PROMOTION OF LIVER CARCINOGENESIS BY OROTIC ACID

乳清酸促进肝癌发生

• 批准号: 3174750
• 负责人: DITTAKAVI S SARMA
• 金额: $ 7.72万
• 依托单位: UNIVERSITY OF TORONTO
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 1987-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3174750
• 关键词: chemical carcinogen; chemical carcinogenesis; high performance liquid chromatography; histochemistry /cytochemistry; histopathology; lipid metabolism; nucleic acid chemical synthesis; orotate; paper chromatography; peroxidation; radiotracer; thin layer chromatography; tumor promoters; ultraviolet spectrometry

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.

目前的建议源于我们最近的发现， 暴露于乳清酸嘧啶核苷酸前体13个月 发展成100%肝细胞癌，并有许多转移到肺部。 的 考虑到许多机制，改变核苷酸库的产生， 在乳清酸喂养后发生似乎是有吸引力的，因为这种 改变的状态可以诱导基因组以及膜扰动。 基因组和细胞膜水平的改变被认为是 在肿瘤发生过程中起重要作用。 在本提案中，实验的目的是表征奥罗蒂奇 Acid模型更详细。 例如，最短时间是多少 暴露于乳清酸需要发展肝细胞癌？ 是 在该模型中形成的增生结节类似于 在其他型号？ 由其他原因引起的核苷酸库的不平衡 是否意味着促进肝癌发生？ 什么类型的基因组干扰 是由核苷酸的不平衡引起的吗 初步实验 进行的研究表明，除了芳香酸喂养，胸腺嘧啶或 胸苷也促进γ-谷氨酰转移酶的出现 1，2-二甲基肼诱导的阳性灶。 在另一个初步 实验中观察到一种由摄食引起的DNA损伤， 芳酸是碱不稳定损伤的诱导物。 该模型的一些吸引人的特征是，乳清酸是正常的 细胞成分，并存在于牛奶中的相当数量。 牛奶、血清和尿液中乳清酸的增加发生在一些遗传性 也可以通过创建多个 代谢紊乱，如必需氨基酸缺乏， 尿素循环中的干扰，不幸的是， 在人类中并不罕见