Excess calcium is well known to induce iron deficiency. Furthermore, excess calcium increases hepatic copper concentration and decreases renal copper concentration. We investigated the effect of iron supplementation on the tissue distribution of copper in rats given a high-calcium diet. Male rats (5 weeks old) were divided into four groups; a control group, and three groups given a diet containing 5-fold higher calcium than its requirement and an intraperitoneal iron supplementation of 0, 1 or 2 mg/week as iron dextran. The animals were fed their respective experimental diets with or without iron supplementation for 4 weeks. Although the high-calcium diet had no effect on calcium concentrations in the liver, kidney, testis, spleen and plasma, it reduced haematocrit and iron concentrations in the liver, kidney and testis and the rats had a moderate iron deficiency. The iron supplementation restored to normal these signs of iron deficiency. The high-calcium diet increased hepatic copper concentration but decreased plasma copper concentration and ceruloplasmin activity, which was restored by the iron supplementation. The copper concentration in bile was neither affected by the high-calcium diet nor the iron supplementation. The high-calcium diet decreased the copper concentration in the kidney, which was not restored by the iron supplementation. These results suggest that secondary iron deficiency stimulates hepatic accumulation of copper in rats given excess calcium by suppressing copper efflux into the circulation. The reduced renal copper concentration by excess calcium is independent of the iron deficiency.

Cu is an essential nutrient that is required for a broad range of cellular and molecular processes. Mammals have efficient systems to control Cu homeostasis that operate at the level of controlling uptake, distribution, sequestration and excretion of Cu. The study of diseases associated with disturbed Cu homeostasis has greatly enhanced our understanding of the molecular mechanisms involved in Cu metabolism. In man the liver is responsible for excreting excess Cu from the body by means of biliary secretion. Wilson disease is a severe human disorder characterized by Cu accumulation in the liver as a result of a deficiency in biliary Cu secretion. This disorder is caused by mutations in the gene that encodes a Cu-transporting P-type ATPase (ATP7B). The MURR1 gene was identified recently, and it was hypothesized that this gene is also essential for biliary Cu excretion and is presumed to act downstream of ATP7B. MURR1 is mutated in canine Cu toxicosis, a disorder with phenotypic characteristics similar to those of Wilson disease. MURR1 encodes a protein that is of unknown function and is without detectable sequence homology to known proteins. MURR1 is readily detected in all tissues and cell types, suggesting that it may exhibit a pleiotropic function in different organs, which may or may not be exclusively linked to Cu homeostasis. The use of genetic, biochemical and genomic tools, as well as the development of appropriate models in organisms other than dog, will allow the elucidation of the molecular and cellular function of MURR1 in relation to hepatic Cu homeostasis and biliary Cu excretion.