Long-term treatment with hepatic tumor promoters inhibits mitogenic responses of hepatocytes to acidic fibroblast growth factor and hepatocyte growth factor.

Studies with hepatocyte cultures have defined four hepatocyte mitogens which can transmit a complete mitogenic signal in cultures kept in completely defined conditions. These four mitogens are epidermal growth factor (EGF), acidic fibroblast growth factor (aFGF), hepatopoietin A/hepatocyte growth factor (HPTA/HGF) and hepatopoietin B (HPTB). In this study, we investigated the effect of aFGF, HGF and the mito-inhibitor transforming growth factor beta (TGF-beta) on cultured hepatocytes isolated from livers of rats treated with the xenobiotic hepatic tumor promoters phenobarbital (PB) and alpha-hexachlorocyclohexane (alpha-HCH). Male F344 rats were treated with each of these two xenobiotics to stimulate hepatic DNA synthesis and augmentative hepatomegaly. At different times on the regimens with tumor promoters, hepatocytes were isolated and placed in primary culture. DNA synthesis of hepatocytes in culture stimulated by these two growth factors and the suppression of DNA synthesis affected by TGF-beta were examined as a function of time of treatment in vivo with these two promoters. Following day 10, hepatocytes from both promoter regimens became unresponsive to these two growth factors for the rest of the duration of the treatment (day 90). TGF-beta suppressed DNA synthesis stimulated by growth factors but did not affect the high background DNA synthesis stimulated by xenobiotics themselves.