tardation, anemia, hypothermia, neutropenia, diarrhea, cardiac hypertrophy, bone fragility, impaired immune function, weak connective tissue, impaired central-nervous-system (CNS) functions, peripheral neuropathy, and loss of skin, fur (in animals), or hair color (Linder and Goode 1991; Uauy et al. 1998; Cordano 1998; Percival 1998).

BIOCHEMISTRY AND PHYSIOLOGY

Copper taken in through the diet might be absorbed partially in the stomach, where the highly acidic environment frees the bound copper ions from partially digested food particles. However, the largest portion of ingested copper passes into the duodenum and ileum, which are the major sites of absorption. As a result of complexing with amino acids, organic acids, or other chelators, a high fraction of copper is soluble in the intestinal tract. Studies on isolated segments of the duodenum suggest that copper ions enter into the mucosal cells lining the intestine by simple diffusion and exit at the basolateral surface by a different mode of transport (Bremner 1980). Recent reports indicate that there is a divalent transporter that might transport copper (Rolfs and Hedinger 1999).

Basolateral transport is markedly reduced in Menkes disease, which results in systemic copper deficiency. Studies of this disease led to the prediction of a copper-transporting adenosine triphosphatase (ATPase) in the basolateral membrane of mucosal cells. The copper-transporting ATPase presumably discharges the copper into the serosal capillaries where the copper binds to albumin and amino acids for transport to the liver via the portal circulation. From the liver, copper is transported to extrahepatic tissues by albumin, amino acids, and, to a lesser extent, ceruloplasmin (Dunn et al. 1991).

A large fraction of circulating copper is returned to the liver as ceruloplasmin-bound copper. Ceruloplasmin, a sialoglycoprotein, is constantly being secreted from the liver into the blood. When ceruloplasmin returns to the liver, the sialic acid can be removed by the outer endothelial cells followed by an endocytosis of the desialated protein via the asialoglycoprotein receptor in the liver parenchyma (Irie and Tavassoli 1986). Likewise, removal of copper from ceruloplasmin hastens its uptake by liver parenchymal cells (Holtzman and Gaumnitz 1970).

As discussed in Chapter 4, Wilson disease, a genetic disease characterized by accumulation of copper mainly in the liver and brain, attests to a potential role for ceruloplasmin biosynthesis in liver homeostasis of copper. Copper-containing fragments of ceruloplasmin are found in the bile of normal subjects and are generally absent from the bile of Wilson patients.



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