Persistence of resistant putative preneoplastic hepatocytes induced by n-nitrosodiethylamine or n-methyl-n-nitrosourea

The administration of either N-nitrosodiethylamine (diethyl-nitrosamine) to intact male F–344 rats or N-methyl-N-nitrosou-rea to similar animals 18 hr after partial hepatectomy results in the induction of altered resistant hepatocytes that persist for up to 36 weeks with no perceptible decrease in their number. The criterion for resistance was the ability to proliferate rapidly and to develop into foci or nodules when exposed to a level of dietary 2-acetylaminofluorene that inhibits the proliferation of the vast majority of hepatocytes when liver cell proliferation is stimulated by surgical or chemical partial hepatectomy. Since this selection procedure, when coupled with a single dose of diethylnitrosamine, is associated with a high incidence of liver cancer as compared to appropriate controls, and since similar foci and nodules were shown previously to be one site of origin for hepatocellular carcinoma in this model, the induction of resistant hepatocytes is interpreted as initiation. Thus, these results suggest that initiation of liver carcinogenesis in this model is irreversible, at least for a period of 36 weeks.