Sequential histologic study of rat liver during peroxisome proliferator [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]-acetic acid (Wy-14,643)-induced carcinogenesis

The livers of male inbred F344 rats fed Wy-14,643 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (CAS: 50892-23-4) in the diet at a concentration of 0.1% (wt/wt) were examined sequentially at 5, 10, 17, 21, 26, 30, 35, 40, 52, 60, and 70 weeks. At 5 weeks the livers were markedly enlarged and histologically showed markedly enlarged hepatocytes with prominent nucleoli. At 21 weeks altered acidophilic areas were seen in 2 of 3 animals that were killed. Between 26 and 52 weeks neoplastic nodules were noted of 1-8 mm containing cells with morphologic features similar to those observed in altered areas. Hepatocellular carcinomas (HCC) were observed in 1 animal killed at 30 weeks and in all the animals sacrificed at 60 weeks and later. [3H]thymidine nuclear labeling studies showed marked proliferative activity of cells in altered areas, neoplastic nodules, and HCC. Altered areas, neoplastic nodules, and HCC were consistently negative for gamma-glutamyltransferase and showed decreased ATPase activity. Glucose-6-phosphatase (Glc-6-Pase) activity was decreased in altered areas and neoplastic nodules. However, some of the HCC showed a strong positive reaction for Glc-6-Pase.