Comparative nephrotoxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) and chlorozotocin: functional-structural correlations in the Fischer 344 rat.

1-(2-Chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) and chlorozotocin (CZ; 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose) are structurally related anticancer agents which differ by virtue of the increased water solubility, and comparatively low carbamylating activity, of CZ relative to MeCCNU. In the present study, a single sc injection of either of these chloroethylnitrosoureas was nephrotoxic to male Fischer 344 rats. However, at equimolar doses, CZ was shown to be a much more potent nephrotoxicant. A lethal 40-mg/kg dose of CZ (127 microM) initially resulted in acute tubular necrosis of the proximal tubules of the cortex, followed later by a necrosis of papillary collecting ducts. In contrast, lethal doses of MeCCNU (100-180 mg/kg; 400-730 microM) produced only minimal proximal tubule injury. A 250-mg/kg (1 mM) dose of MeCCNU resulted in massive papillary necrosis within 7 days, with only limited necrosis to the proximal tubules. Sublethal doses of either drug, resulted in a similar, chronic, progressive nephropathy which was delayed in onset and was characterized by polyuria, enzymuria, a decrease in urine concentrating ability, and in renal slice organic ion accumulation. Alterations in less sensitive indicators of renal toxicity (i.e., proteinuria, glucosuria, and elevated blood urea nitrogen) were observed no earlier than 3 to 7 days after administration of only the highest tested doses of CZ (40 mg/kg) or MeCCNU (250 mg/kg). At sublethal doses, administration of either drug resulted in karyomegaly to the collecting ducts in the renal medulla within 2 to 4 weeks. These studies demonstrate that carbamylation-mediated reactions may not be necessary for nephrotoxicity to develop following administration of this class of antitumor agent.