MECHANISMS OF HEPATIC TUMOR PROMOTION BY PCB'S

多氯联苯是一种普遍存在的环境污染物。 在实验动物模型中致癌的污染物。 单个多氯联苯同系物以及商业多氯联苯混合物都有 在两个阶段中被证明是有效的肝肿瘤促进剂 大鼠肝细胞癌的发生。生物化学的作用机制 然而，多氯联苯促进肝脏病灶和肿瘤从来都不是 下定决心。此外，还不知道多氯联苯的同系物是否起作用。 在两阶段肝癌发生中的协同作用，这一点很重要 因为人类暴露在多氯联苯混合物中。最后，我们还不知道 如何准确估计多氯联苯的促进潜力 不是AH受体的配体。因此，我们建议测试 假设1)多氯联苯通过以下途径促进两阶段肝癌的发生 诱导DNA氧化损伤，增加长期细胞 增殖和/或改变二十烷类代谢；2) 非芳基结合的多氯联苯的促进指数可以通过它们的 诱导细胞色素P-450 2B1/2的能力；3)多氯联苯的作用 在促进肝癌发生方面具有协同作用。在第一个 研究表明，多氯联苯将在不同的时间段内使用，以及 它们能够诱导8-羟基鸟苷，促进细胞增殖 在正常肝细胞中，改变前列腺素浓度 将测定E2、F2pha和其他二十烷类化合物。在 肿瘤促进研究，多氯联苯将在 给他们注射二乙基亚硝胺，我们会确定他们的能力 1)如2B1/2诱导所预测的那样诱导改变的肝脏病灶 活性和2)在诱导肝脏改变中的协同作用 焦点。这些研究将显示多氯联苯如何促进肝脏 致癌，它们是否协同作用，如果他们的 提升能力是很容易预测的。这条信息会有帮助的 在了解和量化暴露于 超级基金化学品公司。

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants which are carcinogenic in experiment animal models. Individual PCB congeners as well as commercial PCB mixtures have been shown to be efficacious hepatic tumor promoters in two-stage hepatocarcinogenesis in rats. The biochemical mechanisms by which PCBs promote hepatic foci and tumors, however, have never been determined. Additionally, it is not known if PCB congeners act synergistically in two-stage hepatocarcinogenesis, which is important since humans are exposed to PCB mixtures. Finally, it is not known how to accurately estimate the promoting potential of PCBs which are not ligands of the Ah receptor. We therefore propose to test the hypotheses that 1)PCBs promote two-stage hepatocarcinogenesis by inducing oxidative DNA damage, increasing long-term cell proliferation, and/or altering eicosanoid metabolism; 2) the promotion index of non-Ah binding PCBs can be estimated by their ability to induce cytochrome P-450 2B1/2; and 3) PCBs act synergistically in the promotion of hepatocarcinogenesis. In the first studies, PCBs will be administered for varying periods of time, and their ability to induce 8-hydroxyguanosine, increase cell proliferation in normal hepatocytes, and alter the concentrations of prostaglandins E2 and F2alpha and other eicosanoids will be determined. In the tumor promotion studies, PCBs will be administered after diethylnitrosamine administration, and we will determine their ability to 1) induce altered hepatic foci as predicted by their 2B1/2 inducing activity and 2) act synergistically in the induction of altered hepatic foci. These studies will show how PCBs promote hepatic carcinogenesis, whether they act synergistically, and if their promoting ability can be easily predicted. This information will help in understanding and quantifying the risks for humans exposed to Superfund chemicals.