Administration of N-nitrosobis (2-oxopropyl)amine during peak DNA synthesis of regenerating pancreas in hamsters has been shown to induce hepatocytelike cells in pancreas. We now present evidence to demonstrate that such cells respond to methyl clofenapate, a peroxisome proliferator. The response includes a marked proliferation of peroxisomes and enhanced activity of peroxisomal enzymes enoyI-CoA hydratase (8.5-to 13-fold), [1-14C] -palmitoyI-CoA oxidation (2.8-to 3.9-fold), catalase (1.6 to 3.4-fold), and carnitine acetyltransferase (>2,000-fold). Cytochemical localization of catalase by the alkaline 3,3'-diaminobenzidine procedure and immunofluorescence localization of heat-labile enoyI-CoA hydratase showed that these peroxisome-associated enzymes are localized strictly in pancreatic hepatocytelike cells, while adjacent acinar, duct, and islet cells appeared consistently negative. Morphometric analyses of hepatocytelike cells showed a significant increase in the numerical density and an eightfold increase in the volume density of peroxisomes in methyl clofenapate treated animals. These results demonstrate that the hepatocytelike cells are responsible for the observed peroxisomal enzyme activity in pancreas of hamsters and suggest that the derepressed peroxisome specific genes in these cells respond to a peroxisome proliferator as do parenchymal cells in hamster liver.A single dose of the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (NBOP) administered to regenerating pancreas of hamster during peak DNA synthesis leads to the appearance of ceils strikingly similar to hepatocytes (16, 21). These cells show many of the morphological and cytochemical features characteristic of normal differentiated hepatocytes. Immanofluorescence staining with appropriate specific antibodies indicated the presence of albumin in the cytoplasm of these cells and the absence of a-amylase and carboxypeptidasetwo marker proteins characteristic of pancreatic acinar cells. Although these cells closely resemble the hepatocytes, their definitive identification and origin remain to be determined. Since exposure of rodents to any of a group of structurally dissimilar compounds which lower plasma triglyoeride levels is predictably associated with a marked proliferation of peroxisomes in hepatic parenchymal ceils (2,(18)(19)(20)(21) 28), and to a lesser extent in proximal tubular epithelium of kidney (4), it appeared particularly relevant to assess the response of these hepatocytelike cells in pancreas to a peroxisome proliferator as a way of further characterizing their nature. This study documents the response of hepatocytelike cells to methyl clofenapate (methyl-2[4-(p-chlorophenyl)phenoxyl2-methyl propiohate), a potent peroxisome proliferator and inducer of augmented synthesis of peroxisome-associated enzymes (19).
MATERIALS AND METHODS
Initiation of Pancreatic Regeneration and Induction of PeroxisomesThe experimental procedure for initiation of pancreatic regeneration is described in a previous communication (25). Briefly...