Altered growth control of rat hepatocytes after treatment with 3,4,3′,4′-tetrachlorobiphenylin vivo and in vitro

Alterations of hepatocyte growth control by inducers of drugmetabolizing enzymes were investigated using 3,4,3',4'-tetrachlorobiphenyl (TCB) as the inducing agent. TCB was chosen as a selective 3-methylcholanthrene-type inducer and liver tumor promoter which probably exerts its biological actions through binding to the aryl hydrocarbon (Ah) receptor. In vivo treatment of rats with TCB (200 mg/kg) markedly stimulated growth of enzyme altered liver foci and [3H]-thymidine incorporation into nuclear DNA. Hepatocyte cultures from TCB-treated rats were more sensitive to exogenous growth factors such as EGF than those from untreated controls. In vitro TCB exposure of hepatocyte cultures also altered hepatocyte growth control in a dose-dependent manner and induced drug-metabolizing enzymes. TCB treatment in vivo enhanced EGF-stimulated autophosphorylation of the EGF receptor in liver plasma membranes. The results suggest that altered growth control is due to a direct effect of TCB on hepatocytes. The proposed model may be useful to elucidate a possible linkage between the functional stress imposed on hepatocytes by sustained overexpression of an adaptive program and modulation of hepatocyte growth control.