conspectus of researchon copper metabolism and requirements

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2000 KARL E. MASON intake of 5.8 mg/ day from diets in India, determined on composites made from selfselected diets in a dozen locations through out the country ( 154), is more than double the mean found for diets in developed countries, for which no explanation is given. In evaluating such reported data one must consider not only the differences in methods of assay and of care against contamination but also differences in sam ple preparation and differences in food preparation in different countries. There is also need to consider phytate and fiber content of diets, which may influence ab sorption or utilization of dietary copper. From what has been said, it is quite ap parent that data based upon the daily in take of copper by peoples in different parts of the globe give relatively little guidance as to what the minimal or optimal level of intake may be. COPPER METABOLISM IN PRENATAL AND POSTNATAL LIFE A preceding section has dealt with the labile and the more firmly protein-bound types of copper in the blood cells and blood serum or plasma of normal adult man. Briefly stated, the labile pools repre sent about 40 and 1%, and the proteinbound pools (superoxide dismutase and ceruloplasmin ) approximately 60 and 93$, of the copper present in blood cells and plasma, respectively. The ratio of cell to plasma copper is about 0.70 ( 100). The copper content of the red blood cells re mains remarkably constant, little influenced by dietary intake or metabolic stresses (286, 435). That of the plasma is subject to rather remarkable changes during preg nancy, reflecting the influence of hormones, particularly estrogens, upon the synthesis and release of ceruloplasmin. There exists a vast literature dealing with 1) the increase of maternal blood copper levels during pregnancy and the influence of estrogenic hormones; 2) the role of the placenta in transfer of copper to the fetus; 3) the role of fetal liver in storage of copper to meet inadequacies of mammary transfer during early lactation and 4) postnatal changes in blood copper levels in the infant and adolescent. Knowl edge and interpretation of these processes are of importance not only in determining the role of copper in reproductive physi ology and neonatal development in man, but also in obtaining a better understand ing of human requirements of copper for the infant and adolescent. It is the pur pose of this section to review briefly what has been learned concerning the rather complex changes, not yet clearly under stood, which occur in the pregnant mother, fetus and young infant. Influence of pregnancy It seems remarkable that the first investi gators to demonstrate the presence of cop per in human blood (827) should also have been the first to recognize not only normal sex differences but also increased levels of copper in the blood of pregnant women (426). These observations were soon verified by many other investigators ( 181, 184, 206, 294, 318, 345, 348, 434, 464, 556, 561, 577-579, 655, 660, 787). However, the significance of these findings remained obscure until evidence was presented that similar increases occur in infants receiving diethylstilbestrol therapeutically for treat ment of hemophilia (794), and in adults of either sex receiving estrogens (183, 245, 368, 651) but not in those receiving pro gesterone or androgens (183). These in vestigations suggest that increased plasma copper levels in pregnancy could be ex plained by increased levels of estrogens, but this may not be the total story. Beginning during the first trimester of pregnancy, there occurs a progressive in crease in maternal plasma copper levels. In groups of pregnant women at successive lunar months of gestation, values have been reported to increase progressively from 146.1 to 277.6 jig/100 ml (181), and 131 to 213 Mg/100 ml (757), and from 172 to 273 /ig/100 ml (54). Similar data are presented by others (158, 524). The in creased plasma copper levels of pregnancy have been well documented (23, 54, 77, 152, 231, 255, 318, 320, 324, 527, 574, 578, 686, 687, 847, 858, 878). The copper con tent of erythrocytes of mother and fetus remains remarkably constant ( 181, 345 ). Hence, the striking rise in plasma copper during pregnancy to about 2 to 3 X normal is attributable almost entirely to increased synthesis of ceruloplasmin (324, 491, 673). Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2001 Since there are no known alterations in absorption or excretion, the major source of the non-dietary copper for this synthesis is presumably the maternal liver. Direct evidence in support of this assumption is the much lower concentration of copper in the liver (as compared to other organs examined) in pregnant as compared to nonpregnant women, all victims of acci dental death (524), and very low liver copper levels in women succumbing to late toxemia of pregnancy associated with unusually high serum ceruloplasmin levels (628). Assuming also increments of about 25% in plasma volume during gestation (166), maintenance of high plasma copper levels places special demands upon ma ternal tissue stores. Associated with in creased plasma ceruloplasmin levels of copper there occurs a reciprocal decrease in plasma zinc levels both in states of pregnancy (152, 300, 324, 388, 843) and following use of oral contraceptives (297), although the latter statement has been questioned (579). Differences in competi tive binding of these two elements under special circumstances may explain these inverse relationships of zinc and copper during gestation. Richterich et al. (638), comparing their data with that of prior investigators (338, 491, 673), indicate general agreement that 1) ceruloplasmin blood levels in pregnant women are two to three times those of nonpregnant women, and that 2) the levels in mothers at term are approximately eight times those in umbilical cord blood. Ceruloplasmin values recorded are quite comparable, whether obtained by the en zymatic method of Ravin (629) or the immunological method of Hitzig (339). Maternal serum copper levels return to non-pregnant levels over a period of 4 weeks or more following legal abortion (54) and normal delivery (388, 561, 777). Since estrogen production and serum ceruloplasmin levels are not proportional during pregnancy, and since blood estro gens decrease rapidly after abortion or delivery compared to ceruloplasmin levels, questions are raised as to whether estrogenie stimuli alone are responsible for the increase of serum copper in pregnancy. A similar dilemma relates to the increase in serum copper levels, over and above those of normal pregnancy, observed in pre eclampsia and eclampsia (205, 527, 552, 578, 628, 777, 847, 858, 868), and in a case of hydatidiform mole (318). Evidence that maternal serum copper levels show even greater increases with intervening infec tious diseases and malignant processes has led to suggestions that increased serum copper levels in pregnancy reflect a re sistance reaction of the maternal organism to continuous invasion of the fetus into the maternal circulation (181). Another con cept relates these changes to a conse quence of hormonal adaptation of the maternal organism to the increased meta bolic and hormonal demands of pregnancy (167). Influence of oral contraceptives Reference has been made to early ob servations (183, 651, 794) of the thera peutic use of estrogens and the ensuing in crease in plasma levels of ceruloplasmin which, in turn, suggested an explanation for the comparable phenomenon observed previously in pregnant women. To this may be added evidence (98) that in nor mal individuals oral contraceptives cause marked increases in serum copper levels involving increased synthesis of ceruloplas min, often greater than that observed in the state of pregnancy. Since that time there has arisen a rather extensive litera ture on the effect of oral contraceptives and intrauterine copper devices in the human female. Since this topic has been well reviewed in recent years (589, 723, 771), it will not be subject to further consideration here. However, it must be emphasized that the continued use of oral contraceptives has been, and will continue to be, an impor tant factor in influencing copper homeostasis in women. Estrogens, whether en dogenous or exogenous, have a remark able capacity to stimulate synthesis of ceruloplasmin in the liver and to increase urinary excretion of copper. The extent to which prolonged use of oral contraceptives may decrease body copper storage and modify the daily copper requirement has not been examined. It does justify special study. 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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