Effects of buthionine sulfoximine on the nephrotoxicity of 1-(2- chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU)

RA Kramer, HM Schuller, AC Smith and MR Boyd

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.

Volume 234, Issue 2, pp. 498-506, 08/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics