EVALUATION OF HEPATOCYTE PROLIFERATION IN AGED RATS TREATED WITH CLOFIBRIC ACID

Clofibric acid, a peroxisome proliferator and non-genotoxic hepatocarcinogen in rodents, was administered to old rats at 9, 000, 4, 500, and 1, 500 ppm in diet for 1 or 13 weeks to investigate hepatocyte proliferation and its relationship to hepatocarcinogenesis. The cumulative number of Sphase hepatocytes over 1 week was scored prior to necropsy at both weeks 1 and 13 by BrdU immunohistochemistry. At week 13, the total number of hepatocytes per liver was determined by stereological procedures and used to calculate the total number of S-phase hepatocytes per liver. Hepatomegaly was evident in the 4, 500 and 9, 000ppm groups at week 1 and in all doses at week 13. During the first week of treatment, a significant burst of hepatocyte proliferation was induced in a dose-dependent manner. However, there was no increase in the number of hepatocytes per liver in any dose groups at week 13, and the hepatomegaly at week 13 was the result of hepatocyte hypertrophy and not hyperplasia. On the contrary, an opposite effect was observed with the hepatocyte labeling index as well as total number of labeled hepatocytes per liver being decreased below the control levels in a dose-related fashion. These data indicate that clofibric acid appears to inhibit DNA synthesis of rat hepatocytes when administered over an extended period of time, and suggest the possible effect as a promoter on rat hepatocarcinogenesis through the mechanism of differential mitoinhibition.