Attenuated p53 Expression and Lack of Effect of TGFalpha on Cell Replication in Enzyme Altered Foci.
Enzyme altered foci (EAF) in rat liver are stress-related precarcinogenic lesions. Control of the cell cycle in EAF hepatocytes is altered, and in vitro data indicate that p53 protein does not accumulate in these cells in response to DNA-damaging agents. In this report we present immunohistological data indicating that this p53 response is also attenuated in EAF in situ. The p53 response was 11 times more frequent in non-EAF than in EAF hepatocytes. The results are compared with previously reported in vitro studies. We also demonstrate that isolated EAF hepatocytes do not respond to TGFalpha and that four different p53-inducing agents, namely DEN, taxol, doxorubicin and araC readily induce p53 in non-EAF, but not in EAF hepatocytes. Taxol induces a similar toxicity in both these cell types. It is suggested that the attenuated response to DNA-damaging agents cannot be explained solely by altered metabolism of xenobiotics. Additional factors, such as an adaptive alteration in the control of p53 expression in EAF hepatocytes, must be involved.
Lennartsson
P
P
Department of Occupational Toxicology, Institute of Environmental Health, Karolinska Institutet, Box 210, 171 Stockholm, Sweden.
Stenius
U
U
Högberg
J
J