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

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 biotransformation produced changes in the level of covalent binding by ethylene-labeled MeCCNU (alkylation) which correlated with the degree of toxicity of MeCCNU in the kidney. Additional evidence supporting a role for hepatic biotransformation in the toxicity of MeCCNU was provided by an in vivo/in vitro colony-forming assay which demonstrated the presence of a cytotoxic metabolite in the bile of a MeCCNU-administered rat. These studies suggest that hepatic metabolism contributes significantly to the alkylating activity of MeCCNU in the liver and the kidney, and indicate that a liver-derived metabolite may be responsible for the renal toxicity of MeCCNU.