Ligands for Peroxisome Proliferator-activated Receptors a and g Inhibit Chemically Induced Colitis and Formation of Aberrant Crypt Foci in Rats

The biological role of the peroxisome proliferator-activated receptors (PPARs) in various diseases, including inflammation and cancer, has been highlighted recently. Although PPARg ligands have been found to inhibit mammary carcinogenesis in rodents, the effects on colon tumorigenesis are controversial. In the present study, three different experiments were conducted to investigate the modifying effects of PPARs ligands (PPARa and PPARg) on colitis and an early phase of colitis-related colon carcinogenesis in male F344 rats. In the first experiment, gastric gavage of troglitazone (PPARg ligand, 10 or 100 mg/kg body weight) or bezafibrate (PPARa ligand, 10 or 100 mg/kg body weight) inhibited colitis induced by dextran sodium sulfate (DSS) and lowered trefoil factor-2 content in colonic mucosa. In the second experiment, dietary administration (0.01 or 0.05% in diet) of troglitazone and bezafibrate for 4 weeks significantly reduced azoxymethane (AOM, two weekly s.c. injections, 20 mg/kg body weight)-induced formation of aberrant crypts foci, which are precursor lesions for colon carcinoma. In the third experiment, dietary administration (0.01% in diet for 6 weeks) of pioglitazone (PPARg ligand), troglitazone, and bezafibrate effectively suppressed DSS/AOM-induced ACF. Administration of both ligands significantly reduced cell proliferation activity in colonic mucosa exposed to DSS and AOM. Our results suggest that synthetic PPARs ligands (PPARa and PPARg) can inhibit the early stages of colon tumorigenesis with or without colitis.