Renal glutathione depletion and nephrotoxicity of cadmium-metallothionein in rats.
Renal glutathione (GSH) concentrations were reduced approximately 80% at 4 hr after a single injection of buthionine sulfoxime (BSO) (4 mmol/kg body wt) and remained reduced for at least 16 hr in male rats. Following BSO injection, rats were injected with a nephrotoxic dose of cadmium-metallothionein (Cd-MT) (0.3 mg Cd as Cd-MT/kg body wt) and killed 1, 4, or 12 hr later. Damage to the kidney was assessed histologically and by measurement of p-aminohippuric acid (PAH) uptake into renal cortical slices. Although the renal accumulation of Cd following Cd-MT injection was significantly lower in BSO-pretreated rats as compared to nonpretreated rats, the damage to kidney was more severe. At 4 and 12 hr, both Cd-MT-induced inhibition of PAH uptake and morphological damage were significantly increased in BSO-pretreated rats. In certain experiments, the induction of renal intracellular MT synthesis by zinc pretreatment slightly decreased the renal toxicity of Cd-MT in the BSO-treated rats. The results demonstrate that although GSH depletion decreases the renal accumulation of Cd in rats injected with Cd-MT, the nephrotoxicity of Cd-MT is increased. Preinduction of MT in the kidney can only partially overcome this increase in toxicity. Therefore both GSH and intracellular MT levels can influence the renal toxicity of injected Cd-MT.
Suzuki
C A
CA
Department of Pharmacology, University of Western Ontario, London, Canada.
Cherian
M G
MG
D000818:Animals; D019328:Buthionine Sulfoximine; D002104:Cadmium / Q000378:metabolism; D005978:Glutathione / Q000032:analysis*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000032:analysis / Q000633:toxicity*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
C004203:cadmium-binding protein; D002104:Cadmium; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D008668:Metallothionein; D005978:Glutathione