Chramostová Katerina, Vondrácek Jan, Sindlerová Lenka, Vojtesek Borivoj, Kozubík Alois, Machala Miroslav
Laboratory of Cytokinetics, Institute of Biophysics, 612 65 Brno, Czech Republic.
Toxicol Appl Pharmacol. 2004 Apr 1;196(1):136-48. doi: 10.1016/j.taap.2003.12.008.
Although many polycyclic aromatic hydrocarbons (PAHs) are recognized as potent mutagens and carcinogens, relatively little is known about their role in the tumor promotion. It is known that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can induce release of rat hepatic oval epithelial cells from contact inhibition by a mechanism possibly involving the aryl hydrocarbon receptor (AhR) activation. Many PAHs are AhR ligands and are known to act as transient inducers of AhR-mediated activity. In this study, effects of 19 selected PAHs on proliferation of confluent rat liver epithelial WB-F344 cells were investigated. Non-mutagens that are weak activators or nonactivators of AhR-mediated activity had no effect on cell proliferation. Relatively strong or moderate AhR ligands with low mutagenic potencies, such as benzofluoranthenes, benz[a]anthracene, and chrysene, were found to increase cell numbers, which corresponded to an increased percentage of cells entering S-phase. Strong mutagens, including benzo[a]pyrene and dibenzo[a,l]pyrene, increased a percentage of cells in S-phase without inducing a concomitant increase in cell numbers. The treatment with mutagenic PAHs was associated with an increased DNA synthesis and induction of cell death, which corresponded with the activation of p53 tumor suppressor. Apoptosis was blocked by pifithrin-alpha, the chemical inhibitor of p53. Both weakly and strongly mutagenic PAHs known as AhR ligands were found to induce significant increase of cytochrome P4501A activity, suggesting a presence of functional AhR. The results of the present study seem to suggest that a release from contact inhibition could be a part of tumor promoting effects of AhR-activating PAHs; however, the genotoxic effects of some PAHs associated with p53 activation might interfere with this process.
尽管许多多环芳烃（PAHs）被认为是强效诱变剂和致癌物，但它们在肿瘤促进过程中的作用却鲜为人知。已知2,3,7,8-四氯二苯并对二恶英（TCDD）可通过一种可能涉及芳烃受体（AhR）激活的机制诱导大鼠肝卵圆上皮细胞从接触抑制中释放出来。许多PAHs是AhR配体，并且已知可作为AhR介导活性的短暂诱导剂。在本研究中，研究了19种选定的PAHs对汇合的大鼠肝上皮WB-F344细胞增殖的影响。作为AhR介导活性的弱激活剂或非激活剂的非诱变剂对细胞增殖没有影响。发现具有低诱变潜力的相对较强或中等的AhR配体，如苯并荧蒽、苯并[a]蒽和芘，可增加细胞数量，这与进入S期的细胞百分比增加相对应。包括苯并[a]芘和二苯并[a,l]芘在内的强诱变剂可增加S期细胞的百分比，但不会导致细胞数量随之增加。用诱变PAHs处理与DNA合成增加和细胞死亡诱导有关，这与p53肿瘤抑制因子的激活相对应。凋亡被p53的化学抑制剂pifithrin-α阻断。已知作为AhR配体的弱诱变和强诱变PAHs均能诱导细胞色素P4501A活性显著增加，表明存在功能性AhR。本研究结果似乎表明，从接触抑制中释放可能是AhR激活型PAHs肿瘤促进作用的一部分；然而，一些与p53激活相关的PAHs的遗传毒性作用可能会干扰这一过程。
