Studies on the mechanism of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)-induced hepatotoxicity

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Abstract
The present study characterizes the biochemical, morphological, and histological sites of CCNU-induced hepatotoxicity and investigates the effect of modifiers of drug metabolism on this toxicity. A single oral dose (100 mg/kg) of CCNU caused four- and ninefold increases in serum GOT and GPT respectively 48 h after administration in rats. A 25-fold rise in serum bilirubin, a total loss of bile flow, and a decrease in BSP clearance were also observed. Cytochrome P-450 content and EM-N-demethylase activity were significantly decreased to 88% and 66% of control values respectively. A histopathological time course study of CCNU-induced injury showed a progression of acute inflammation, edema, and fibrin deposition in portal areas over 24 h with necrosis and sloughing of bile duct epithelium at 24 and 36 h. Treatment of rats with PB (40 mg/kg/day for 4 days, i.p.) 24 h prior to CCNU administration protected against CCNU-induced hepatotoxicity. Thus, the levels of serum GOT, GPT, and bilirubin were only 2.5 and 4 times higher than in untreated or PB-treated controls. Histopathological examination also showed reduced severity of bile duct lesions in PB-pretreated animals. In rats receiving both PB and CCNU, bile flow was restored and BSP clearance was increased compared to the CCNU-treated rats. The mixed-function oxidase activity in PB–CCNU-treated rats was not significantly different from that in PB-treated controls. It is concluded that pretreatment of rats with PB can markedly suppress the hepatotoxic manifestations, including histopathological changes, the rise in serum bilirubin, and the cholestasis observed in CCNU-treated rats.