Study on the mechanism of the carcinogenesis of the biliary tract.

胰胆管异常愈合和胆道内存在结石或寄生虫是胆道癌的高危人群，但其癌变机制尚不清楚。由于大多数化学物质是在肝脏代谢的，因此如果被摄入，胆上皮首先直接暴露于活化的致癌物中。然而，胆道癌的发病率并没有想象的那么高。其中一个原因可能是在无病状态下，胆汁通过胆道迅速排泄到十二指肠，这使得接触致癌物的时间太短，上皮DNA没有受到损伤。在高危人群中，胆汁淤积使暴露时间长到足以造成DNA损伤。此外，胆汁淤积可通过诱导细胞变性和再生来增加胆道上皮细胞周期。我们认为细胞周期的增加增加了DNA损伤的机会。本研究采用原代胆囊上皮细胞培养/原位缺口翻译模型，研究细胞周期调节因子及细胞周期延长对DNA损伤的影响。EGF和石胆酸增加了BrdU标记的细胞，EGF和石胆酸的存在显著增强了MNNG对DNA的损伤。因此，我们的假设，即在高危人群中发生的细胞周期的增加增加了DNA损伤的机会，这必须是致癌物质的第一步，这一假设已经得到证实。目前正在研究性激素、胆固醇和/或其他胆汁酸的作用。

Anomalous pancreaticobiliary duct union and presence of stones or parasites in ttie biliary tract are well-known high risk groups of biliary tract cancers, liowever, the mechanisms of the carcinogenesis have not been elucidated. Since most of the chemicals are metabolized in the liver, biliary epithelium are firstly and directly exposed to the activated carcinogens if they are ingested. Nevertheless the incidence of the biliary tract cancer is not so high as supposed. One of the reasons may be the rapid excretion of bile through biliary tract to the duodenum in disease free state, which makes the exposure time to the carcinogens too short for the epithelial DNA to be itijured. In the high risk groups bile stasis makes the exposure time lorig enough for DNA injury. In addition bile stasis should increase the cell cycle of the biliary epithelium by induction of the cell degeneration and the regeneration. We supposed that the increase in the cell cycles makes the chance of DNA injury enhanced. In the present study we investigated the modulators of cell cycle and the effect of the increase in the cell cycle on DNA injuries by the use of primary gallbladder epithelial cell culture/ in situ nick translation model. EGF and lithocholic acid increased the BrdU labeled cells and DNA injuries by MNNG were significantly enhanced by the presence of EGF arid/or lithocholic acid. Thus our hypothesis that the increase in the cell cycle as occurred iii the high risk groups enhances the chance of DNA injury which must be the first step of carcinogenests has been verified. The roles of sex hormones, cholesterol and/or other bile acids are now on study.