Differential activation of hepatic NF-κB in rats and hamsters by the peroxisome proliferators Wy-14,643, gemfibrozil, and dibutyl phthalate

Nuclear factor-κB (NF-κB) is an oxidative stress-activated transcription factor involved in the regulation of cell proliferation and apoptosis. We found previously that the peroxisome proliferator ciprofibrate activates NF-κB in the livers of rats and mice. These species are sensitive to the hepatocarcinogenic effects of peroxisome proliferators, whereas other species such as Syrian hamsters are not. In the present study we examined the effects of 3 different peroxisome proliferators on NF-κB activation in rats and Syrian hamsters. The peroxisome proliferators Wy-14,643, gemfibrozil, and dibutyl phthalate were administered to animals for 6,34, or 90 days. NF-κB activity was determined using electrophoretic mobility-shift assays and confirmed using supershift assays. Wy-14,643 increased the DNA binding activity of NF-κB at all 3 time points in rats and produced the highest activation of the 3 chemicals tested. Gemfibrozil and dibutyl phthalate increased NF-κB activation to a lesser extent in rats and not at all times. There were no differences in hepatic NF-κB levels between control hamsters and hamsters treated with any of the peroxisome proliferators. This study demonstrates species-specific differences in hepatic NF-κB activation by peroxisome proliferators.