Wölfle D, Münzel P, Fischer G, Bock K W
Department of Pharmacology and Toxicology, University of Göttingen, FRG.
Carcinogenesis. 1988 Jun;9(6):919-24. doi: 10.1093/carcin/9.6.919.
Alterations of hepatocyte growth control by inducers of drug-metabolizing 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.
以3,4,3',4'-四氯联苯（TCB）作为诱导剂，研究了药物代谢酶诱导剂对肝细胞生长控制的影响。选择TCB作为一种选择性的3-甲基胆蒽型诱导剂和肝肿瘤促进剂，它可能通过与芳烃（Ah）受体结合发挥其生物学作用。用TCB（200mg/kg）对大鼠进行体内处理，显著刺激了酶改变的肝灶生长以及[3H]-胸腺嘧啶核苷掺入核DNA。与未处理的对照组相比，来自TCB处理大鼠的肝细胞培养物对外源生长因子如表皮生长因子（EGF）更敏感。肝细胞培养物的体外TCB暴露也以剂量依赖的方式改变了肝细胞生长控制并诱导了药物代谢酶。体内TCB处理增强了肝细胞膜中EGF受体的EGF刺激的自磷酸化。结果表明生长控制的改变是由于TCB对肝细胞的直接作用。所提出的模型可能有助于阐明由适应性程序的持续过表达施加于肝细胞的功能应激与肝细胞生长控制调节之间的可能联系。
