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
Yx. Li et al., 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, BIOCH PHARM, 59(4), 2000, pp. 427-434
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.