Mechanism of nephrotoxicity induced by repeated administration of cadmium chloride in rats.
To explore the mechanism of Cd nephrotoxicity, CdCl2 was subcutaneously injected to rats, at 3 mg Cd/kg body weight once a day, for 8 d. In the liver, Cd bound to metallothioneins (MTs-Cd) rose from d 1 after the initiation of CdCl2 administration, and reached a plateau after the administration ceased. In the plasma, MTs-Cd rose from d 4, peaked on d 8, and gradually fell thereafter. In the kidneys, leucine aminopeptidase (LAP) and N-acetyl beta-D-glucosaminidase (NAG) fell during d 6-20, and Cd bound to cellular membranes (Mem-Cd) rose from d 1 and reached a plateau during d 6-20. The Mem-Cd levels were significantly correlated with the reduction in the LAP and NAG activity; the values of MTs-Cd plus Mem-Cd were almost equivalent to those of total Cd. These findings showed that the hepatic synthesis of MTs-Cd occurred followed by its release into plasma; the extent of renal injury was aggravated as the plasma level of MTs-Cd rose; and a greater part of the renal Cd distributed intracellularly as the MTs-binding form, while the residual Cd distributed as the cellular membrane-binding form. Also, it was suggested that Cd that occurred as the cellular membrane- binding form in the kidneys was involved in manifestation of renal injury.
Sudo
J
J
Department of Clinical Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
Hayashi
T
T
Kimura
S
S
Kakuno
K
K
Terui
J
J
Takashima
K
K
Soyama
M
M
D000118:Acetylglucosaminidase / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001806:Blood Urea Nitrogen; D002104:Cadmium / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D019256:Cadmium Chloride; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007279:Injections, Subcutaneous; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007931:Leucyl Aminopeptidase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D002273:Carcinogens; D002712:Chlorides; D002104:Cadmium; D008668:Metallothionein; D000118:Acetylglucosaminidase; D007931:Leucyl Aminopeptidase; D019256:Cadmium Chloride