Jt. Hong et Hp. Glauert, Stimulation of the DNA binding activity of AP-1 by the peroxisome proliferator ciprofibrate and eicosanoids in cultured rat hepatocytes, TOXICOLOGY, 131(2-3), 1998, pp. 99-107
Peroxisome proliferators induce hepatic peroxisome proliferation and hepati
c tumors in rodents. These chemicals increase the expression of the peroxis
omal beta-oxidation pathway and the cytochrome P-450 4A family, which metab
olize lipids, including eicosanoids. Peroxisome proliferators also induce i
ncreased cell proliferation in vivo. However, peroxisome proliferators are
only weakly mitogenic and are not comitogenic with epidermal growth factor
(EGF) in cultured hepatocytes. Our earlier studies found that the peroxisom
e proliferator ciprofibrate is comitogenic with eicosanoids. We therefore h
ypothesized that the comitogenicity of the peroxisome proliferator ciprofib
rate and eicosanoids may result from a synergistic increase of the DNA bind
ing activity of AP-1. Primary rat hepatocytes were cultured on collagen gel
s in serum-free L-15 medium with ciprofibrate, eicosanoids, and/or growth f
actors. The DNA binding activity of AP-1 was determined in nuclear protein
extracts by electrophoretic mobility shift assay. The DNA binding activity
of AP-1 was not induced by ciprofibrate or eicosanoids alone, but the addit
ion of eicosanoids along with ciprofibrate increased the induction of DNA b
inding activity of AP-1 at 30 min and 2 h after exposure. The combination o
f ciprofibrate and PGF(2 alpha) blocked the inhibitory effect of transformi
ng growth factor (TGF)-beta on the DNA binding activity of AP-1 induced by
EGF. These results show that the peroxisome proliferator ciprofibrate and e
icosanoids co-stimulate the DNA binding activity of AP-1 and suggest that c
hanges in eicosanoid concentrations may modulate mitogenic signal transduct
ion pathways by the peroxisome proliferator ciprofibrate. (C) 1998 Elsevier
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