conspectus of researchon copper metabolism and requirements

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1990 KARL E. MASON that after oral administration of radio active copper the isotope appears rapidly in the blood, reaching maximum levels within 1 to 3 hours, as further discussed below. Concepts of the processes of absorp tion of copper from dietary sources in man are based in large part upon studies of experimental animals. Animal studies indicate that at least two mechanisms are concerned in copper ab sorption ( 132, 256 ). One of these, pre sumably an energy-dependent one, in volves the absorption of complexes of cop per and amino acids. There is also evidence that L-amino acids facilitate the absorption of copper, and that absorption progres sively decreases with increasing molecular size of copper-amino acid complexes (408 ). The other mechanism is an enzymatic one involving the binding of copper to, and successive release from, macromolecular proteins. Studies of experimental animals indicate that mechanisms of copper storage and transfer involve not only metallothionein as first identified in the chick intestinal mu cosa (733), but that there also may exist a variety of metallothioneins, differing slightly in amino-acid content and metalbinding characteristics (518, 562). There is real need for better determination of the extent to which findings in experimental animals have application to the problem of copper absorption and metabolism in man. This applies also to the many factors in animals which are known to interfere with copper absorption through various mecha nisms (competition for binding sites by zinc, perhaps to a much lesser extent by cadmium; interactions between molyb denum, sulphates and copper; the effects of dietary phytates, and the influence of ascorbic acid intake). In the case of the latter, dietary deficiency results in in creased liver and plasma copper (337), whereas increased oral intake decreases the absorption and retention of copper in the chick (333), rabbit (370), pig (254) and rat (199). Moreover, in the pig, high intake of ascorbic acid can overcome the effects of excess copper either by inter fering with copper absorption or by in creasing the absorption and utilization of iron (254). Such evidence raises questions as to whether due consideration has been given to the secondary effects that may be related to the somewhat astronomical hu man intakes of ascorbic acid currently in vogue. It is also important to note that the type, configuration and degree of polymeri zation of amino acids present in the in testine can influence the absorption of cop per (798). Moreover, little is known re garding the chemical forms of copper in foods, and the influence of different meth ods of cooking upon its availability. The great difficulty in determining that portion of dietary copper which is ab sorbed becomes apparent when one con siders the many variable factors affecting copper absorption such as: competition for protein-binding sites in the intestinal lumen and mucosa; inhibition of binding at these sites; difficulties in measuring the amount of copper secreted by the bile, by accessory glands of the digestive tract and by the in testinal mucosa; and possible reabsorption by the intestinal mucosa of some of the secreted copper. Excellent reviews of this subject have been presented by Dowdy (169), Evans (192), Hambidge and Wairavens (301) and Van Campen (804). Mechanisms The general concept of the mechanism involved in copper absorption is as follows: from ingested foodstuff copper is released either as ionic copper or as a copperamino acid complex. In the intestinal lumen there exists a high molecular weight protein which binds copper and preferen tially releases it to the plasma membranes on the luminal side of the absorptive cells of the mucosa. Within the absorptive cells is metallothionein (or metallothionein-like proteins) rich in sulfhydryl groups, which binds copper through formation of mercaptide bonds. Since this cuproprotein serves as a storage depot and also releases copper to the plasma cell membrane on the serosal side, it is considered to provide one of the protective and regulatory mecha nisms in copper homeostasis. However, it is not quite that simple, since its binding to copper is constantly in competition with other trace elements and can also be in fluenced by other dietary components such as the sulphate radical, phytates, fiber and ascorbic acid. Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 1991 Dynamic studies with radioactive cop per have yielded important information. In man, oral administration of 64Cu or 67Cu is followed by a prompt appearance of the isotope in the blood serum, indicating at least major absorption from the stomach and duodenum (40, 42, 80, 179, 387, 832). Within 1 or 2 hours the isotope is bound to serum albumin and amino acids (41, 80). There follows a sharp decline as the isotope is taken up by the liver. Subse quently, there occurs increased activity of the serum for 48 to 72 hours as the liver incorporates the radioisotope into newly synthesized ceruloplasmin and releases it into the blood (40, 41, 80, 179). That not immediately extracted by the liver remains in the serum attached to albumin or amino acids, or is used to maintain erythrocyte copper levels. Amount The proportion of dietary copper that is actually absorbed is very important in the making of judgments on balance studies and their bearing upon normal human re quirements for copper. Unfortunately the information currently available is both meager and somewhat inconclusive. Van Ravensteyn (805) estimated that about 25% of copper (as CuSO4) added to the diet of normal men, is absorbed. Later, Cartwright and Wintrobe ( 105) stated that about 32% of ingested copper is absorbed. Early studies employing oral and intra venous administration of 64Cu to small numbers of control subjects in investiga tions primarily designed to determine whether or not there is an absorption de fect in Wilson's disease gave quite variable results, in terms of the percentage of the dose recovered in the feces over periods of 3 to 4 days (41, 80, 498). Furthermore, since radio-copper is both excreted into and absorbed by the gastrointestinal tract, fecal excretion provides a measure of re tention but not of true absorption. Assum ing that after 48 hours the serum concen tration of 64Cu is proportional to either an intravenous dose or to a certain fraction of an oral dose absorbed, Sternlieb (736) estimates that on the basis of studies on 49 normal subjects the mean absorption of an oral dose of 2 mg of copper daily, is 0.8 mg, or 40%. Weber et al. (832), em ploying similar methodology, concluded that the net absorption of orally administerred copper varies from 15 to 97%, with a mean of about 60%. A more sophisticated approach by Strickland et al. (752), in volving four normal adults given 64Cu orally and ti7Cu intravenously, with copper absorption calculated by whole body counting and by plasma 64Cu and 07Cu concentrations, gave a mean copper ab sorption value of 56% (range 40-70%). It was their opinion that if Sternlieb (736) had made allowance for a 20%) fecal ex cretion of copper (753), the three studies mentioned would have been in close agree ment. Quite recently King et al. (407) re ported an overall copper absorption of 57% based upon balance studies with the stable isotope 65Cu. On the basis of the evidence presented above, it seems reasonable to assume an absorption of 40 to 60% of the oral intake of copper, accepting the fact that there is wide individual variation. Copper absorption may be significantly impaired in states of severe, diffuse disease of the small bowel produced by sprue, lymphosarcoma, or scleroderma (739), or protein calorie malnutrition (474). In Menkes' steely-hair syndrome defects in intestinal transport and release constitute one of the primary bases for this disorder (p. 2007). Information concerning the role of the lymphatics in the absorption of copper is sadly lacking. Sternleib et al. (748) re port that in the dog and man the amount of an oral dose of 64Cu absorbed by the intestinal lymphatics is negligible. On the other hand, Trip et al. (789) found con centrations of copper ( non-ceruloplasmic ) in the thoracic duct of three patients equivalent to or higher than in serum. It must be noted that these subjects suffered from carcinoma and Hodgkin's disease and cannot be considered normal. Regrettably, the impossibility of obtaining thoracic duct lymph from normal healthy subjects offers little hope of determining the role of the intestinal lymphatics in absorption of copper. TRANSPORTOF COPPER Intestine to liver Following release from the intestinal mucosa, copper becomes bound to albumin Downloaded from jn.nutrition.org by guest on February 27, 2013
Page 1 and 2: A CONSPECTUS OF RESEARCH ON COPPER
Page 3 and 4: INTRODUCTION The discovery of coppe
Page 5 and 6: COPPER METABOLISM AND REQUIREMENTS
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Page 55 and 56: Ã®1co 1stW Â»aÂ«a3 COPPER MET
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COPPER METABOLISM AND REQUIREMENTS
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