Regeneration,
hyperplasia and
neoplasia are three different responses to injury in the rat liver. These phenomena were induced in rat liver and the parameters of ploidy, nuclearity and
DNA synthesis were examined. Analysis of hepatocytes from animals undergoing liver regeneration following two-thirds partial
hepatectomy revealed that there is an increase in the cycling of diploid hepatocytes and a large increase in the frequency of binucleated
tetraploid cells undergoing
DNA synthesis and amitotic cytokinesis to mononucleated
tetraploid cells. This results in an overall increase in the ratio of
tetraploid:diploid cells but no change in the proportion of binucleated cells. The liver appears, temporarily, to undergo an increased rate of maturation. In both
hyperplasia inducted by
oral administration of 25 mg/kg
methylclofenapate or diethylhexylphthalate (1 g/kg for 4 weeks) and
neoplasia induced by the hepatocarcinogens
3'-methyl-4-dimethylaminoazobenzene (3'M), 6-p-dimethylaminophenylazobenzthiazole (6BT), 5-phenylazoindazole (5I),
diethylnitrosamine (DEN) and
thioacetamide (TA) the binucleated cell is sensitive to the action of the chemicals, although its response is different. Both types of
carcinogen induce a reduction in the frequency of binucleated cells but the mononucleated diploid cells produced by cytokinesis without a preceding S phase as a result of the action of genotoxic
carcinogens appear to be incapable of polyploidization and give rise to a liver with a permanently depressed
tetraploid:diploid hepatocyte ratio. The nongenotoxic
carcinogens methylclofenapate and
DEHP cause an initial hyperplastic response due to the rapid conversion of binucleated cells to mononucleated
tetraploids by amitotic cytokinesis following S phase. Over a longer period of exposure there is an increase in the
tetraploid:diploid ratio due to the continued conversion of newly formed binucleates to
tetraploid mononucleates.