Schrenk D, Schmitz H-J, Bohnenberger S, Wagner B, Wörner W
Food Chemistry and Environmental Toxicology, University of Kaiserslautern, Erwin-Schroedinger-Strasse 52, D-67663 Kaiserslautern, Germany.
Toxicol Lett. 2004 Apr 1;149(1-3):43-50. doi: 10.1016/j.toxlet.2003.12.019.
Multistage carcinogenesis in rat liver is widely used as an experimental model for the study of the critical events in tumor promotion. After an initial treatment with a genotoxic liver carcinogen ('initiation'), subsequent application of certain non-genotoxic agents can lead to the clonal expansion of putative preneoplastic cells ('promotion'). Obviously, the expansion of these clones is correlated with an increased occurrence of benign and malignant liver tumors at later time points. Since both proliferation and apoptosis were reported to be enhanced in putative preneoplastic liver foci, inhibition of apoptosis was suggested to play a critical role in tumor promotion. In rat hepatocytes in primary culture, the liver tumor promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibited apoptosis initiated by treatment of the cultures with UV irradiation but did not affect apoptosis in non-irradiated cultures. The suppression of apoptosis with TCDD coincided with an attenuated increase of the tumor suppressor protein p53 observed upon UV irradiation. Furthermore, TCDD treatment resulted in a marked hyperphosphorylation of p53. The fact that almost identical concentration-response curves were obtained for the phosphorylation of p53 and the induction of cytochrome P450(CYP)1A-catalyzed 7-ethoxyresorufin O-deethylase (EROD) activity indicates that p53 phosphorylation after TCDD treatment is mediated by the aryl hydrocarbon receptor (AhR) signaling cascade. With tumor-promoting 'non-dioxin-like' polychlorinated biphenyls inhibition of UV-induced apoptosis was also observed. A comparative study investigating the effects of various concentrations did not reveal, however, a clear correlation between the suppression of apoptosis and the induction of CYP2B-catalyzed 7-pentoxyresorufin O-dealkylase (PROD) activity. In summary, inhibition of UV-induced apoptosis with liver tumor promoters is observed in rat hepatocytes in culture. Hyperphosphorylation of key proteins of apoptosis including p53 seems to play a role in this effect.
大鼠肝脏的多阶段致癌作用被广泛用作研究肿瘤促进关键事件的实验模型。在用遗传毒性肝脏致癌物进行初始处理（“启动”）后，随后应用某些非遗传毒性剂可导致假定的癌前细胞发生克隆性扩增（“促进”）。显然，这些克隆的扩增与后期良性和恶性肝肿瘤发生率的增加相关。由于据报道在假定的癌前肝灶中增殖和凋亡均增强，因此有人提出抑制凋亡在肿瘤促进中起关键作用。在原代培养的大鼠肝细胞中，肝脏肿瘤促进剂2,3,7,8-四氯二苯并-对-二恶英（TCDD）抑制了用紫外线照射处理培养物引发的凋亡，但不影响未照射培养物中的凋亡。TCDD对凋亡的抑制与紫外线照射后观察到的肿瘤抑制蛋白p53的减弱增加相一致。此外，TCDD处理导致p53明显的过度磷酸化。p53磷酸化和细胞色素P450（CYP）1A催化的7-乙氧基异吩恶唑酮O-脱乙基酶（EROD）活性诱导获得几乎相同的浓度-反应曲线这一事实表明，TCDD处理后p53磷酸化是由芳烃受体（AhR）信号级联介导的。对于具有肿瘤促进作用的“非二恶英类”多氯联苯，也观察到对紫外线诱导凋亡的抑制。然而，一项研究不同浓度影响的比较研究并未揭示凋亡抑制与CYP2B催化的7-戊氧基异吩恶唑酮O-脱烷基酶（PROD）活性诱导之间的明确相关性。总之，在培养的大鼠肝细胞中观察到肝脏肿瘤促进剂对紫外线诱导凋亡的抑制。包括p53在内的凋亡关键蛋白的过度磷酸化似乎在这种效应中起作用。
