Responsiveness of hepatocytes to epidermal growth factor, transforming growth factor-beta and norepinephrine during treatment with xenobiotic hepatic tumor promoters.

Previous studies with xenobiotic hepatic tumor promoters have shown that prolonged treatment with these substances decreases the level of epidermal growth factor (EGF) receptors and the response of hepatocytes to EGF. In this study we show that, in contrast to prolonged exposure, the early stage of exposure to tumor promoters is associated with enhanced responsiveness to EGF. Differences in the patterns of responsiveness to EGF are noticed between two tumor promoters, phenobarbital (PB) and alpha-hexachlorocyclohexane (alpha-HCH). Norepinephrine is one of the strongest comitogens (mitogenic amplifiers) for hepatocytes. In addition to altering responsiveness to EGF, treatment with the tumor promoters eliminated the response to norepinephrine during the early stage of treatment. Transforming growth factor-beta (TGF-beta), a well known inhibitor of EGF mitogenesis in hepatocytes, inhibited the EGF-induced DNA synthesis but did not affect the DNA synthesis stimulated directly by the tumor promoters. Long term treatment with the tumor promoters inhibited responsiveness to both EGF and norepinephrine. The implications of these findings for mechanisms of tumor promotion in the liver are discussed.