The nephrotoxicity of intravenously administered cadmium-metallothionein: effect of dose, mode of administration, and preexisting renal cadmium burden.
Exogenously administered cadmium-metallothionein (Cd-MT) is highly nephrotoxic, producing renal damage similar to that seen following chronic Cd exposure. However, nephrotoxicity following Cd-MT administration occurs at a much lower renal Cd concentration than that following chronic Cd exposure. In the present study, the sensitivity of female rats to bolus and infused doses of Cd-MT was evaluated. The Cd-MT was administered via the jugular vein either as a bolus or infused over a 24-hr period via osmotic minipumps in naive rats and in rats which had been pretreated with 5 microM CdCl2/kg, sc, five times/week, for 9 weeks. Renal toxicity was evaluated by urinary lactate dehydrogenase, protein, and MT excretion. In naive rats, a bolus dose of 0.15 mg Cd/kg as Cd-MT was nephrotoxic. In comparison, a two-fold higher infused dose was required to cause nephrotoxicity. In Cd-pretreated rats, a bolus dose of 0.45 mg Cd/kg as Cd-MT was necessary to produce nephrotoxicity, presumably because Cd pretreatment yielded renal MT levels that were about 15 times higher than the levels in naive animals. Although a bolus dose of 3 mg Cd/kg as CdCl2 resulted in a renal Cd concentration about 1.5 times that found after administration of 0.15 mg Cd/kg as Cd-MT, it did not produce any nephro-toxicity. The results of this study suggest that a renal Cd concentration, which is nephrotoxic if the Cd-MT is administered as a bolus dose, is well tolerated if the Cd-MT is delivered at a sustained level over a 24-hr period. Furthermore, the preexisting renal Cd burden reduces the sensitivity to nephrotoxicity of Cd-MT, presumably due to elevated MT levels available for sequestration of incoming Cd. We conclude that mere accumulation of Cd in the kidney does not necessarily result in nephrotoxicity; instead, the circulating Cd-MT level, as well as the intracellular MT concentration, appear to be the more important determinants of nephrotoxicity.
Vestergaard
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P
Department of Pharmacology and Toxicology, University of Rhode Island, Kingston 02881.
Shaikh
Z A
ZA
D000818:Animals; D002104:Cadmium / Q000008:administration & dosage / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008668:Metallothionein / Q000008:administration & dosage* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
C004203:cadmium-binding protein; D002104:Cadmium; D008668:Metallothionein