Effects of dosage and sex on the liver injury and incidence of hepatocellular tumors induced by 3-benzylsydnone-4-acetamide in rats.

Abstract

3-Benzylsydnone-4-acetamide (BSA), mixed in the pellet feed or dissolved in drinking water, was given to Donryu rats of both sexes. In male rats fed diet containing 200 and 60 ppm BSA (30mg and 9mg daily in 15g of feed) for 15 weeks, hepatocellular carcinomas developed in 20 out of 21 (95.2%) and 2 out of 14 (14.3%) rats, respectively, in 71 weeks. None of 13 rats fed diet with 20 ppm (3mg/day) continuously for 104 weeks had liver tumors at sacrifice. Daily dose of 15.3mg/animal (60ppm in drinking water) of BSA to the male and 46.2mg (200ppm) to the female rats for 41 weeks induced hepatocellular carcinomas at the rate of 92.9% (13/14) and 66.7% (6/9), respectively, but none of 7 female rats ingesting 15.5mg/day (60ppm) of BSA had liver tumors, indicating that the male rats are more susceptible to BSA than the female in liver carcinogenesis. Hepatic tumors were multiple in almost all cases. Histologically they were well differentiated (most common) or poorly differentiated hepatocellular carcinomas, or cholangiocarcinomas (rare). From two hepatocellular carcinomas, ascitic and solid tumor cell lines were established by serial intraperitoneal transplantation. Initially BSA caused centrilobular necrosis of the liver, with elevated serum GPT activity, then appeared proliferating liver cell clusters from which adenomatous and neoplastic changes developed.