Activation of nuclear factor-kappa B by the peroxisome proliferator ciprofibrate in H4IIEC3 rat hepatoma cells and its inhibition by the antioxidantsN-acetylcysteine and vitamin E

Peroxisome proliferators are a class of hepatic carcinogens in rodents and are proposed to act in part by increasing reactive oxygen species such as h ydrogen peroxide. We previously showed that treatment of rats with ciprofib rate, a peroxisome proliferator, results in increased hepatic nuclear facto r-kappa B (NF-kappa B) DNA binding activity. In this study, we have examine d the link between peroxisome proliferators and NF-kappa B activation in he patoma cell lines to test whether increased nuclear NF-kappa B levels activ ate NF-kappa B-regulated genes and to determine the mechanism of NF-kappa B activation. Electrophoretic mobility shift assays demonstrated NF-kappa B induction by ciprofibrate in peroxisome proliferator-responsive H4IIEC3 rat hepatoma cells but not in peroxisome proliferator-insensitive HepG2 human hepatoma cell lines. In addition, we found that stably transfected NF-kappa B-regulated reporter genes were activated by ciprofibrate in H4IIEC3 cells . This reporter gene activation was blocked by the antioxidants N-acetylcys teine and vitamin E. These studies suggest that hepatocytes are at least pa rtially responsible for peroxisome proliferator-mediated hepatic NF-kappa B activation, and support the possibility that this activation is dependent upon reactive oxygen species. BIOCHEM PHARMACOL 59;4:427-434, 2000. (C) 200 0 Elsevier Science Inc.