Animal model for liver dysfunction using lomustine in Wistar rats.

ABSTRACT

AIM: To induce intrahepatic cholestasis in rats using lomustine 1(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU). METHODS: Doses of 10 mg, 20 mg and 30 mg/Kg body weight of CCNU were injected intraperitoneally in separate groups of animals. RESULTS: With 10 mg/Kg body weight of CCNU, serum bilirubin levels increased for up to 72 hours and then slowly returned to normal. With a dose of 20 mg/Kg body weight of CCNU, serum bilirubin, AST, ALT and alkaline phosphatase levels increased for 72 hours and then returned to normal over 4-5 weeks. With a dose of 30 mg/Kg body weight peak levels of serum bilirubin were reached on day 17. Pathological studies were carried out after injection of 30 mg/Kg body weight of CCNU. After 72 hours hepatocytes were normal, with minimal nonspecific inflammation and bile duct proliferation. After 16 days, triaditis was observed with deposition of collagen. Focal fibrosis was also noticed. There was no significant abnormality of hepatocytes. After 75 days, hepatocytes showed focal ballooning. Bile duct proliferation was seen invading the parenchyma. Nodules of hepatocytes separated by irregular fibrous bands indicated cirrhosis. CONCLUSIONS: An animal model of intrahepatic cholestasis has been developed using CCNU; this model may be used to assess the utility of hepatobiliary radiopharmaceuticals.