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

Toxicology and Applied Pharmacology
R A KramerJ H Dees

Abstract

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 sensi...Continue Reading

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