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

Abstract

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.

Effect of Standardized Decoction of <i>Nigella sativa</i> Seed, <i>Hemidesmus indicus</i> Root and <i>Smilax glabra Rhizome on the Expression of p53 and p21 Genes in Human Hepatoma Cells (HepG2) and Mouse Liver with Chemically-Induced Hepatocarcinogenesis

“…Up regulation of expression of both p53 and p21 genes in a time-and dose-dependent manner was evident in the human hepatocellular carcinoma cell line HepG2 in-vitro and in the DEN-induced mouse hepatic cancer model in-vivo. Although up regulation of expression of p53 in the mouse liver in response to DEN ( ( *** *** * ** *** alone has been previously reported [21,22], we observed further enhancement of p53 expression in response to the decoction over and above DEN-induced p53 expression. It has been suggested that the induction of p53 by DEN is not related to a cytotoxic effect, but most likely results from DNA strand breaks induced directly by this genotoxic compound or formed as a result of DNA-repair [20,21].…”

Wild-type p53-mediated Induction of Rat mdr1bExpression by the Anticancer Drug Daunorubicin

“…In addition, it has been known that the mdr1b expression in rat liver can be rapidly activated by chemical carcinogens such as 2-AAF and aflatoxin B1 (12,13), however, in rat hepatocellular carcinomas induced by these carcinogens, p53 mutations do not always occur (55,56). More importantly, van Gijssel et al (57) recently reported that p53 activity can be also induced by 2-AAF and aflatoxin B1 in rat liver. When rat hepatoma H-4-II-E cells (contain wild-type p53) were treated with 2-AAAF, p53 activity was also been induced.…”

The suppression of hematopoiesis function in Balb/c mice induced by prolonged exposure of microcystin-LR

“…P53 has been considered to induce apoptosis. It can affect cell cycle through controlling the progression of G1 stage (Van Gijssel et al, 1997). Cytochrome c release is an almost universal event in the mitochondrial apoptotic pathway.…”