Dose-response relationship for phenobarbitone promotion of liver tumours initiated by single dose dimethylnitrosamine

A single dose of 15 mg/kg dimethylnitrosamine is an initiator of hepatic tumour formation in rats but does not produce tumours without further treatment. Subsequent promotion by Na phenobarbitone (1000 micrograms/ml drinking water) leads to 40% or more of the rats developing hepatocellular carcinoma. Four days of dietary treatment designed to produce a wave of DNA synthesis at the time of initiation leads to an even greater yield of tumours and nodules after promotion. This effect of phenobarbitone does not appear to be directly related to its ability to induce enzyme activity in the liver because lower doses of phenobarbitone (100 micrograms/ml or less) did not promote tumour development in spite of being adequate for the induction of cytochrome P-450 and associated enzyme activity. A similar incidence of hepatocellular carcinoma was found in both the groups given DMN and the top dose of Na phenobarbitone (1000 micrograms/ml) whether or not they had been given the dietary pretreatment. However, hyperplastic nodules were seen only in the diet pre-treated group. This is discussed in relation to the hypothesis that hyperplastic nodules are precursors of hepatic carcinoma.