PROMOTION OF LIVER CARCINOGENESIS BY OROTIC ACID

目前的建议源于我们最近的发现，即引发老鼠 接触一种嘧啶核苷酸前体--口香酸13个月 发展为100%的肝细胞癌，并有许多肺转移。的 所考虑的许多机制是，创建改变的核苷酸池 在喂食口香酸后发生似乎很吸引人，因为这样的 状态改变可以引起基因组和细胞膜的扰动。 基因组和膜水平的改变被认为是起作用的 在肿瘤发生过程中的重要作用。 在本方案中，实验被设计用来描述北极圈 更详细的ACID模型。例如，最短的时间是多少 接触玫瑰花酸会导致肝细胞癌吗？是 在此模型中形成的增生性结节与已开发的类似 在其他型号中？由其他因素引起的核苷酸池的不平衡 手段促进肝癌的发生？哪些类型的基因组扰动 会不会是由核苷酸失衡引起的？初步实验 调查显示，除了芳香酸喂养外，胸腺嘧啶或 胸苷还促进了γ-谷氨酰转移酶的出现 1，2-二甲基肼诱导的阳性灶。在另一场预赛中 实验中观察到一种类型的DNA损伤是由进食引起的 芳香酸是诱导碱性不稳定损伤的主要原因。 这个模型的一些吸引人的特点是，冬凌草酸是一种正常的 牛奶中有相当数量的细胞成分和存在。 在一些遗传性疾病中，牛奶、血清和尿液中的玫瑰花酸增加 通过创建几个 代谢紊乱，如必需氨基酸缺乏和 尿素循环中的干扰，不幸的是，这种干扰是 在普通人群中并不少见。

The present proposal stems from our recent finding that initiated rats exposed for 13 months to orotic acid a pyrimidine nucleotide precursor developed 100% hepatocellular carcinoma with many metastases to lungs. Of the many mechanisms considered, creation of altered nucleotide pools that occurs following orotic acid feeding appears attractive because such an altered state can induce both genomic as well as membrane perturbations. Alterations at genomic and at membrane levels are considered to play important roles in tumorigenic process. In the present proposal experiments are designed to characterize the Orotic Acid Model in greater detail. For e.g. what is the minimum time of exposure to orotic acid required to develop hepatocellular carcinoma? Are the hyperplastic nodules developed in this model similar to those developed in other models? Can an imbalance of nucleotide pools caused by other means promote liver carcinogenesis? What types of genomic perturbations can be caused by an imbalance of nucleotides? Preliminary experiments carried out revealed that in addition to arotic acid feeding, thymine or thymidine also promoted the appearance of Gamma-glutamyl transferase positive foci induced by 1,2-dimethylhydrazine. In another preliminary experiment it was observed that one type of DNA damage caused by feeding arotic acid is the induction of alkali labile lesions. Some attractive features of this model are, orotic acid is a normal cellular constituent and present in the milk in considerable quantities. Increased orotic acid in milk, serum and urine occurs in some hereditary disorders and such and increase can also be achieved by creating several metabolic disturbances such as an essential amino acid deficiency and disturbances in urea cycle and unfortunately disturbances of this kind are not uncommon in human population at large.