Competition between copper and silver in Fischer rats with a normal copper metabolism and in Long-Evans Cinnamon rats with an abnormal copper metabolism

Abstract

Long-Evans Cinnamon (LEC) rats inherently lacking in serum ceruloplasmin (CP) activity and biliary Cu excretion were established from a closed colony of Long-Evans rats. These deficiencies, linked to a dysfunction of P-type ATPase, stimulate deposition of Cu and then of Cu metallothionein (MT) in the liver. Male LEC and Fischer rats were injected subcutaneously with Ag (AgNO3), which is an antagonist to Cu. They were operated on 24 h after the injection while under anesthesia. Total uptake of Ag into the liver was not stimulated, but its uptake into the MT fraction increased significantly in the LEC rats. Ag injection notably decreased the activity of serum CP in the Fischer rats, but not in the LEC rats. The decrease was accompanied by a reduction of serum Cu. In Fischer rat serum treated with Ag, Ag was detected mainly in the albumin region and partly in the CP fraction. In LEC rat serum, however, the Ag concentration was about 1/20 of that in the Fischer rats, and Ag was not detected in the CP fraction. Ag injection decreased the biliary excretion of Cu in the Fischer rats (0.183-0.052 microg Cu/20 min sampling), but not in the LEC rats (0.014-0.014 microg Cu/20 min sampling). On the other hand, biliary excretion of Ag was much greater in the Fischer rats (1.25 microg Ag/20 min) than in the LEC rats (0.04 microg Ag/20 min). Our results suggest that uptake of Ag into the liver is not dependent on the hepatic Cu content and status, but that biliary excretion of Ag from the liver is affected by these. Hepatic MT is not a transporter of hepatobiliary excretion of Cu and Ag. It seems likely that, unlike Cu excretion, Ag is excreted by not only the CP route but also by another route into the serum. Ag may compete with Cu in the uptake into CP (conversion of apo-CP to holo-CP).

Serum depletion of holo-ceruloplasmin induced by silver ions in vivo reduces uptake of cisplatin

“…Apparently, copper metabolism in liver cells was not disturbed. These results do agree with Sugawara's data showing that an uptake of silver into liver is not dependent on hepatic copper status [36].…”

Silver Ions as a Tool for Understanding Different Aspects of Copper Metabolism

“…Free silver ions, or ions associated with low-molecular substances, were not detected in the blood serum. In Ag-treated mouse liver, silver was found to be associated with both metallothionein and high-molecular-weight proteins residing in the membranes of the secretory pathway [63]. Ag treatment leads to a reduction of two parameters related to copper status in the serum—the total copper concentration and oxidase activity associated with ceruloplasmin (Cp)—but it does not affect the Cp protein concentration [55,64,65].…”

“…Ag treatment leads to a reduction of two parameters related to copper status in the serum—the total copper concentration and oxidase activity associated with ceruloplasmin (Cp)—but it does not affect the Cp protein concentration [55,64,65]. In rats that received Ag fodder over a long period of time, silver appeared in the urine [63,65], as is observed for copper in Wilson disease [66]. This indicates a substantial overlap between the pathways and molecular players that distribute copper throughout the body.…”

A Pharmacological and Toxicological Profile of Silver as an Antimicrobial Agent in Medical Devices

“…Experimental studies in rats have also demonstrated that copper and the antioxidants selenium and vitamin E can influence the hepatobiliary transport and retention of silver in the liver [104–106]. Copper and silver are known to interact in MT and caeruloplasmin binding whereas selenium exhibits a strong tendency to precipitate silver as silver selenide, thereby promoting silver retention in the tissue [105]. …”