PROMOTION OF LIVER CARCINOGENESIS BY OROTIC ACID

乳清酸促进肝癌发生

• 批准号: 3174749
• 负责人: DITTAKAVI S SARMA
• 金额: $ 7.67万
• 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 1987-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3174749
• 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.

目前的提议源于我们最近的发现，该发现引发了老鼠 暴露于乳清酸（一种嘧啶核苷酸前体）13 个月 100% 发展为肝细胞癌，并有多处转移至肺部。 的 考虑了许多机制，创建改变的核苷酸库 乳清酸喂养后发生的情况似乎很有吸引力，因为这样的 状态的改变会引起基因组和膜的扰动。 基因组和膜水平的改变被认为发挥了作用 在肿瘤发生过程中发挥重要作用。 在本提案中，实验旨在表征 Orotic 更详细的酸模型。 例如最短时间是多少 接触乳清酸会导致肝细胞癌吗？ 是 该模型中形成的增生结节与所形成的增生结节类似 在其他型号中？ 核苷酸库失衡是否可能由其他原因引起 意味着促进肝癌发生？ 基因组扰动有哪些类型 可能是核苷酸不平衡造成的？ 初步实验 进行的研究表明，除了添加芳香酸外，还可以添加胸腺嘧啶或 胸苷还促进γ-谷氨酰转移酶的出现 1,2-二甲基肼诱导的阳性病灶。 在另一场预赛中 实验观察到，进食引起的一种 DNA 损伤 芳香酸可诱导碱不稳定病变。 该模型的一些吸引人的特点是，乳清酸是正常的 细胞成分，并在牛奶中大量存在。 乳汁、血清和尿液中乳清酸的增加发生在某些遗传性疾病中 疾病等的增加也可以通过创造几个来实现 代谢紊乱，例如必需氨基酸缺乏和 尿素循环的干扰，不幸的是这种干扰是 在广大人群中并不少见。