Toxicological Sciences 54, 95-103 (2000)
Copyright © 2000 by the Society of Toxicology
Xenobiotics Modulate the p53 Response to DNA Damage in Preneoplastic Enzyme-Altered Foci in Rat Liver; Effects of Diethylnitrosamine and Phenobarbital
* Occupational Toxicology Group, Institute of Environmental Medicine, Karolinska Institutet, Box 210, S-171 77 Stockholm, Sweden; and
National Institute of Working Life, S-171 84 Solna, Sweden
Enzyme-altered foci (EAF) develop in rat liver in response to carcinogen treatment. Our hypothesis is that EAF adapt to genotoxic stimuli by lowering their expression of p53 and that such decreased p53 expression confers a growth advantage on the hepatocytes present in EAF. After a single neonatal dose of diethylnitrosamine (DEN), rats were treated with either 2 – 12 additional doses of DEN or phenobarbital (PB) for 3 – 14 months. Twenty-four hours prior to sacrifice, all rats also received a challenging dose of DEN. The numbers of p53-positive hepatocytes (demonstrating immunohistological staining in the nucleus) in EAF and surrounding tissue were subsequently determined. In DEN-treated rats, p53 expression was attenuated in EAF compared to surrounding tissue. The longer the period of treatment and the larger the size of the EAF, the fewer the p53-positive hepatocytes/mm2 were observed in these lesions. These data were confirmed by Western blot analysis. PB-treated rats did not demonstrate this effect seen in DEN-treated rats. In this case, the expression of p53 was not related to size of EAF or length of treatment. Many EAF in PB-treated animals contained very large numbers of p53-positive cells. Upon staining for terminal deoxynucleotidyl transferase-mediated X-dUTP nick-end labeling (the TUNEL procedure), many apoptotic hepatocytes were also seen in EAF. These data indicate that the p53 response to DNA damage can be modulated by xenobiotics. This can be explained as an adaptive alteration in the p53 response.
Key Words: p53; preneoplastic enzyme-altered foci; diethylnitrosamine; phenobarbital; adaptation; genotoxicity; dose response; carcinogenesis; risk assessment.
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