Liver Tumor Promoting Effects of Febantel in a Two-stage Hepatocarcinogenesis Model of Rats Using D-galactosamine and Diethylnitrosamine

To examine whether febantel has a tumor promoting activity, a total of 50 male F344 rats, divided into five groups each consisting of 10 rats, were initiated with a single intraperitoneal injection of 100 mg/kg of diethylnitrosamine (DEN). Starting 1 week later, Groups 1, 2, and 3 were fed diet containing 2,500,500, and 0 ppm febantel, respectively, for 7 weeks. D-galactosamine (DGA) of 300 mg/kg was administered intraperitoneally at Weeks 1 and 6 of febantel treatment. The remaining two groups (Groups 4 and 5) were fed diet containing 2,000 or 0 ppm febantel without DGA treatment for 7 weeks. Animals in the DEN/DGA + 2,500 ppm group showed a significant depression of body weight gain, as compared to the DEN/DGA + 0 ppm group. Significant increases in the absolute and relative liver weights were observed in the DEN/DGA + 2,500 ppm and DEN +2,000 ppm groups in comparison with the corresponding controls. Similar increases in the relative liver weights were also seen in the DEN/DGA + 500 ppm group. Histologically, centrilobular hepatocellular hypertrophy was observed in the DEN/DGA + 2,500 ppm and DEN +2,000 ppm groups. Significant induction of CYP1A1/2, 2B1/2 and 4A1/3 was observed in the DEN/DGA + 2,500 ppm and DEN +2,000 ppm groups, as compared to the corresponding control groups. Similar induction of CYP1A2 and 2B1 was observed in the DEN/DGA + 500 ppm group. Significant increases in GST-P positive cells and/or mini-foci in the liver were observed in the DEN/DGA + 2,500 ppm group. These results suggest that febantel exerts liver tumor promotion potential. Since no increases in GST-P positive cells and/or foci in the liver were observed at the dose level of DEN/DGA + 500 ppm febantel, this dose is considered to be a no effect level for this promotion effect.