conspectus of researchon copper metabolism and requirements

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2036 KARL E. MASON maintained on total parenteral nutrition for 8 days to 7.5 weeks (mean, 4.5 weeks). The infÃºsate, providing nitrogen as crystal line L-amino acids, contained no copper detectable by a method sensitive to 20 itg/liter. Usually more than 2 months of total parenteral nutrition with unsupplemented infusÃ¢tesare required before clini cal evidence of copper deficiency becomes apparent (590 ). The need for more general inclusion of trace elements, especially cop per and zinc, in parenteral fluids is obvious. Despite the widely recognized need for adequate provision of copper and other trace elements in intravenous solutions, recommendations and practices of differ ent investigators reveal wide variations. According to the calculations presented by Jacobson and Wester (379), the rec ommendations for copper in trace element mixtures per 24 hours in total parenteral nutrition for 70 kg adults vary from 1.54 mg (173), 1.0 mg (709, 710), 0.11 mg (367), 0.3 mg (864) and 0.1 mg (379). It is the opinion of Jacobson and Wester (379) that a daily intake of 0.3 mg repre sents the best recommendation. This again represents an oral intake less than 1 mg/ day. It is of particular interest to find that data based upon milk intake in infants and upon balance studies and prolonged main tenance with total parenteral nutrition have shown remarkably good agreement. Briefly stated, the evidence suggests that copper requirements for the maintenance of good health lie within the range of 0.025 to 0.05 mg/kg for young infants, 0.05 to 0.1 mg/kg for older children and adolescents, and in the neighborhood of 1.0 to 1.5 mg/day for adult man. RESUME There has been presented a review of research findings relative to the distribu tion of copper in the human body: the nature and function of a large array of cuproproteins; the omnipresence of copper in foods; its absorption, transport and ex cretion; naturally occurring states of cop per deficiency; dietary interrelationships and states of toxicity; the congenital dis orders of Menkes' disease and Wilson's disease; copper metabolism of pregnancy, neonatal and postnatal life; and copper re quirements of infancy, adolescence and adulthood as determined by balance studies and data derived from experiences with parenteral nutrition. The human body contains approximately 75 mg of copper, about one-third of which is present in the liver and brain. Lesser concentrations exist in the heart, kidney, pancreas, spleen, bone and skeletal muscle. In organs and tissues copper is bound to a wide variety of cuproproteins, most of which have properties of enzymes. Among the trace elements copper is unique in terms of the large number of metabolically important enzymes of which it is an essen tial component, and the wide variety of organs and tissues in the mammalian organism whose functional and structural integrity are dependent upon these en zymes. Of these, ceruloplasmin, Superoxide dismutase, cytochrome c oxidase, lysyl oxidase, tyrosinase and neonatal mitochrondrocuprein are recognized as impor tant in human metabolism. Metallothionein and similar low molecular weight cupro proteins, non-enzymatic in nature, have roles in copper storage and detoxification. Still awaiting further investigation are other cuproproteins some of which might well prove to have important but as yet unrecognized roles in human metabolism. Ceruloplasmin, whose biological role has long been a mystery, is now recognized as a multifunctional cuproprotein possessing a broad spectrum of oxidase activity. Its role as feroxidase I in the mobilization of plasma iron provides a satisfying answer to questions raised 50 years ago concerning the role of copper in nutritional anemia. Its role as a cuproprotein transferring cop per to tissues for the synthesis of vitally important enzymes, the most important of which is cytochrome c oxidase, has been relatively unexplored. The same may be said of the possible capacity of ceruloplas min to maintain and control blood and tis sue levels of biogenic amines. In view of the importance of these amines in normal brain functions and the neurological defi cits found in both Wilson's and Menkes' disease, this will unquestionably be a fruit ful area for future investigation, both ex perimental and clinical. Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2037 Cytochrome c oxidase, an enzyme vital to essentially all forms of life, has been clearly shown in experimental and farm animals to be involved in the myelination of nerve fibers and in maintaining struc ture and function of myocardial tissue. What relevance such observations may have to brain and cardiac functions in man offer challenging avenues for future re search. Aside from lysyl oxidase, well rec ognized as essential for the cross-linking of elastin and collagen, are other monoamine oxidases in mammalian tissues which future research may well show to be of great importance in the metabolism of man. Metallothionein, a nonenzymic cuproprotein, may well prove to be merely one of a family of cuproproteins of relatively low molecular weight playing important roles in the mechanisms of intestinal ab sorption and transport, and of liver storage and transfer. There is urgent need for bet ter identification of such proteins and in creased knowledge of their metabolic roles. New information of this nature may add greatly to understanding the nature and treatment of the two well recognized in born errors of copper metabolism and possibly of other disorders not yet well recognized. Copper is ubiquitous in nature and its relative amount in different foods is well established. Very little is known regarding the chemical forms in which it exists in foods or the influence which methods of processing and cooking may have upon its availability. In man, there is only limited knowledge of how absorption of available copper may be influenced by interactions in the gut between it and other trace ele ments, metallothionein-like proteins, di etary phytates, sulfates and ascorbic acid. Copper is absorbed chiefly by gastric and duodenal mucosa, and approximately 40 to 60r/c of that ingested is actually ab sorbed, bound to albumin and amino acids and transported to the liver. The liver serves as the control center for copper metabolism and homeostasis by virtue of its functions as a major storage depot, the major site of copper excretion via the bile and the only site of ceruloplasmin syn thesis. In blood, the ratio of copper in red cells to that in plasma is approximately 0.7. Of that in erythrocytes, which is remarkably constant in normal man, 40% is in a labile form bound to amino acids and 60% is more firmly bound in Superoxide dismutase. Of the copper in blood serum, about 1% is labile, bound more to albumin than to amino acids, the remaining 93% being firmly bound as an important component of ceruloplasmin, synthesized only by the liver. States of hypocupremia in man are rela tively rare, occur usually in children and, except for high urinary loss of ceruloplas min in the nephrotic syndrome, are gen erally due to hypoproteinemia and inabil ity to provide adequate amounts of apoprotein for ceruloplasmin synthesis. On the other hand hypercupremia, due almost ex clusively to hyperceruloplasminemia, is commonly observed in pregnancy, after oral intake of contraceptives and in associ ation with innumerable disease states and disorders. Elevated serum ceruloplasmin in states where inflammation is involved re flects its function as an "acute phase reactant"; in non-inflammatory states reasons for its increase are shrouded in mystery. There are unsettled questions concern ing placental transfer of ceruloplasmin. But of far greater importance is the need for much more information on fetal copper metabolism, including the distribution and nature of protein binding of copper in dif ferent organs and tissues of the fetus. Such information is of particular relevance to a better understanding of the basic defect in Menkes' disease. Because of ethical and other restrictions, the answers may have to come from studies on lower primates which, to date, have not been utilized in studies on copper metabolism. Menkes' steely-hair disease, first de scribed in 1962, represents a state of cop per deficiency induced in young infants by a sex-linked recessive defect in copper me tabolism. The primary metabolic defect is unknown. Some findings suggest a block in the transfer of copper across absorptive cells of the intestinal mucosa, but there are possibilities of a defect in placental trans fer of copper or the presence of an atypi cal protein-binding of copper in the liver Downloaded from jn.nutrition.org by guest on February 27, 2013
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A CONSPECTUS OF RESEARCH ON COPPER
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INTRODUCTION The discovery of coppe
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COPPER METABOLISM AND REQUIREMENTS
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