P53 PROTEIN EXPRESSION BY HEPATOCARCINOGENS IN THE RAT-LIVER AND ITS POTENTIAL ROLE IN MITOINHIBITION OF NORMAL HEPATOCYTES AS A MECHANISM OF HEPATIC TUMOR 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. T his gives cells additional time to repair their DNA-damage. However, i t may trigger apoptosis if damage is too high, Loss of p53 function ap pears to be an important step in carcinogenesis because 50% of human t umours 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 hepatotoxi c compounds. Administration of hepatocarcinogenic compounds increased p53 protein levels in the liver as detected by immunoprecipitation fol lowed by SDS-PAGE and Western blotting with ECL-detection. The hepatoc arcinogens included N-hydroxy-2-acetylaminofluorene, aflatoxin B1, and diethylnitrosamine. Their structural analogues N-hydroxy-4-acetylamin obiphenyl and ethyl methanesulphonate which are not hepatocarcinogenic , did not induce p53, Also, two hepatotoxic compounds (carbon tetrachl oride, D-galactosamine) did not induce p53. Other compounds that induc ed 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 proliferati on of normal hepatocytes. Because this is not observed with non-hepato carcinogenic analogues, it suggests an involvement of p53 expression i n hepatic tumour promotion. A possible mechanism is discussed.