Carcinogenesis, Vol 18, 1027-1033, Copyright © 1997 by Oxford University Press
HE van Gijssel, CB Maassen, GJ Mulder and JH Meerman
The tumour suppressor gene p53 is expressed in response to DNA-damage; its
protein product blocks cells in the G1-phase of the cell cycle. This gives
cells additional time to repair their DNA-damage. However, it may trigger
apoptosis if damage is too high. Loss of p53 function appears to be an
important step in carcinogenesis because 50% of human tumours have lost
functional p53. In order to study the role of p53 in experimental
hepatocarcinogenesis, we determined the expression of p53 in rat liver in
response to various hepatocarcinogenic and hepatotoxic compounds.
Administration of hepatocarcinogenic compounds increased p53 protein levels
in the liver as detected by immunoprecipitation followed by SDS-PAGE and
Western blotting with ECL-detection. The hepatocarcinogens included
N-hydroxy-2-acetylaminofluorene, aflatoxin B1, and diethylnitrosamine.
Their structural analogues N-hydroxy-4- acetylaminobiphenyl and ethyl
methane-sulphonate which are not hepatocarcinogenic, did not induce p53.
Also, two hepatotoxic compounds (carbon tetrachloride, D-galactosamine) did
not induce p53. Other compounds that induced p53 in the rat liver were
2-aminofluorene (administered by drinking water for two weeks) and
tris-(2,3- dibromopropyl)phosphate. Benzo[a]pyrene did not induce p53.
N-Hydroxy-2- acetylaminofluorene, aflatoxin B1, and diethylnitrosamine are
potent hepatic tumour promoters. At the same time, they induce p53 protein
expression and inhibit proliferation of normal hepatocytes. Because this is
not observed with non-hepatocarcinogenic analogues, it suggests an
involvement of p53 expression in hepatic tumour promotion. A possible
mechanism is discussed.
ARTICLES
p53 protein expression by hepatocarcinogens in the rat liver and its potential role in mitoinhibition of normal hepatocytes as a mechanism of hepatic tumour promotion
Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
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