Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit chemically induced colitis and formation of aberrant crypt foci in rats

The biological role of the peroxisome proliferator-activated receptors (PPA Rs) in various diseases, including inflammation and cancer, has been highli ghted recently. Although PPAR gamma ligands have been found to inhibit mamm ary carcinogenesis in rodents, the effects on colon tumorigenesis are contr oversial. In the present study, three different experiments were conducted to investigate the modifying effects of PPARs ligands (PPAR alpha and PPAR gamma) on colitis and an early phase of colitis-related colon carcinogenesi s in male F344 rats. In the first experiment, gastric gavage of troglitazon e (PPAR gamma ligand, 10 or 100 mg/kg body weight) or bezafibrate (PPAR alp ha ligand, 10 or 100 mg/kg body weight) inhibited colitis induced by dextra n sodium sulfate (DSS) and lowered trefoil factor-2 content in colonic muco sa. In the second experiment, dietary administration (0.01 or 0.05% in diet ) of troglitazone and bezafibrate for 4 weeks significantly reduced azoxyme thane (AOM, two weekly s.c. injections, 20 mg/kg body weight)-induced forma tion of aberrant crypts foci, which are precursor lesions for colon carcino ma. In the third experiment, dietary administration (0.01% in diet for 6 we eks) of pioglitazone (PPAR gamma ligand), troglitazone, and bezafibrate eff ectively suppressed DSS/AOM-induced ACF. Administration of both ligands sig nificantly reduced cell proliferation activity in colonic mucosa exposed to DSS and AOM. Our results suggest that synthetic PPARs ligands (PPAR alpha and PPAR gamma) can inhibit the early stages of colon tumorigenesis with or without colitis.