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.
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.
van Gijssel
H E
HE
Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
Maassen
C B
CB
Mulder
G J
GJ
Meerman
J H
JH
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002455:Cell Division; D018736:DNA Adducts; D004052:Diethylnitrosamine / Q000494:pharmacology; D005020:Ethyl Methanesulfonate / Q000494:pharmacology; D006498:Hepatectomy; D006881:Hydroxyacetylaminofluorene / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D011233:Precipitin Tests; D018809:Proliferating Cell Nuclear Antigen; D051381:Rats; D017208:Rats, Wistar; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D002273:Carcinogens; D018736:DNA Adducts; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene; D004052:Diethylnitrosamine; D006881:Hydroxyacetylaminofluorene; D005020:Ethyl Methanesulfonate; D000410:Alanine Transaminase