Mechanisms of copper absorption

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Copper absorption in humans has been found to depend on a number of factors, of which the most important is probably dietary copper intake.6 The efficiency of copper absorption is regulated to maintain body copper status, with levels of uptake rising to 70% during periods of deficiency,63 and falling to 12% in high-copper diets.61 This modulation of absorption, which provides a means of adapting to changing dietary intake, appears to develop during childhood, with copper absorption in infants operating at a lower level than in adults.38 While a low level of copper absorption occurs in the stomach, the main site of absorption is the duodenum. Copper absorption from the gut lumen by enterocytes involves both passive and active carrier-mediated systems, which uptake copper across the brush-border, and transport it across the basolateral membrane into the plasma.

Most of the copper in foods is found as a component of macromolecules. Inorganic mineral salts are present in dietary supplements but otherwise probably do not contribute substantially to dietary copper intake.64 In the UK only 1-2% of adults report taking supplements containing copper65 although in the US the figure may be as high as 15%.17 The sulphate, nitrate, chloride and acetate are easily absorbed, but copper oxide and copper porphyrin are unavailable.63 Gastric acid can solubilise the carbonate and facilitate the release of copper from macromolecules.64

Most of the copper in human diets is supplied by vegetable foods, and vegetarian diets generally provide a higher intake. Plant materials, however, are generally less digestible than animal tissues. A substantial proportion of the copper in whole grains is associated with lectins and glycoproteins. Vegetable tissues frequently require more enzymatic attack to digest the copper-binding matrix than do animal proteins, which are generally more easily solubilised, so that percentage copper absorption may in fact be substantially higher from an animal protein diet than from a plant-protein diet.66 Even so, the greater copper content of a vegetarian diet is likely to provide more available copper.67 Dairy products contain relatively little copper, with cow's milk being particularly poor. Absorption is estimated at 24% for human milk and 18% for cow's milk. The quaternary protein structure is thought to exert an effect on the availability of copper in food, as cooked meat has been found to supply more available copper than raw.64 The efficiency of absorption from food is modified by a variety of luminal factors including copper intake levels, other dietary factors and aspects of the intestinal environment. Dietary components known to modify absorption include protein, amino acids, zinc, manganese, iron, tin, molybdenum, sugars, dietary fibre and ascorbate.55

Studies of dietary protein and copper retention in young women have found highest retention with a diet high in protein.68 However, copper bioavailability in high-protein foods may be decreased by heat treatments which promote condensation reaction, such as the Maillard Reaction, between sugars and amino acids.69 The formation of products such as lactulosyl-lysine and lysinoalanine depletes the food of free amino acids. This leaves fewer sites available for the formation of organo-metallic complexes, from which copper is highly bioavailable.70 The bioavailabilities of copper-lysine and copper-methionine complexes, relative to copper sulphate, have been reported as 120% and 96% respectively.71

Copper uptake by the intestinal mucosa is strongly influenced by chelation of copper ions by amino acids. Chelation may even be a mandatory requirement for copper absorption.64 Yet, although dietary amino acids can enhance copper absorption, when present in excess they may result in copper malabsorption, possibly by competing with binding proteins on the enterocyte membrane. The ratio of chelate to metal may determine whether there is a net inhibition or promotion of copper uptake. In one human study, methionine supplementation was found to increase copper absorption.72 Animal studies have provided less straightforward results. One study of rats found that excess dietary methionine decreased indices of copper status.73 Jejunal copper uptake has been found to be decreased by high levels of dietary proline or histidine,74 while excessive cystine and cysteine have been shown to exacerbate the effects of dietary copper deficiency.75 Cysteine is thought to decrease copper bioavailability by reducing Cu (II) to Cu (I).71

The high bioavailability of copper in human milk, compared to cow's milk, may be a consequence of the two foods' protein and amino acid content. Ruminant milk has a higher level of low-molecular-weight ligands, which can inhibit copper absorption. In addition, copper is differently-distributed among the milks'

constituents: human milk has a much larger fraction of its copper content bound to whey, as well as to lipids.64 The antagonistic nature of the copper-zinc relationship has been known for decades. In animals, dietary zinc intake has an inverse relationship with copper absorption.76 In patients with Wilson's disease, zinc salts are given orally to lower copper status by limiting absorption.77

Copper in the gut lumen competes for absorption with zinc, as well as iron and other divalent metal ions. Divalent metals, with their similar electron configurations, can form similar co-ordination complexes.65 This could reduce absorption by displacing copper from specific transporter molecules on the brush border membrane78 or by competing for ligands which are necessary for uptake by these receptors.55 After uptake by enterocytes, intracellular zinc may exert a further antagonistic effect on copper transport. High zinc concentrations are thought to induce the metal-binding protein metallothionein, which has a higher affinity for copper than for zinc. This binding blocks the export of copper, as well as zinc, across the basolateral membrane.55 Recent studies have elucidated a further aspect of the copper-zinc relationship.79 Dietary zinc inadequacy was found to be more detrimental to copper status than moderately high zinc intake, suggesting a degree of interdependence. Although at high levels of intake the two metals act antagonistically, adequate zinc levels are beneficial for copper utilisation.

