Activation of nuclear factor-κB by the peroxisome proliferator ciprofibrate in H4IIEC3 rat hepatoma cells and its inhibition by the antioxidants N-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 hydrogen peroxide. We previously showed that treatment of rats with ciprofibrate, a peroxisome proliferator, results in increased hepatic nuclear factor-kappa B (NF-kappa B) DNA binding activity. In this study, we have examined the link between peroxisome proliferators and NF-kappa B activation in hepatoma cell lines to test whether increased nuclear NF-kappa B levels activate 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-acetylcysteine and vitamin E. These studies suggest that hepatocytes are at least partially 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) 2000 Elsevier Science Inc.