Nephrotoxicity of intravenously injected cadmium-metallothionein: critical concentration and tolerance.
The nephrotoxicity of Cd-metallothionein (Cd-MT) was examined after iv administration of various dosages to mice. The lowest dosage of Cd-MT that produced renal injury was 0.2 mg Cd/kg. This dosage of Cd-MT resulted in 10 micrograms Cd/g in the kidneys 24 hr after administration. A time-course experiment utilizing a higher (0.3 mg Cd/kg) nephrotoxic dose of Cd-MT demonstrated that the renal Cd concentration at 4 and 12 hr was much higher than the critical concentration, but thereafter decreased to about 10 micrograms Cd/g wet tissue by 24 hr. Thus, Cd in excess of 10 micrograms/g appears to damage the kidney and then distributes to other tissues and/or is excreted into urine. When a total of 0.3, 0.4, and 0.8 mg of Cd/kg as Cd-MT was administered in divided dosages over 4 days, as much as 30 micrograms Cd/g was detected in the kidney but no renal injury was observed. Thus, the critical concentration for producing renal injury after acute administration of Cd-MT is estimated to be approximately 10 micrograms Cd/g wet weight. However, with repeated exposure to Cd-MT, this acute critical concentration can be exceeded without producing renal injury, as tolerance to the nephrotoxic effects of Cd-MT develops.
Maitani
T
T
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66103.
Cuppage
F E
FE
Klaassen
C D
CD
D000818:Animals; D002104:Cadmium / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D008099:Liver / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000633:toxicity*; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
C004203:cadmium-binding protein; D002104:Cadmium; D008668:Metallothionein