Carcinogenesis, Vol 19, 925-931, Copyright © 1998 by Oxford University Press
NJ Plant, NJ Horley, RL Savory, CR Elcombe, TJ Gray and DR Bell
Peroxisome proliferator-induced mitogenesis is believed to play a role in
hepatocarcinogenesis, but it has not been possible to demonstrate high
level induction of DNA synthesis by peroxisome proliferators in cultured
hepatocytes. We now show that four structurally dissimilar peroxisome
proliferators (methylclofenapate, Wy-14 643, tetradecyl-3- thia acetic acid
and clofibrate) cause high level induction of DNA synthesis in primary
cultures of rat hepatocytes, routinely 7-9 fold above control, with up to
29% of cells undergoing S-phase. Peroxisome proliferators induce DNA
synthesis rapidly, with maximal response 24 h after dosing [compared with
48 h for epidermal growth factor (EGF)]; indeed, peroxisome proliferators
were mitogenic in a chemically defined medium, i.e. with no added exogenous
growth factors. EGF-treated hepatocytes that had undergone DNA synthesis
comprised 23% binucleated cells, whereas hepatocytes induced into S-phase
by peroxisome proliferators contained only 3% binucleated cells,
demonstrating a distinct response of hepatocytes to peroxisome
proliferators and EGF. The presence of a glucocorticoid was essential for
peroxisome proliferator-induced DNA synthesis, but not for EGF-induced DNA
synthesis, demonstrating that the requirement for glucocorticoids is
selective for peroxisome proliferators. Hydrocortisone was shown to induce
the expression of peroxisome proliferator activated receptor- alpha (PPAR
alpha), and we propose that it is the glucocorticoid- induced expression of
PPAR alpha that is essential for peroxisome proliferator mitogenesis. This
in vitro system provides a powerful tool for investigating the mechanism
and role of peroxisome proliferator- induced mitogenesis in liver growth
and carcinogenesis.
ARTICLES
The peroxisome proliferators are hepatocyte mitogens in chemically- defined media: glucocorticoid-induced PPAR alpha is linked to peroxisome proliferator mitogenesis
Department of Life Science, University of Nottingham, UK.
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