The Histopathology and Biochemistry of Phenobarbitone-Induced Liver Nodules in C3H Mice

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Abstract
The sequential development of hepatic nodules induced by phenobarbitone (PB) has been studied in the C3H/He strain of mouse, a strain prone to the development of spontaneous liver tumours. PB was administered in the diet to young male animals at a dose level of 85 mg/kg/day for up to 91 weeks. Control and PB-treated mice developed hepatic nodules within 60 weeks. In control animals the nodules consisted of small basophilic cells, and by 80 weeks a small proportion of the animals had developed unequivocal hepatocellular carcinoma. The basophilic nodules were similar in many respects to those induced by N-nitrosodiethylamine. In PB-treated mice the incidence of basophilic nodules was similar to that in controls. These animals also developed hepatic nodules formed of large eosinophilic cells which were readily dissectable from the surrounding host tissue by 60 weeks. Biochemical investigations into the large eosinophilic nodules from PB treated mice showed that both Phase I and Phase II types of xenobiotic metabolizing enzyme activities were induced to levels either similar to, or greater than in the surrounding host tissue. In contrast, enzyme activities in basophilic nodules from untreated mice killed at 91 weeks, were generally similar to or lower than in the surrounding host tissue. The presence of eosinophilic nodules did not lead to an increase in the incidence of hepatocellular carcinoma in the PB-treated C3H/He mice. Concurrent experiments conducted in the C57BL/6 strain of mouse did not result in the development of liver nodules at 60 weeks. Thus, the eosinophilic nodules induced by phenobarbitone in C3H/He mice appear to be distinctly different from the basophilic liver nodules arising spontaneously or to basophilic nodules produced by the hepatocellular carcinogen N-nitrosodiethylamine.