Carcinogenesis, Vol 19, 631-637, Copyright © 1998 by Oxford University Press
V Nilakantan, BT Spear and HP Glauert
Peroxisome proliferators are a group of non-genotoxic hepatic carcinogens
that have been proposed to act by increasing oxidative damage in the liver.
To test this hypothesis, we have examined if hepatic catalase
overexpression in peroxisome proliferator-treated mice influences the
induction of cell proliferation or the activation of transcription factors
involved in cell proliferation. Transgenic mice or non-transgenic
littermates were fed either 0.01% ciprofibrate or a control diet for 21
days. Fatty acyl CoA oxidase activity was not significantly affected by
catalase overexpression, although the ratio of fatty acyl CoA oxidase to
catalase was significantly decreased in transgenic animals. The labeling
index in hepatocytes was significantly increased by ciprofibrate in
non-transgenic mice, but catalase overexpression significantly inhibited
this increase. Ciprofibrate increased the activation of nuclear factor
(NF)-kappaB in non- transgenic mice, but this increase was inhibited by
catalase overexpression. Ciprofibrate also increased AP-1 activation, but
catalase overexpression did not significantly inhibit this increase,
although AP-1 activation was 40% lower in transgenic mice. These results
support the hypothesis that active oxygen plays a role in the induction of
cell proliferation by the peroxisome proliferator ciprofibrate and
therefore may be important in the carcinogenicity of these agents.
ARTICLES
Liver-specific catalase expression in transgenic mice inhibits NF- kappaB activation and DNA synthesis induced by the peroxisome proliferator ciprofibrate
Graduate Center for Toxicology, University of Kentucky, Lexington 40506, USA.
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