In vivo studies on the relationship between hepatic metabolism and the renal toxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU)

Toxicology and Applied Pharmacology
R A KramerM R Boyd

Abstract

Administration of a single sc dose of the nephrotoxic anticancer agent 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) to rats led to a time-dependent decrease in renal function (i.e., renal slice anion accumulation, renal concentrating ability, and urinary output) which was correlated with the accumulation of carbamylating and alkylating intermediates of 14C-labeled MeCCNU that bound irreversibly to kidney protein. MeCCNU also produced a dose-dependent decrease in glutathione (GSH) preferentially in liver, but not in kidney. Pretreatment with piperonyl butoxide (PIP) decreased the renal toxicity and covalent binding of MeCCNU, and ameliorated the MeCCNU-dependent decrease in liver and kidney GSH. Radioactivity detected in the urine from the PIP-pretreated group was markedly lower than that in the MeCCNU-only group. In contrast, PIP pretreatment increased the accumulation of parent MeCCNU into fatty tissue. Pretreatment with phenobarbital (PB) increased the renal toxicity of MeCCNU. Moreover, PB pretreatment resulted in the increased alkylation of both liver and kidney macromolecules and to an increase in the urinary clearance of ethylene-labeled MeCCNU. In all experiments, modifiers of hepatic biotransfor...Continue Reading

Citations

Sep 1, 1990·Toxicology Letters·R F Borch, T J Montine
Jul 1, 2009·Nature Reviews. Nephrology·Vaibhav SahniZiauddin Ahmed
Feb 15, 2011·Journal of Veterinary Internal Medicine·C D TrippJ N Bryan
Jan 1, 1987·Critical Reviews in Oncology/hematology·M A Lea
Feb 24, 2001·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·P E Kintzel
Jun 1, 1989·Journal of Neurology, Neurosurgery, and Psychiatry·J W Langston

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