction of intestinal cell metaUothionein, which blocks copper absorption from the intestinal tract. Negative copper balance is caused by blockade not only of absorption of food copper but by blockade of reabsorption of the considerable amount of endogenously secreted copper in saliva, gastric juice, and intestinal secretions. It is therefore effective in controlling copper concentrations and toxicity in Wilson s disease. 

Zinc sulfate can cause copper deficiency by inducing the production of metaUothionein in intestinal cells and thus lowering copper absorption copper deficiency can lead in turn to sideroblastic anemia (8), neutropenia, and osteopenia (9). 

The mechanism of this eflFect is not known. Hill and Starcher (49) postulated that reduction of copper from its divalent (cupric) state to its monovalent (cuprous) state accounted for the impaired absorption of copper in the presence of ascorbic acid they produced the same effect with another reducing agent, dimercaptopropanol (BAL). This explanation has been accepted by others (56), although the oxidation state of copper for maximum intestinal absorption has not been established. An intramucosal competition of ascorbic acid for sulfhydryl sites on metallo-thioneins was demonstrated (57). If this ligand has any regulatory role in copper uptake, this alternative mechanism of ascorbic acid-copper interaction could explain the mechanism. Experimental confirmation of an ascorbic-acid-induced inhibition of copper absorption in the human intestine has not been presented. 

The ability of zinc ions to block copper absorption, possibly by formation of- intestinal metallothionein that strongly binds copper, has led to its use in pharmacological doses in the management of Wilson s disease/ Similarly molybdate ion can form insoluble copper-molybdate complexes in the intestine that limit copper absorption. The detrimental effects of organic phosphate (phytic acid) in limiting zinc absorption are aggravated by excess dietary calcium, probably by formation of a highly insoluble Ca-Zn-phytate complex. The subject of these and other interactions has been reviewed, ... 

Copper absorption mainly occurs in the small intestine, although gastric uptake has been shown to occur to a smaller extent. Some copper may also be incorporated by inhalation and skin absorption. The extent of intestinal copper absorption varies with dietary copper content and is around 50% at low copper intakes (<1 mg Cu per day) but only 20% at higher intakes (>5mg Cu per day). Copper intestinal uptake is pH dependent and relatively efficient. Absorption is reduced by other dietary components, such as zinc (via metallothionein), molybdate, and iron, and increased by amino acids and by dietary sodium. ... 

Treatment of active, symptomatic Wilson s disease is aimed at increasing urine copper excretion to eliminate excess copper from tissue. The primary therapy for Wilson s disease involves chelating agents such as o-penicillamine and trientine, which is now more widely used because of its lower rate of side effects. In patients with minimal symptoms or in asymptomatic family members, zinc is used to competitively inhibit copper absorption from the intestinal tract. Lifelong therapy with one of these types of treatment is required and is usually successful in limiting further damage. 

Copper is absorbed from food in the upper small intestine. The absorption is primarily dependent on the quantity of the copper present in the diet. High intake of zinc diminishes copper absorption by inducing metallothionein formation in the mucosal cells. Metallothioneins, due to their high affinity for copper, bind it preferentially and the bound copper is lost during the sloughing of cells from the villi. Copper accumulation in patients with Wilson s disease can be reduced by giving oral zinc acetate, which decreases absorption (discussed later). Absorbed copper is transported to the portal blood where it is bound to albumin (and probably transcuprein), amino acids, and small peptides. Copper binds to albumin at the N-terminal tripeptide (Asp-Ala-His) site. The recently absorbed copper is taken up by the liver, which plays a central role in copper homeostasis. 

Although certain factors influencing the absorption of copper from the intestine are recognized, we have no concept of the mechanism of absorption nor do we know the regulatory mechanisms which influence the rate of absorption. The suggestion of Scheinberg and Morell (S16) that ceruloplasmin may be involved in the regulation of copper absorption could not be substantiated. 

Individuals who are at risk for copper deficiency include people who are recovering from abdominal surgery, which causes decreased absorption of copper from the intestine. Others at risk are premature babies and people who are sustained solely by intravenous feedings that are deficient in copper. In addition, people who ingest high doses of antacids or take excessive supplements of zinc, iron, or vitamin C can develop copper deficiency because of reduced copper absorption. Because copper is involved in so many processes in the body, it is not surprising that the symptoms of copper deficiency are many and diverse. They include anemia decreased red and white blood cell coimts heart disease increased levels of serum cholesterol loss of bone defects in the nervous system, im-mime system, and connective tissue and abnormal hair. 

Fischer PWF, Giroux A, L Abbe MR. 1981. The effect of dietary zinc on intestinal copper absorption. Am J Clin Nutr 34 1670-1675. 

Ogiso T, Ogawa N, Miura T. 1979. Inhibitory effect of high dietary zinc on copper absorption in rats II. Binding of copper and zinc to cytosol proteins in the intestinal mucosa. Chem Pharm Bull (Tokyo) 27(2) 515-521. 

High levels of administered zinc limits copper uptake in humans and certain animals, and provides protection against toxicosis produced by copper in pigs and sheep. Excessive zinc in humans interferes with copper absorption from the intestine, resulting in copper deficiency, and eventually to cardiovascular diseases hi zinc intakes also decrease iron bioavailability, leading to a reduction of erythrocyte life span by 67%. Copper deficiency induced by excess dietary zinc is associated with lameness in horses, donkeys, and mules. 

Average single day s diet may contain 10 mg or more copper. Studies indicate that about half of dietary copper is not absorbed but rather excreted in the feces. Absorption and excretion are normally in the range of 1-5 mg daily. The mechanisms by which copper is absorbed and transported by the intestine are unknown. Copper absorption is impaired in severe diffuse diseases of the small bowel, including spruce, lymph sarcoma, and scleroderma. Radioactive copper given by mouth to human subjects appears very rapidly in the blood. 

The exact role of metallothionein in the intestinal absorption of copper is not well understood although zinc diminishes copper absorption by increased production of metallothionein in mucosal cells which then binds copper preferentially [4]. Excessive zinc administration was shown to indyce copper deficiency in humans [5] and to reduce copper accumulation in patients with Wilson s disease [6,7]. Thus intestinal metallothionein may have some function in maintaining copper homeostasis. After absorption, copper is immediately transported in plasma bound to albumin and to amino acids [8]. 

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