The hepatotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in rats

Abstract

A few cases of liver involvement have been reported in patients receiving treatment with the antineoplastic nitrosourea CCNU. A single oral dose of 20 or 50 mg/kg CCNU in female Wistar rats induced an important increase in transaminases between day 2 and day 6, followed by a second, moderate increase between day 21 and day 28. Alkaline phosphatases and conjugated hyperbilirubinemia (threefold-increase) were noted for the two doses and were greater for the highest dose. Histological and ultrastructural studies disclosed hepatic lesions of two types: during the first phase of transaminase increase, inflammation of the portal tracts; during the second phase marked dilation of bile canaliculi and numerous filamentous bundles distributed at random throughout the liver cell cytoplasm like normal microtubules. Thus, CCNU induced pericholangitis and intrahepatic cholestasis with microtubular abnormalities. The long-term evolution of hepatic alterations revealed that in the 3rd month after a single oral dose of 20 mg/kg CCNU, lesions were persistent but stable; no reversibility was observed in the 3rd month after 50 mg/kg CCNU, and evolution towards cholangiolysis and biliary cirrhosis was noted. We suggest that CCNU causes a bimodal hepatotoxicity in rats: an early and prolonged ductal injury and a delayed anti-liver cell microtubule toxicity.

Prospective Randomized Clinical Trial Assessing the Efficacy of Denamarin for Prevention of CCNU‐Induced Hepatopathy in Tumor‐Bearing Dogs

“…The mean starting CCNU dose was 70.6 mg/m 2 (median, 71.4 mg/m 2 ; range, 54.9-81.3 mg/m 2 ) and the median number of CCNU doses administered was 3 (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Seven (28%) dogs in group A and 9 (36%) dogs in group B received CCNU every 28 days alternating with vinblastine.…”

“…7,8,12 Rodents treated with very high doses of CCNU develop acute biliary stasis and hepatocyte necrosis leading to death. 13 The toxicity of CCNU was further investigated in healthy beagle dogs given a single dose of 4 mg/kg. 9 Histopathologic evaluation of liver biopsy samples showed Kupffer cell hyperplasia, cloudy swelling of hepatocytes, and periportal fibrosis in all treated dogs.…”

Hepatotoxicity Associated with CCNU (Lomustine) Chemotherapy in Dogs

“…Preclinical studies of CCNU have shown the drug to be a potent hepatotoxin in several species, including rats, dogs, and monkeys. 14,15,17,18,[20][21][22][23][24] When rats were given single high doses of CCNU PO, hepatic lesions occurred soon after treatment and consisted primarily of bile duct injury with associated cholestasis. Focal hepatocyte necrosis occurred later and was mainly periportal, suggesting hepatocyte injury was secondary to bile duct injury.…”

“…20,21 Ultrastructural changes included alterations of microtubules affecting all hepatocytes and bile canaliculi. 22 Preclinical studies in dogs receiving CCNU dosages ranging from 40 to 200 mg/m 2 (given all at once or divided over several days) revealed the dose-limiting adverse effect to be hematopoietic toxicity. Dogs treated with lower dosages survived hematopoietic toxicity but exhibited hepatic toxicity, renal toxicity, or both.…”

“…2,14 Another possible explanation is that isocyanates carbamylate tubulin in hepatocytes, leading to mitotic spindle inhibition and G2 cell cycle arrest or to disruption of secretory functions such as bile secretion, which in turn results in cholestasis and sec-ondary hepatocyte injury. 22,24 Finally, alkylating agents cause depletion of glutathione, lipid peroxidation, and cytotoxicity in isolated rat hepatocytes. 26 Use of different thiol compounds shortly after administration of alkylating agents reduced cytotoxicity.…”