conspectus of researchon copper metabolism and requirements

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2024 KARL E. MASON metallothionein or metallothionein-like proteins, complex as these interactions ap pear to be (518), provides the best ex planation. These proteins are present in the liver, kidney, intestinal mucosa, pan creas and spleen. They play an important role in copper homeostasis. In man, these reciprocal interactions are less apparent than in animals where the intake and im balance of the elements can be more spe cifically controlled. However, a striking example is the reported occurrence of typi cal copper deficiency, with microcytic hypochromic anemia and leukopenia, in one patient, and very low levels of serum cop per in 7 of 13 others, receiving unusually high levels of zinc for the treatment of sickle cell anemia (64). All responded favorably to daily supplements of copper. The question of the dietary ratio of zinc to copper has been given considerable at tention by Kelvay (416-418, 420) in sup port of a hypothesis that high zinc to cop per ratio and the associated hypercholesteremia increase the risk of ischemie heart disease, and may also play an important role in the genesis of arteriosclerosis. This hypothesis has received limited support (81, 82). Of some relevance are recent ob servations that myocardial lesions associ ated with hypercholesteremia occur in rats fed a copper-deficient diet for 7 to 9 weeks after weaning (16). Cardiac hypertrophy, subendocardial hemorrhage, necrosis of muscle fibers, abnormalities of elastic tis sue of the aorta but not of the coronary arteries, and occasional heart rupture are described. In other studies with copperdeficient rats similar lesions have been ob served and ascribed to a marked reduction in cytochrome c oxidase activity (3, 401). With repletion of copper, cytochrome c oxidase activity is normalized, after which cardiac hypertrophy and splenomegaly are greatly reduced (3). Unquestionably, in terest has been stimulated, but there is need for specific research on man directed toward the possible role of zinc/copper ratios and cholesterol status in ischemie heart disease. HUMAN REQUIREMENTS In discussing requirements of any nu trient, a variety of terms are in common usage, such as "basic," "minimal" and "optimal" requirements; and "recom mended" allowances. An excellent discus sion and definition of these terms has been presented by Mertz (514). According to his interpretation, the "basic" requirement for a trace element represents that daily intake permitting absorption of an amount just sufficient to prevent a state of de ficiency; whereas the "optimal" require ment represents that daily intake which will allow maintenance at a near-optimal level of all biological and physiological functions in which the element is involved, under the various stress conditions of life. The somewhat intermediate term "mini mal," traditionally used in balance studies, is defined as that daily intake which equals the daily excretory loss from the body. This term best fits the nature of the data on which estimates of human requirements for copper are based. The term "optimal" is somewhat comparable to the term "rec ommended dietary allowance." According to Harper (307), the RDA represents esti mates of the amount of an essential nu trient which "each person in a healthy population must consume in order to pro vide reasonable assurance that physiologi cal needs will be met." In the case of copper requirements, the problem is not as simple as it might ap pear. Most difficult to evaluate are the reported differences in the copper content of foods, diets, body fluids and tissues attributable to the great variety of analyti cal methods employed over the past half century, and to possible contamination of samples prior to or during analytical pro cedures. An excellent discussion and criti cal appraisal of methods in use up to 1965 for the determination of copper and ceruloplasmin in biological materials is presented by Sass-Kortsak (666). The methods de scribed have been variably modified and newer ones introduced. In some instances there is rather remarkable agreement be tween early and later reports. In other instances there appear differences which, on inspection, might reflect variable sensi tivity of the methods employed. Any ef fort to identify and evaluate methodolo gies used in particular studies would be rather futile. Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2025 What has been outlined in this con spectus, up to this point, has been an assessment of past and current knowledge regarding the role that copper may play in the metabolism of man, with occasional reference to ancillary information gained from observations on laboratory and farm animals. Attention has been called to the distribution of copper in the body; the vast array of cuproproteins and evidence as to their roles in maintaining functional and morphological integrity of specific tis sues and organs; the absorption, transport and excretion of copper; its omnipresence in foods; its important roles in prenatal and postnatal life, and; the nature of states induced by naturally occurring, experimen tally induced and congenitally determined copper deficiency. It is hoped that this digest of knowledge will provide an ade quate basis for considerations of the mini mal copper requirements of man. In considering human requirements for copper there are many factors whose in fluence is exceedingly difficult to evaluate because of limited knowledge available. A few examples may be cited. That portion of dietary copper which is actually absorbed probably varies considerably, depending upon its chemical state in the foods con sumed and the influence of other dietary components. Best estimates indicate an absorption of 40 to 60% of the oral intake (p. 1991). In addition to the unabsorbed copper and biliary copper components of the feces, inadequate consideration has been given to contributions provided by secretions of the salivary glands, gastric and intestinal mucosa and pancreas, and by dehiscence of epithelial cells of intesti nal villi. At least, the extent of reabsorption of copper released via these various pathways has not been clearly determined. Despite frequent statements in the litera ture that some of the copper in bile may be reabsorbed, there exists other evidence that this copper is so firmly bound to pro teins that it is not reabsorbed by the gall bladder or intestinal mucosa in any signifi cant amounts (266). Balance studies are limited by the pre cision with which intake and output can be measured. For an element such as cop per which has a slow rate of turnover, a variable degree of intestinal absorption, strong homeostatic mechanisms and an almost exclusive output via the feces, in terpretations of balance studies becomes very difficult. The sporadic nature of defe cation and rather wide individual variation make balance studies of 7 to 14 days neces sary for obtaining valid data. Replacement of carmine by polyethylene glycol 4000, as a fecal marker, should shorten this time period (848). Biological availability is also an impor tant but largely unknown factor. Little is known about the chemical nature of cop per in foods, the extent to which it may react with chelating substances such as dietary fiber, or how its absorption may be influenced by the protein-binding poten tialities of other trace elements such as zinc and molybdenum. To these factors must be added the inflence of acute and chronic infections, use of antimicrobial agents, dys function of the gastrointestinal tract and other stress states. Usually, in well con ducted copper balance studies on man, healthy subjects are selected and as many as possible of the above mentioned in fluences are eliminated. The discussion to follow will focus on accumulated evidence from balance studies and from experiences with total parenteral nutrition as to what may represent the minimal requirements of man for copper during infancy, child hood and adulthood. Infants Specific requirements of healthy human infants for copper have been difficult to determine with any degree of accuracy. To provide a picture of the problem, it seems appropriate to review current infor mation with respect to: 1) milk as a source of copper for the premature and full-term infant; 2) copper balance studies on in fants; 3) naturally occurring states of cop per deficiency; and 4) studies on infants largely or totally dependent upon total parenteral nutrition (hyperalimentation ) for extended periods of time. Milk as a source of copper. It has long been recognized that the copper content of human milk is two to three times higher than that of cow's milk, and that the con tent of human colostrum is two to three 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
Page 45: COPPER METABOLISM AND REQUIREMENTS
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Page 55 and 56: Ã®1co 1stW Â»aÂ«a3 COPPER MET

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