Comparison of the acute and chronic mitogenic effects of the peroxisome proliferators methylclofenapate and clofibric acid in rat liver

Peroxisome proliferators are well known to cause liver enlargement in rodents. In this investigation, we have examined the effect of acute (1 week) and chronic (26 week) exposure to the peroxisome proliferators methylclofenapate (MCP) and clofibric acid (CA), at 0.05 and 0.5% in the diet respectively, on hepatocyte replication in the Sprague-Dawley rat. Both compounds induced an early increase in hepatocyte replication, with a concomitant increase in peroxisome proliferation as assessed by induction of palmitoyl CoA oxidation. However, after 26 weeks of treatment, there was no difference in the labelling index (LI) of control and CA-treated rat livers, while in MCP-treated rats the LI was 5- to 6-fold above control. Palmitoyl CoA oxidation remained elevated in both treated groups at 26 weeks. Analysis of the slides by a ‘zonal’ scoring procedure demonstrated that the induced replication was predominantly periportal after 1 week of treatment with either compound. The number of 5-bromo-2'-deoxyuridine (BrdU)-positive hepatocyte nuclei per field in the periportal region increased ∼4-fold after CA treatment and 7-fold after MCP treatment. There was no significant difference in the number of BrdU-positive nuclei per field in the centrilobular areas of control and treated rats after 1 week. After 26 weeks of treatment, periportal replication was still elevated in the MCP-treated animals (∼10-fold above control), but there was no difference in periportal replication between control and CA-treated rats. CA induced a significant reduction in the replication of centrilobular areas at 26 weeks, while there was no effect of MCP. In summary, these results demonstrate that the acute mitogenic effects of MCP and CA are predominantly periportal, and, in the case of MCP, the mitogenicity is sustained up to 26 weeks of treatment.