Copper status can also be impaired by high intakes of manganese.80 Iron and tin, in their divalent forms, have also been shown in animals to compete with copper when present in the diet at high levels.81 Both metals have been known to contaminate food from cooking vessels. Animal studies have suggested that high iron intake affects copper absorption only when copper status is low or mar-ginal.65 In the context of a copper-normal diet its influence on copper absorption in adults may be minimal. However, babies fed an iron-enriched formula have been found to absorb less copper than infants on the same, but lower-iron, formula.82 In rhesus monkeys, which are excellent models of human babies, infants fed a commercially-available iron-enriched formula for 5 months had significantly lower copper status than those fed a lower-iron formula.83

In sheep and other ruminants, interactions between copper and molybdenum have frequently been observed. Chronic molybdenum poisoning in livestock (teart disease) can depress tissue and blood copper levels and produce anaemia and bone deformities, generally symptoms of copper deficiency. In humans, high molybdenum intake has been found to increase urinary copper excretion and result in lowered blood copper.121 The symptoms of excessive molybdenum intake can generally be improved by increasing copper intake.122 Molybdenum is also known to influence intestinal copper absorption: the unabsorbable molybdenum complex, thiomolybdate, inhibits intestinal copper uptake and has been used as a treatment for Wilson's disease.85

Dietary carbohydrate choice can also influence copper status. The interactions of dietary sugars with copper absorption in humans are not yet well understood, but there is evidence to suggest both systemic and luminal influences upon copper absorption. Glucose polymers are thought to enhance copper uptake by increasing mucosal water uptake.64 Dietary fibres such as phytate may somewhat decrease copper uptake, but it is likely that other divalent ions are more strongly bound. Dephytinisation, a process frequently used by food processors to improve the bioavailability of metals, can therefore indirectly reduce absorption of dietary copper by increasing the availability of free, competing, divalent ions.64

In animals, palmitic and stearic acids have been found to reduce the rate of copper uptake from the jejunum.86 In the literature on humans, there is little data regarding the relationship between dietary lipid intake and copper absorption. One human study of the influence of fatty acids on metal absorption indicated that polyunsaturated fatty acids have no effect on copper uptake.87 High dietary levels of ascorbate are thought to reduce Cu (II) to Cu (I), thereby lowering its intestinal absorption rate.88 Conversely, however, utilisation of copper is increased by tissue ascorbate, as it facilitates the release of copper from caerulo-plasmin.22 High intakes of ascorbate have been found to decrease serum caeruloplasmin activity and serum copper.89 A moderately raised intake (605 mg ascorbate/day) has proved sufficient to lower caeruloplasmin activity by 21% without altering intestinal absorption or other markers of copper status.90 Other organic acids, including citric acid, have also been shown to form soluble complexes with copper. It is probably for this reason that fruit intake has a positive effect on copper status.91 The efficiency with which any dietary nutrient is absorbed and utilised in the body is described as bioavailability. It is an essential consideration in the nutritional evaluation of foods and diets.12

In studies of the bioavailability of some minerals, the degree of utilisation may be inferred by measuring some functional endpoint such as the level of synthesis, or activity, of certain biomolecules. Iron bioavailability, for instance, can be determined by measuring the incorporation of a stable isotope into haemoglobin. For copper, however, no single index of utilisation has yet been identified. As a result, estimates of bioavailability have previously focused on measuring intestinal absorption, or bodily retention, rather than utilisation.92 Nonetheless, copper utilisation is influenced by a number of endogenous factors not directly related to luminal absorption rates. By exerting nonluminal effects upon copper utilisation, such factors may result in impaired copper status.

The copper-depleting effect of excess dietary histidine in rats is associated with increased urinary excretion of chelated copper.93 The high level of low-molecular-weight chelates in cow's milk may help to explain the copper deficiency sometimes observed in infants fed on unmodified cow's milk. This may be particularly relevant during periods of anabolic activity, such as recovering from malnutrition.

An association has also been observed between very high intake of fructose or sucrose and a worsening of the effects of copper deficiency in rats,94,95 but not in pigs.96 In humans, similar experiments97 have produced changes including cardiac arrhythmia and reduction of erythrocyte SOD activity with apparently increased copper balance, suggesting that high fructose intake acts systemically to raise body copper requirements. Experimental evidence implicating high fat intake as a further aggravating factor98 suggests that the fructose-copper interaction may be associated with altered energy metabolism.64

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