Dose-related effects of the peroxisome proliferator methylclofenapate in rat liver

Male Sprague–Dawley rats were fed diets containing 0 (control) and 2.5–750 ppm of the peroxisome proliferator methylclofenapate (MCP) for 1, 4 and 13 weeks. In other studies MCP has been shown to produce liver tumors at dietary levels of 50 and 250, but not 10 ppm. MCP treatment produced increases in relative liver weight and activities of peroxisomal and microsomal fatty acid oxidising enzymes at all time points at doses as low as 10 and 2.5 ppm, respectively. Replicative DNA synthesis was studied by implanting osmotic pumps containing 5-bromo-2′-deoxyuridine during study weeks 0–1, 3–4 and 12–13. Hepatocyte labelling index values were significantly increased by treatment with 10–750 ppm MCP for 1 week and 150–750 ppm MCP for 13 weeks. Treatment with 50–750 ppm MCP for 13 weeks increased hepatic peroxisome proliferator-activated receptor alpha and transforming growth factor-β1 gene expression to 150–165 and 150–170% of control, respectively. These results demonstrate that while low doses of MCP produce sustained hepatomegaly and peroxisome proliferation in rat liver, higher doses are required to produce a sustained stimulation of replicative DNA synthesis.