Effects of buthionine sulfoximine on the nephrotoxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU).
Administration of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1 1-nitrosourea (MeCCNU; 50-500 mg/kg) to male F344 rats caused a time- and dose-related decrease of glutathione (GSH) preferentially in the liver, but not in the kidney. A 500-mg/kg dose of MeCCNU decreased liver, lung and kidney GSH by 69, 15 and 3%, respectively, 2 hr after dosing. However, MeCCNU had no effect on the ratio of GSH/oxidized GSH or on GSH reductase activity in any tissue tested. A single i.p. dose of DL-buthionine-SR-sulfoximine, an inhibitor of GSH biosynthesis, caused tissue GSH levels to decrease at a rate which reflected the biological half-life of GSH in the respective organs. The T 1/2 for GSH in kidney, liver and lung was found to be 1.5, 5 and 9 hr, respectively. MeCCNU administered s.c. to DL-buthionine-SR-sulfoximine-pretreated rats resulted in a depletion of hepatic and renal GSH concentrations which was additive to the effects of either of these treatments alone. DL-Buthionine-SR-sulfoximine also markedly increased the nephrotoxicity of MeCCNU and resulted in a hepatotoxicity not ordinarily seen when MeCCNU was administered alone. These results suggest that a reactive electrophilic intermediate may be involved in the mechanism of MeCCNU nephrotoxicity. Moreover, that renal GSH may play a protective role against MeCCNU-induced nephrotoxicity.
D000818:Animals; D019328:Buthionine Sulfoximine; D005978:Glutathione / Q000032:analysis; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D007668:Kidney / Q000032:analysis / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000032:analysis / Q000187:drug effects; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009607:Nitrosourea Compounds / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012673:Semustine / Q000633:toxicity*
D009607:Nitrosourea Compounds; D012673:Semustine; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005980:Glutathione Reductase; D005978:Glutathione