Effects produced by the non-genotoxic hepatocarcinogen methylclofenapate in dwarf mice: peroxisome induction uncoupled from DNA synthesis and nuclearity changes.

Both Snell dwarf mice (dw/dw) and their phenotypically normal heterozygotes (dw/+) were dosed with methylclofenapate (MCP) at daily intervals by gavage (25 mg/kg). Animals were killed at 12, 24, 36 and 72 h after the initial dose and the parameters of ploidy, nuclearity and DNA synthesis were measured in hepatocytes isolated by collagenase perfusion. The occurrence of peroxisome proliferation was assessed by electron microscopy after daily administration of 25 mg/kg MCP by gavage for 28 days. The hepatocytes from both phenotypes exhibited similar degrees of peroxisome proliferation but hyperplasia occurred only in the heterozygous animals. The incidence of binulceated hepatocytes in heterozygotes was approximately 50%, and at the end of acute hyperplasia this had reduced to approximately 20%; by contrast the livers of dwarf animals contained approximately 20% binucleated cells and this remained unchanged throughout the period of dosing. The hyperplasia in the wild-type mice, as measured by the occurrence of S-phase, occurred predominantly in binucleated hepatocytes. These observations are further confirmation that acute hyperplasia induced by MCP and similar liver growth inducers occurs predominantly in a sensitive sub-population of binucleated hepatocytes. The results also indicate that peroxisome proliferation and hyperplasia can occur as independent phenomena.