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Kidane, Theodros Z., Eric Sauble, and Maria C. Linder. Release of iron from ferritin requires lysosomal activity.

We know that blood plasma contains many proteins and also other components that bind copper. The largest contributor to copper in the plasma is ceruloplasmin, which accounts for 40-70 percent. Apart from ceruloplasmin and albumin, most of these components have not been studied extensively, and even for ceruloplasmin and albumin, much remains to be discovered. New components with new functions, and new functions of known components are emerging, some warranting reconsideration of earlier findings. The author's laboratory has been actively involved in research on this topic. This review summarizes and updates our knowledge of the nature and functions of ceruloplasmin and the other known and emerging copper-containing molecules (principally proteins) in this fluid, to better understand how they contribute to copper homeostasis and consider their potential significance to health and disease.

In adult humans, the net absorption of dietary copper is approximately 1 mg/d. Dietary copper joins some 4-5 mg of endogenous copper flowing into the gastrointestinal tract through various digestive juices. Most of this copper returns to the circulation and to the tissues (including liver) that formed them. Much lower amounts of copper flow into and out of other major parts of the body (including heart, skeletal muscle, and brain). Newly absorbed copper is transported to body tissues in two phases, borne primarily by plasma protein carriers (albumin, transcuprein, and ceruloplasmin). In the first phase, copper goes from the intestine to the liver and kidney; in the second phase, copper usually goes from the liver (and perhaps also the kidney) to other organs. Ceruloplasmin plays a role in this second phase. Alternatively, liver copper can also exit via the bile, and in a form that is less easily reabsorbed. Copper is also present in and transported by other body fluids, including those bathing the brain and central nervous system and surrounding the fetus in the amniotic sac. Ceruloplasmin is present in these fluids and may also be involved in copper transport there. The concentrations of copper and ceruloplasmin in milk vary with lactational stage. Parallel changes occur in ceruloplasmin messenger RNA expression in the mammary gland (as determined in pigs). Copper in milk ceruloplasmin appears to be particularly available for absorption, at least in rats.

Serum ferritin isolated from the horse was structurally compared with horse spleen ferritin and was found to differ markedly in molecular weight, iron content, carbohydrate, subunit size and amino acid sequence. The results are summarized and initial results obtained with candidate clones of pieces of two serum ferritin subunits are described.

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The time course of distribution of high-specific activity 67CuCl2 to tissues and plasma components was followed in adult, female rats. Immediately after intubation or injection, tracer 67Cu associated with two components of the blood plasma separable on columns of Sephadex G-150: albumin and another (larger) component, which was not ceruloplasmin. The latter, tentatively named transcuprein, had an apparent molecular weight of 270,000 and a high affinity for Cu2+, as judged by processing through Chelex-100, dilution, and exchange with albumin copper, in vitro and in vivo. It was capable of donating copper to tumor cells in serum-free medium. Analysis of "cold" plasma by furnace atomic absorption confirmed the presence of 10-15% of plasma copper in this peak. Plots of percent dose and 67Cu specific activity against time showed that copper followed a very specific pathway after binding to albumin and transcuprein, entering mainly the liver, then reappearing in the plasma on ceruloplasmin, and then achieving peak distribution in peripheral tissues (muscles, brain, etc.). 67Cu disappeared from liver and kidney with an apparent half-life of 4.5 days, the same exponential rate found for whole body turnover. Apparent turnover of ceruloplasmin copper was more rapid. Even after 7-12 days, tracer copper in plasma was still found exclusively with ceruloplasmin. The results indicate that copper follows a carefully prescribed path, on entering the blood and binding to a new transport protein.