p53 expression and TGF-alpha-induced replication of hepatocytes isolated from rats exposed to the carcinogen diethylnitrosamine.

Previous reports indicate that the expression of transforming growth factor alpha (TGF-alpha) is increased in enzyme-altered foci (EAF) arising in livers of rats treated with a carcinogen. Here we have investigated the effects of TGF-alpha on EAF cells in vitro. Hepatocytes were isolated from rats that had received repeated treatment with diethylnitrosamine (DEN) and whose livers contained glutathione S-transferase P (GST-P)-positive EAF. Primary cultures of GST-P-positive and GST-P-negative hepatocytes were exposed to TGF-alpha. TGF-alpha (20-40 ng/ml) increased DNA replication in the GST-P-negative, but not in the GST-P-positive cells. Furthermore, it was shown that this effect on GSTP-negative cells could be blocked by p53 antisense oligonucleotides. We conclude that EAF hepatocytes do not respond to TGF-alpha in vitro. This lack of response may reflect the attenuated expression of p53 in these cells. These data corroborate previous findings that, in response to DNA damage, many EAF hepatocytes do not accumulate p53.