conspectus of researchon copper metabolism and requirements

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1994 KARL E. MASON labile pool, is less firmly bound in large part to albumin and in smaller part to amino acids (553), especially to histidine, threonine and glutamine (554). The smaller portion of "free" copper bound to amino acids, the existence of which was first demonstrated by Neumann and Sass- Kortsak (553, 554) and Sakar and Kruck (658), may be important as a transport form of copper in the blood, capable of actively diffusing across cell membranes such as those of erythrocytes, whereas al bumin-bound copper preferentially releases its copper to receptor proteins of the plasma membrane of hepatocytes and other cells. After exposure of human serum to a centrifugal force greater than necessary to sediment albumin, copper may be demon strated in serum in the form of mixed amino acid-complexes consisting of one atom of copper and two different amino acids, predominantly complexes of cop per wittÃ¬histidine, threonine and glutamine (553, 554). Moreover, in ultrafiltrates of human serum there can be identified not only these complexes but also a mixed com plex of histidine-copper-threonine (554). In the red blood cells copper exists both in a labile pool, much like that in the plasma but proportionately much larger, and also in a firmly bound form, almost entirely as erythrocuprein ( Superoxide dismutase). Total erythrocyte copper in nor mal man is about 89 Â±11.4 /Â¿g/100ml of packed red cells (492). The labile pool represents copper complexed with amino acids, freely dialyzable and probably in volved in providing copper for Superoxide dismutase. It contains about 4Q% of the erythrocyte copper. The remaining 60% is almost entirely bouYid to erythrocuprein, a cuproprotein first isolated by Markowitz et al. (490), described more fully by Kimmel et al. (406), and later identified as superoxide dismutase by McCord and Fridovich (501). In addition, a small amount of cop per is thought to be bound to a pink cop per-binding protein isolated by Reed et al. (631). This may correspond to the nonerythrocuprein copper fraction observed in human red blood cells by Shields, et al. (708). This protein has no amine oxidase or Superoxide dismutase activity, and its biological function remains to be demon strated. It is apparent that neither whole blood, blood cell nor blood plasma levels of cop per provide useful information regarding nutritional copper status in man. The erythrocyte copper of both compartments is remarkably stable regardless of dietary intake, and is not involved in transport of copper to tissues. The latter function is mainly ensured by the small compartment of plasma copper (about 7c/f of the total) bound largely to albumin and to a lesser degree to amino acids, the latter com plexes being essential for active transport of copper across cell membranes. The al bumin and amino acid-bound forms of plasma copper, together with minute amounts of free ionic copper, represent the direct reacting copper of serum which may increase with intake only temporarily be fore liver homeostasis comes into play. The much larger compartment of ceruloplasmin copper is generally not influenced by di etary intake of copper but does react to a great variety of conditions responsible for states of hypocupremia and hypercupremia, as discussed later (pp. 2014-2020). A small diurnal variation in plasma copper has been reported (434, 460). EXCRETION OF COPPER As previously stated (p. 1991) in normal man perhaps up to 40 to 60% of dietary copper is actually absorbed, with the gas tric and duodenal mucosa playing the major role. Such estimates are, in large part, based upon differences between oral and intravenous intake and fecal excretion, since urinary excretion of copper plays a very minor role. Therefore, the real prob lem in evaluating these differences lies in determining what fecal excretion truly represents. Presumably, it represents unabsorbed dietary copper plus copper ex creted via the biliary tract (a major fac tor), salivary glands and gastric and in testinal mucosae, minus copper which may be reabsorbed by the gastrointestinal tract in the course of transit. Aside from these considerations are losses of copper via sweat and the menses, which are measur able with a limited degree of accuracy. It is hoped that the discussion to follow may Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 1995 delineate the state and lack of current knowledge concerning many of the physi ological mechanisms mentioned. Biliary excretion Sheldon and Ramage (705) were the first to note the presence of copper in bile and to suggest that this represents a chan nel of excretion. They also hypothesized, on the basis of the high values obtained from gall bladder bile, that the body may attempt to conserve its supply of copper by reabsorption through the highly vascu lar wall of the gall bladder. The latter re mains an unsettled question. An isolated report of phenomenally high concentra tion in pigment gall stones (689 ) seems not to have been confirmed. In 1944 Van Ravensteyn (805) stated that "We could not find in the medical lit erature any data on copper excretion with the bile or via the intestinal wall in man after administration of copper by mouth or by intravenous injection of copper com pounds." In his studies he found that, un like iron, oral copper had little effect upon blood levels, but caused a marked increase in bile and feces. He also discussed the possible reabsorption of biliary copper by the small intestine and of fecal copper by the colon. For the latter there is little or no evidence. This suggestion was based upon his observations that biliary excretion and fecal excretion did not run parallel, follow ing intravenous injections of a non-toxic organic salt of copper. For the duodenal bile of eight normal subjects, Van Raven steyn found the average copper content to be 0.118 mg/100 ml (range 0.03-0.20 mg/ 100 ml). These may be compared to an average content of 0.2 mg/100 ml (range 0.06-0.32 mg/100 ml) for common duct bile in three subjects, and of 0.48 mg/100 ml (range 0.09-1.07 mg/100 ml) in gall bladder bile from 19 cases of chronic chole cystitis, obtained at the time of operation for bladder stones, as reported the same year by Judd and Dry ( 391 ). As noted by the next investigators to contribute to this subject ( 105), a number of factors makes it very difficult to deter mine with a reasonable degree of accuracy the amount of copper excreted via the biliary tract. The daily outflow is inter mittent and may vary from 250 to 1,100 ml/day. Bile cannot be collected quanti tatively from normal subjects, even those with exterioration of the bile duct or in dwelling T-tube, since in these situations the volume of bile flow is not normal. Moreover, copper in bile aspirated from the gall bladder during surgery or post mortem is considerably concentrated as compared to liver bile or duodenal bile, and the latter is subject to contamination by duodenal contents and the tubes used for the collection. It is reported ( 105) that copper in gall bladder bile obtained post mortem from six normal subjects ranged from 0.024 to 0.54 mg/100 ml, with an average value of 0.329 mg/100 ml. One subject with a cutaneous bile fistula follow ing complete obstruction of the common duct excreted an average of 0.46 mg/100 ml copper per day. Another subject with primary biliary cirrhosis and T-tube drain age, gave an average value of 0.05 mg/100 ml (range 0.03-0.95 mg/100 ml) in bile collected daily for 17 days. No data on total daily output of copper were obtained. In their conclusions, Cartwright and Wintrobe ( 105) state that assuming a daily intake of 2.0 to 5.0 mg of copper, 0.6 to 1.6 mg (32%) is absorbed. From 0.01 to 0.06 mg is excreted in urine, 0.1 to 0.3 mg passes directly into the bowel, and 0.5 to 1.3 mg is excreted in the bile. The latter estimate is, in reasonable accord with a later report of Frommer (235) indicating that in 10 control subjects biliary excretion approximated 1.2 mg/day, based upon bile aspirated from the duodenum after over night fasting. Walshe (822) states that in subjects with external biliary drainage up to 107' of ingested labeled copper can be recovered in the bile within 24 hours. Human bile is said to contain copperbinding complexes of low and high molecu lar weight, the former predominating in hepatic bile and the latter in gall bladder bile (263, 266). However, the high molecu lar weight fractions may represent artifacts in Chromatographie procedures, and essen tially all of the copper may be bound to complexes of low molecular weight (4,000- 8,000 daltons) (236), as observed in bile of the rat ( 196) which, by the way, pos sesses no gall bladder. The question of an 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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