conspectus of researchon copper metabolism and requirements

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2022 KARL E. MASON foods such as green peas, beans and pickles. The early studies of Drummond (171) failed to demonstrate in experimen tal animals (dogs, cats) any deleterious effects from consumption of such "greened" vegetables. It is now generally accepted that in the processes of cooking, canning and storage of foods and beverages any increment in copper content is largely re lated to contact with copper in the vessels and conduits utilized. In present day societies hazards are reduced to a mini mum. These and other aspects of copper toxicity are well reviewed by Lieh (459). INTERRELATIONSHIPS BETWEEN COPPER AND OTHER TRACE ELEMENTS Studies on laboratory and farm animals have revealed numerous interrelationships between copper and other trace elements and substances (notably iron, zinc, molyb denum, cadmium and ascorbic acid) in mammalian metabolism ( 332, 333 ). On the basis of some of these reactions, Hill and Matrone (332) advanced the thesis that "those elements whose physical and chemi cal properties are similar will act antago nistically to each other biologically." This concept has since been well substantiated. Davies ( 149, 150) classifies interactions between trace elements as non-competitive, and multi-element reactions. The noncompetitive type is exemplified by the re quirement of dietary copper for mobiliza tion of iron for hemoglobin synthesis, as dis cussed earlier (pp. 1985-1986), and by inter actions between molybdenum, sulfur and copper in ruminants as recently reviewed by Suttle (766) and Pitt (603). Inter actions of this type are not predictable from a knowledge of the chemistry of the elements in question, as are those of the competitive type. The latter type is evident in the mutually antagonistic effects of cop per and zinc, such as the protective effect of copper in reducing toxicity resulting from high dietary intakes of zinc in chicks (332); and the effect of increased dietary intake of zinc in increasing the tolerance of pigs to excess intake of copper (767, 768). The multi-element type of inter action is seen in studies with chicks where dietary zinc induces or exacerbates a con ditioned deficiency of copper which in turn restricts the utilization of iron (332). Speaking in general terms, in non-rumi nants interactions of copper with iron and zinc are of particular significance whereas in ruminants interactions of copper with molybdenum in the presence of sulfur take precedence, especially in terms of practical considerations in animal husbandry. Molyb denum toxicity, long recognized in grazing cattle in many parts of the world, causes biochemical and pathological changes closely resembling those of copper defi ciency, as well recognized in the pioneer studies of Davis (150). They are readily prevented or cured by copper sulfate. Compared to cattle, sheep are less suscept ible to high dietary intakes of molybdenum and more susceptible to low intake of molybdenum, which can lead to chronic copper poisoning (798). Species reactions vary greatly (603). Non-ruminants are much more tolerant of excess molybdenum and of high copper intake than are ruminants. Moreover, ef fects of high dietary copper can be accen tuated by low levels of zinc and iron, and low copper intake by ascorbic acid which is thought to interfere with the absorption of copper. An interesting difference is that in ruminants dietary sulfur potentiates a copper-molybdenum antagonism such that tissue copper levels are decreased, whereas in non-ruminants sulfur alleviates this an tagonism. Moreover, the capacities of di etary sulfur to accentuate or ameliorate the toxic effects of molybdenum vary with the copper status of the animal. Among the proposals offered to explain the basic mechanisms involved have been: 1) for mation in the rumen of unabsorbable com plexes such as thiomolybdate, cupric sulfide or cupric molybdate; 2) interference of liver uptake of copper by molybdenum and sulfur; and 3) formation of stable complexes of copper and molybdenum in the plasma. Obviously, much remains to be clarified. Copper is quite routinely incorporated in mineral mixtures added to commercial livestock feeds to increase rate of weight gain and food efficiency and is recognized as a safe ingredient (up to a level of 15 ppm), but regulations prohibit molyb denum additions. Under conditions in which both forage and feeds are naturally Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2023 low in molybdenum, states of copper toxicity, often fatal, have occurred in flocks of sheep (798). This practice of add ing excess copper without molybdenum to livestock and poultry feeds represents a potential hazard to the consuming public, especially to the young infant consuming baby foods made from liver (71). The practical as well as the purely scientific aspects of trace element interactions, com plex as they may be, fully justify some consideration. For further information on the complex interrelationships between molybdenum, sulfate and copper, the reader is referred to a number of reviews on the subject (71, 110, 140, 165, 493, 517, 603, 766, 798) and to a series of recent research reports (110). In man, there is but fragmentary evi dence of significant interrelationships of copper and molybdenum, and of a role of molybdenum in human nutrition. By virtue of molybdenum being a component of xanthine oxidase, it may participate in the reduction of cellular ferric to ferrous fer ritin such that high copper-molybdenum ratio may contribute to abnormalities of iron metabolism and utilization (698, 699). It is postulated that high copper-molyb denum ratios in the American diet may contribute to iron-deficiency anemias and may also have influence upon metabolic abnormalities of copper metabolism such as seen in Wilson's disease (699). From India come several interesting reports dealing with high molybdenum-copper ratios. Volunteers fed diets containing sorghum with increasing content of molyb denum showed increasing levels of urinary copper excretion, which appeared to reflect mobilization of copper from body stores (164). In regions where creation of large dams brings about marked changes in trace element balance in the soil, food grains and drinking water tend to acquire a high molybdenum-copper ratio as molybdenum is leached out by alkaline conditions and the ratio possibly increased further by high fluoride content of soils. As a result the poorest groups of the population whose staple food is sorghum, which accumulates more molybdenum than rice or wheat, be come victims of genu valgum and osteo porosis of the long bones (9, 428). Genu valgum, previously considered the result of fluoride toxicosis, now appears to represent either a state of molybdenosis or one of copper deficiency induced by excess mo lybdenum, or a modification of either by high fluoride intake. In experimental and farm animals there are characteristic dif ferences in osseous lesions in these two conditions, as well described by Asling and Hurley (26). In the studies discussed above no reference is made to the status of farm animals in the same localities, or to any plan to test effects of the sorghum versus other diets upon experimental ani mals. Returning to the capacity of molyb denum to reduce tissue copper levels and to increase urinary excretion of copper, Suttle (766) has questioned whether or not molybdenum might have therapeutic value in the treatment of Wilson's disease, apparently unaware of one report (74) of its ineffectiveness in four cases of the dis ease treated for 4 to 11 months. In the case of trace elements occurring mainly in ionic form, such as molybdenum, selenium and iodine, deficiencies and ex cesses are readily reflected in components of the food chain and in not only grazing animals but also in man himself (515). An interesting example of this and of coppermolybdenum interactions may be cited. In mountainous areas of Russia where the soil is notoriously high in molybdenum, a high incidence of molybdenum toxicity, characterized not by genu valgum but by increased blood xanthine oxidase and uric acid, and urinary uric acid, leading to symptoms of gout, was observed in the population of one province but not in that of another where molybdenum intake was equally high; the difference was ascribed to significantly higher blood copper and resultant lower blood molybdenum levels in the non-affected population (424, 425). Data pertaining to these studies are sum marized by Mertz (515). The explanation proposed is in accord with extensive knowl edge of such interactions in experimental and farm animals. Interactions between copper and zinc have long been recognized in animals and man. Excess of one is often associated with diminution of the other in body fluids and liver. Competition for binding sites on 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 43: COPPER METABOLISM AND REQUIREMENTS
Page 53 and 54: s &5Â°.S0 0lÃ¬Â»"oPH o^â€
Page 55 and 56: Ã®1co 1stW Â»aÂ«a3 COPPER MET

conspectus of researchon copper metabolism and requirements

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