conspectus of researchon copper metabolism and requirements

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1992 KARL E. MASON and to amino acids in the portal blood. In the form of these complexes it can be mea sured colorimetrically following reaction with diethyldithiocarbamate, a copper chelator. It is referred to as "direct react ing" or "labile" copper. By virtue of its homeostatic mechanisms the liver allows a portion of these loosely bound copper com plexes to pass directly to the systemic cir culation, where they constitute about 1% of plasma copper. Upon arrival at the liver, copper is released from albumin to hepatocyte cell membrane receptors from which it is transferred to the cytosol where it is bound to metallothionein (or metallothionein-like cuproproteins ). Metabolism and distribution Copper apparently binds also to pro teins other than metallothionein in the hepatocytes, as revealed by analyses of subcellular fractions of the liver of laboratory animals. How applicable these findings are to man is not clear. In a review of the sub ject Evans (192) lists four different frac tions as follows: 1) microsomal fraction containing about 10% of liver copper, most of which is probably located in newly syn thesized cuproproteins being prepared for transport to other sites; 2) nuclear frac tion, with about 20c/( of total liver copper, which may represent a temporary site of storage; 3) large granule fraction, with about the same amount of copper, contain ing both mitochondria and lysosomes, the latter being especially involved in seques tering copper prior to biliary excretion; and 4) the cytosol, containing about one-half of total liver copper, in which a small per centage is in copper-dependent enzymes and the predominant portion in the form of a copper-binding protein similar to metal lothionein. Evans (192) also describes in teresting differences in the copper content of these cell fractions in the newborn and during postnatal development, and also changes observed in animals given dietary excess of copper. The latter studies indi cate that in metallothionein there is prefer ential binding, after which excess copper is distributed to other fractions. He notes that the binding capacity of metallothio nein is limited, and that the lysosomes and nuclear proteins assist in maintaining cop per homeostasis. Marceau and Aspin (488, 489) have shown that when rats are given [07Cu]ceruloplasmin intravenously the 67Cu is taken up by all tissues, but primarily by the liver where it appears in a specific protein fraction of the hepatocyte cytosol having a molecular weight of 30,000 to 40,000 daltons and exhibiting Superoxide dismutase activity. It also becomes tightly bound to cytochrome c oxidase in the mito chondria. Since no [G7Cu]ceruloplasmin is demonstrable in the cell, it is assumed that copper is released at or within the cell membrane. In contrast, the G7Cuof [n7Cu]albumin complexes with proteins of about 10,000 daltons in the soluble cell fraction and becomes loosely bound to cytochrome c oxidase. Similar distribution of the two plasma proteins is observed in the rat brain and spleen. In addition to serving as the major path way of copper excretion via the biliary tract, the liver releases copper to maintain the labile pool of copper in the serum and blood cells. This pool provides copper for incorporation into Superoxide dismutase and into the many other copper-containing enzymes of body tissues, some of which may be synthesized in the liver itself. How ever, a major function of the liver is the synthesis of ceruloplasmin. This form of tightly bound copper is referred to as "in direct reacting" copper, since it requires acidification to release its 0.3% copper which can then be measured, as in the case of "direct reacting" copper, by the diethyl dithiocarbamate reaction. Its more reliable measurement by enzymatic and immunological methods has been discussed earlier (p. 1984). Once synthesized, ceruloplasmin is released by the liver such that it com prises approximately 93r/f of plasma cop per. In healthy adult humans this level is remarkably constant. There is no inter change in the blood stream between ce ruloplasmin copper and other forms of copper (742). Animal studies (741) indi cate that the liver microsomes are the site of ceruloplasmin synthesis. Despite evi dence that almost 0.5 mg of copper is in corporated into ceruloplasmin daily, close to the estimated daily absorption from the Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 1993 diet (742), the physiological role of ceruloplasmin has only recently begun to be clari fied (pp. 1984-1986). Copper in blood The first evidence of the presence of copper in blood, that of the ox, was re corded in 1830 by Sarzeau (665). The first demonstration of copper in human serum was reported almost 100 years later by Warburg and Krebs (827) and Krebs (426), who employed a catalytic method developed by Warburg. Although the values obtained were somewhat below those currently accepted, they did recog nize lower levels in normal males (aver. 0.82 /xg/100 ml) than in females (aver. 0.98 ^ig/100 ml), and also increased levels in pulmonary tuberculosis (aver. 1.55 /Â¿g/ 100 ml) and in the later stages of preg nancy (aver. 2.07 /Â¿g/100ml). Quite com parable values were reported by Locke et al. (464 ), who were among the first to em ploy diethyldithiocarbamate as a reagent for the detection and estimation of copper. While not recognized at the time, the rou tine acidification of samples necessary for release and measurement of copper in ceruloplasmin did not make it possible to recognize that the increased levels in preg nancy and infectious states were due pri marily to increases in ceruloplasmin. Because of the diversity of chemical, bio physical and immunological methods for the estimation of copper and ceruloplas min in blood and other tissues for over more than 50 years, the values presented in the literature for whole blood, plasma, serum and red cells show considerable variation. An excellent description and ap praisal of methods used up to 1965 has been presented by Sass-Kortsak (666). There has not come to the author's atten tion a comparable review and critique of methods developed since that time. Even with the employment of a single method such as atomic absorption spectrometry values obtained for copper levels in serum, plasma and urine vary considerably, due in large part to differences in preparation of the sample (763). Blood levels of copper are commonly expressed either as serum or plasma levels, with little or no distinction made be tween the two. Cartwright ( 100) states that since the ratio of the volume of erythrocytes to leukocytes and platelets in nor mal blood is about 47/0.7, failure to sepa rate the latter from erythrocytes results in an insignificant difference in copper values obtained. It must be recognized, however, that white blood cells do contain a small amount of copper (about l/4th the con centration in erythrocytes) even though they represent a rather small component of total blood cells. A recent report (646) records significant differences between serum and plasma copper levels in 28 adult subjects studied on the same day, mean values being 119 and 127 /ug/100 ml, re spectively. These findings require con firmation. Investigators suggest that cop per might be released from platelets, leukocytes or erythrocytes during coagu lation and clot reaction. Heilmeyer et al. (319) summarized 10 prior studies on adult humans employing six different methods and proposing nor mal values ranging from 65 to 200 /Â¿g/lOO ml in blood serum. Their own studies yielded mean values of 106.2 /Â¿g/100ml for 15 males and 106.9 /Â¿g/100ml for 15 fe males, thus failing to reveal the sex differ ences reported in later studies. In a review of the literature up to 1950, Cartwright ( 100) gives data from seven different studies involving a total of 184 males and 274 females from which can be calculated average mean values of 106 and 114 /Â¿g/ 100 ml for plasma of males and females, respectively. Neale et al. (551 ) report cor responding mean serum levels of 100 and 108 jug/100 ml for 53 normal subjects of each sex. Wintrobe et al. (857) record plasma copper values, of 105 Â±16 and 116 Â±16 /xg/100 ml for males and females, respectively. An increase in serum copper with age is said to occur in males but not in females (871), but no adequate ex planation is offered. In plasma (or serum) most of the cop per is bound to ceruloplasmin as indirect reacting copper (119, 286). In man it was first estimated that this represents 96% of total plasma copper (286). There are later estimates of 93% (105) and of 90% (75, 321). Most investigators now accept 93%. The remaining copper, constituting the 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 13: 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
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COPPER METABOLISM AND REQUIREMENTS
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