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Abstract

During the last decade there has been a surge of interest and activity in exploring the metabolic links between copper and iron. This review describes more than a century and a half of effort that has led to our current understanding. Particular attention is given to the early events since these are less well-known and appreciated. The landmark 1928 paper of Hart, Elvehjem and coworkers is generally given credit for the start of the copper/iron field, and specifically for the discovery of the role of copper in forming hemoglobin and in overcoming anemia. However, some credit for the ideas, observations, and experiments should be shared with several investigators of the previous century. These scientists and physicians were primarily motivated to find the causes and cures of chlorosis, a common form of anemia at the time. From his chemical determination of copper in red blood cells in 1848, Millon proposed a form of chlorosis due to copper deficiency. Likewise, Pécholier and Saint-Pierre, observing the robust health of young women working in copper factories, concluded that copper was helpful in preventing and overcoming chlorosis. The first direct experimental evidence for the theory was provided by the Italian physician Mendini, who in 1862 reported that supplementation of the diet with copper salts overcame chlorosis in young women. In the 1890s Cervello and his students in Italy, using semi-quantitative hematological measurements, confirmed the beneficial effects of copper on anemia both in patients and in animal models. There was nearly a 30-year period of inactivity, but the decade of the 1930s saw renewed interest and exciting developments in the field. The Elvehjem report of 1928 was quickly verified and extended by multiple laboratories on four continents. In the 1950s and 1960s Wintrobe and Cartwright and their colleagues localized, and started to systematically evaluate, the potential sites at which copper was likely to effect iron for hemoglobin synthesis, namely, intestinal absorption, release from storage, and cellular utilization during synthesis. The copper/iron connection also has a 'flip-side', i.e., iron status can influence copper metabolism as first described by Warburg and Krebs in 1927. Thus, there are opportunities for feedback mechanisms at the cellular and physiological level that are not yet understood. The evaluation of these processes continues to this day, aided by modern molecular and genetic approaches. Studies of two copper proteins, ceruloplasmin and its recently discovered homologue hephaestin, have provided two molecular links connecting the pathways of copper and iron metabolism. The recent identification of other proteins of iron and copper metabolism, for example, copper ATPases and the membrane iron transporters DCT1/DMT1/Nramp2 and IREG1/MTP1/ferroportinl, are likely to fill crucial pathway gaps. The ongoing discovery of genes and gene mutations involved in the metabolism of copper and iron provides an important key to a deeper understanding of the connections between the p...

Menkes Copper ATPase (Atp7a) Is a Novel Metal-responsive Gene in Rat Duodenum, and Immunoreactive Protein Is Present on Brush-border and Basolateral Membrane Domains

“…The interplay of copper and iron homeostasis has been recognized for more than 150 years, and both trace minerals are required to prevent anemia (34). This observation has now been confirmed at the molecular level with the discovery of CP and HP, which are multicopper ferroxidases that play roles in iron export from some tissue types (12).…”

“…CP is a circulating ferroxidase of hepatic origin, and HP is a membrane-anchored ferroxidase that is important for iron release from duodenal enterocytes. The exact role of CP in intestinal iron absorption has not been resolved conclusively (34), although some experimental results have shown a positive effect of CP on iron release from enterocytes (35). Recently, the CP gene was disrupted in mice in an effort to produce an animal model of aceruloplasminemia, which is the lack of CP (17).…”

The Copper Metallome in Eukaryotic Cells

“…Yeast also has the conserved transporters responsible for uptake and distribution of copper across membranes (Ctr1 and Ccc2) 1 [ 8 ] . This framework has meant that yeast has been the theater for major discoveries about copper homeostasis.…”

Effect of Lactoferrin on Consequences of Acute Experimental Hemorrhagic Anemia in Rats

“…Correction of experimental anemia with copper salts was studied in rats and mice fed whole milk diet [4]. Ceruloplasmin (CP), a plasma and nervous tissue copper-containing protein in mammals, the main serum ferroxidase, is a common component in the metabolism of these trace elements [4,9]. Physio logical role of CP-catalyzed oxidation of Fe(II) to Fe(III) for iron incorporation into transferrin and further transport in the body was shown.…”

“…CP is now used as a drug for correction of some pathologies including anemia [4,9]. Ceruloplasmin for this purpose is isolated from donor material.…”