Studies on the hyperplastic responsiveness of binucleated rat hepatocytes

Rats were dosed by gavage for 28 days with 25 mg/kg of 3'methyl-4-dimethylaminoazobenzene (3'M) followed by 4 days dosing with 0.5 ml/100 g corn oil. Livers from animals were taken at intervals during the 4 days of corn oil dosing and examined for S-phase activity and nuclearity. The treatment regime caused an increase in the proportion of diploid (2N) cells in the hepatocyte population, a decrease in the proportion of binucleated (2×2N) cells of ∼50%, and induced an increase in cell replication. A second group of rats was dosed for 28 days with 0.5 ml/100 g corn oil followed by 4 days administration of 25 mg/kg methylclofenapate (MCP). Analysis of hepatocytes taken during the MCP treatment revealed that there was acute hyperplasia, involving mainly the 2×2N hepatocytes, resulting in a reduction of ∼50% of the 2×2N cells and an accompanying increase in the proportion of 4N cells. When a third group was given 3'M for 28 days followed by 4 days administration of MCP, there was, at the outset of MCP dosing, a hepatocyte population typical of 3'M dosed animals, with an elevated proportion of 2N cells and a 2×2N fraction that was reduced to ∼50% of control levels. During the 4 days of MCP dosing there was a wave of hyperplasia involving S-phase activity in the remaining 2×2N hepatocytes. The proportion of 2×2N cells decreased further during this period and there was a concomitant increase in 4N cells. The 2N fraction, already elevated, was not further affected. These results indicate that both genotoxic and non-genotoxic hepatocarcinogens induce acute changes in the rat hepatocyte population that involve 2×2N cells, and that the effects appear to involve separate sub-populations of 2×2N hepatocytes.