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A cytological comparison between regeneration, hyperplasia and early neoplasia in the rat liver
Imperial Chemical Industries PLC, Central Toxicology Laboratory Alderley Park, Macclesfield, Cheshire, UK
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 amnitotic cytokinesis to mononucleated tetraploid cells. This results in an overall increase in the ratio of tetra ploid: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 induc ed by oral administration of 25 mg/kg methylclofenapate or diethylhexylphthalate (1 g/kg for 4 weeks) and neoplasia in duced by the hepatocarcinogens 3'-methyl-4-dimnethylamino-azobenzene (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 poly-ploidization and give rise to a liver with a pennanently depressed tetraploid:diploid hepatocyte ratio. The non-genotoxic carcinogens methyiclofenapate 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 ex posure there is an increase in the tetraploid:diploid ratio due to the continued conversion of newly formed binucleates to tetraploid mononucleates.
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