DOSE DEPENDENCE OF PHENOBARBITAL PROMOTION OF PRENEOPLASTIC HEPATIC-LESIONS IN F344 RATS AND B6C3F1 MICE - EFFECTS ON DNA-SYNTHESIS AND APOPTOSIS

Phenobarbital (PB), a non-genotoxic hepatocarcinogen in rodents, has b een studied extensively but its mechanism of carcinogenic action is un clear. PB appears to function as a tumor promoter by selectively induc ing the growth of preneoplastic hepatocytes. In the present study, the comparative effects of PB at tumor-promoting and non-promoting doses were examined in male B6C3F1 mice and male F344 rats, In addition, the mechanism by which PB produced the selective induction of preneoplast ic cell growth (increased DNA synthesis/cell proliferation and/or decr eased apoptosis) was investigated, Preneoplastic focal lesions were pr oduced using diethylnitrosamine (DEN), After the lesions were histolog ically apparent, mice and rats were fed PB (10, 100, or 500 mg/kg NIH- 07 diet) or control diet and sampled after 7, 30 and 60 days of treatm ent, In both mice and rats, 100 and 500 mg PB/kg increased the number and the relative volume of focal lesions, In rats and mice, 10 mg PB/k g did not enhance focal lesion growth, The preneoplastic lesions that clonally expanded due to phenobarbital treatment were predominantly eo sinophilic in appearance, In addition, DNA synthesis in focal hepatocy tes was significantly increased in the 100 and 500 mg PB/kg diet, In P B-treated mice and rats, there also was a significant decrease in the rates of apoptosis in focal hepatocytes. Therefore, our data showed th at PB at doses of 100 and 500 mg/kg diet promoted focal hepatic lesion growth both by increasing DNA synthesis and cell proliferation and by decreasing the rate of apoptosis.