Metabolism of intracellular zinc and copper following single and repeated injections of gold sodium thiomalate

Abstract

Repeated injections of gold sodium thiomalate were given to Wistar rats and the effect of gold on the binding of endogenous zinc and copper to the cytosolic proteins in the liver and kidneys was studied. The tissue levels of gold and the tissue uptake of zinc and copper as a function of gold dose was also studied.The result of the multiple-dose study show that in the liver the tissue gold levels rose rapidly following the first five gold injections (one injection/week) and then stabilized. In the kidneys the gold concentrations continued to increase with each additional dose. Uptake of zinc into the high molecular weight proteins (MW > 60,000 daitons) and the supernxide dismutase fractions were significantly increased following the repeated gold injections in the liver and kidney cytosoi. The uptake of copper into the high MW proteins were decreased in the liver as well as the kidneys. Copper levels in the superoxide dlsmutase and the low MW (< 4000 daltons) fractions initially increased then decreased from the sixth gold dose onwards (possibly related to the overall decrease in tissue copper levels in the liver). The incorporation of eopper into the hepatie metallothioneins appeared to be unaltered. In the kidney eytosol, the uptake of copper was significantly increased into the metallothionein fractions. The uptake into the other fractions decreased over the multiple-dose period.Gold sodium thlomalate inereased the tissue eoncentratlon of zinc in the liver as well as the kidneys. The level of copper in the liver was decreased and that in the kidneys increased. Practically all the additional copper in the kidneys was incorporated in the thioneins.These observations indieate that gold sodium thiomalate has a major role in providing a stimulus for the liver, kidney and perhaps other cells to bring about a redistribution of body zlne and copper. The various cytosolic proteins, including the inducible metalloproteins, superoxide dismutase and metallothioneins, seem to help the cell carry out this task. In view of the importanee of these essential metals in physiological processes of relevance to rheumatoid arthritis, it is suggested that gold salts may mediate, to some extent, their antiarthrltic activity through an effect on the metabolism of zinc and copper.

Comparative Ability of Exogenously Administered Metals to Alter Tissue Levels and Urinary Output of Copper and Zinc

“…In the present study, a 4-fold increase in renal copper levels was observed after a single dose of gold (III) chloride. Earlier studies have found copper levels in the kidney to be greatly elevated by treatment with various gold complexes [25], particularly the gold(I) compounds used in the treatment of rheumatoid arthritis, con firming the findings reported here.…”

Role of metallothionein in cellular uptake and disposition of gold sodium thiomalate

“…However, the binding of gold to MT in the liver as well as the kidney tissues can be significantly enhanced by predosing with MT synthesis stimulating agents such as zinc and Cu (17). In fact the high incorporation of gold into the renal MT following GST injections may to some extent be attributable to the marked influx of Cu into the kidney and the subsequent additional induction of MT synthesis by Cu (18,19).…”

Triethylphosphine gold: Cellular uptake and disposition after single and repeated oral doses in rats

“…However the extent of gold binding to MT is limited by the amount of pre-synthesized MT (e.g. synthesis induced by zinc) present intracellularly and the ability of gold itself to induce additional synthesis (Sharma & McQueen 1982). It is possible, therefore, that at low tissue gold concentrations a large proportion of the cellular gold is localized in the cytosol via additional incorporation into storage proteins such as MT (which may bind as much as 50% of the cytosolic gold).…”

“…studies have not (Gerber et a1 1972;Gottlieb & Smith 1974). More recent studies suggest that the effector sites for clinical response (Mirabelli & Crooke 1983;) and toxicity (Eiseman & Alvares 1978;Nechay 1980;Sharma & McQueen 1982) may both be at intracellular gold-binding sites. In this context the time course and interrelationships of gold concentrations in various tissues and their subcellular compartments may be critical.…”