No abstract

In humans, copper is an important micronutrient because it is a cofactor of ubiquitous and brain-specific cuproenzymes, as well as a secondary messenger. Failure of the mechanisms supporting copper balance leads to the development of neurodegenerative, oncological, and other severe disorders, whose treatment requires a detailed understanding of copper metabolism. In the body, bioavailable copper exists in two stable oxidation states, Cu(I) and Cu(II), both of which are highly toxic. The toxicity of copper ions is usually overcome by coordinating them with a wide range of ligands. These include the active cuproenzyme centers, copper-binding protein motifs to ensure the safe delivery of copper to its physiological location, and participants in the Cu(I) ↔ Cu(II) redox cycle, in which cellular copper is stored. The use of modern experimental approaches has allowed the overall picture of copper turnover in the cells and the organism to be clarified. However, many aspects of this process remain poorly understood. Some of them can be found out using abiogenic silver ions (Ag(I)), which are isoelectronic to Cu(I). This review covers the physicochemical principles of the ability of Ag(I) to substitute for copper ions in transport proteins and cuproenzyme active sites, the effectiveness of using Ag(I) to study copper routes in the cells and the body, and the limitations associated with Ag(I) remaining stable in only one oxidation state. The use of Ag(I) to restrict copper transport to tumors and the consequences of large-scale use of silver nanoparticles for human health are also discussed.

The influence of short and prolonged diet containing silver ions (Ag-diet) on copper metabolism was studied. Two groups of animals were used: one group of adult rats received a Ag-diet for one month (Ag-A1) and another group received a Ag-diet for 6 months from birth (Ag-N6). In Ag-A1 rats, the Ag-diet caused a dramatic decrease of copper status indexes that was manifested as ceruloplasmin-associated copper deficiency. In Ag-N6 rats, copper status indexes decreased only 2-fold as compared to control rats. In rats of both groups, silver entered the bloodstream and accumulated in the liver. Silver was incorporated into ceruloplasmin (Cp), but not SOD1. In the liver, a prolonged Ag-diet caused a decrease of the expression level of genes, associated with copper metabolism. Comparative spectrophotometric analysis of partially purified Cp fractions has shown that Cp from Ag-N6 rats was closer to holo-Cp by specific enzymatic activities and tertiary structure than Cp from Ag-A1 rats. However, Cp of Ag-N6 differs from control holo-Cp and Cp of Ag-A1 in its affinity to DEAE-Sepharose and in its binding properties to lectins. In the bloodstream of Ag-N6, two Cp forms are present as shown in pulse-experiments on rats with the liver isolated from circulation. One of the Cp isoforms is of hepatic origin, and the other is of extrahepatic origin; the latter is characterized by a faster rate of secretion than hepatic Cp. These data allowed us to suggest that the disturbance of holo-Cp formation in the liver was compensated by induction of extrahepatic Cp synthesis. The possible biological importance of these effects is discussed.