8-OHDG AND A CARCINOGENIC CHOLINE-DEFICIENT DIET

8-OHDG 和致癌的胆碱缺乏饮食

• 批准号: 2098392
• 负责人: OSCAR SUDILOVSKY
• 金额: $ 20.97万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2098392
• 关键词: DNA damage; adduct; alanine transaminase; antioxidants; cell cycle; cell cycle proteins; chemical carcinogenesis; choline deficiency; chromosome deletion; cytotoxicity; deoxyguanosine; dietary control; fibrosis; free radical oxygen; gene mutation; genetic strain; hepatocellular carcinoma; immunocytochemistry; laboratory rat; necrosis; neoplasm /cancer genetics; nutrition related neoplasm /cancer; nutrition related tag; preneoplastic state; proliferating cell nuclear antigen

We have used a model of liver carcinogenesis based on feeding rats a choline deficient (CD) diet, either as an initiator or as a promoter. The method causes the appearance of cirrhosis, and since in humans 60-90% of hepatocarcinomas develop in cirrhotic livers, it may allow is to scrutinize whether there are common mechanism(s) involved in both processes. Consistent with the long-term goal of our investigations, i.e., to elucidate the mechanism(s) of liver carcinogenesis under conditions in which there is concomitant fibrosis, what have found that F344 rats given a CD diet for 24 wks show the expected formation of preneoplastic foci and in addition, an accumulation of 8- hydroxydeoxyguanosine (8-OHdG). This DNA adduct, generated by reactive oxygen species, is normally low in the liver of rats given sufficient choline. The appropriate treatment time at which it should be measured in treated animals, however, is not known. Hence, it will become imperative to evaluate the 8-OHdG content at various time of feeding the CD diet. We have fond also the F344 and both sexes of the PVG strain of rats are resistant to the development of preneoplastic markers, to cirrhosis and to changes in the values of 8-OHdG. our hypothesis is that the CD diet induces increased levels of oxygen free radical and oxidative damage, with accumulation of 8-OHdG. This, if not repaired, prompts DNA mutations and/or deletions. Along with the DNA alterations, oxidative changes result in cellular toxicity and necrosis, followed by cell proliferation and fibrosis. To support this thesis, the effect of antioxidants on 8-OhdG will be determined together with number and size of foci and of the liver fibrosis. We will measure, as well, the values of serum alanine aminotransferase and the existence of PCNA/Cycline in rat liver tissues. By estimating toxicity and cell replication in this manner, and in conjunction with the preceding variables, we will attempt to explain if toxicity and levels of 8-OHdG are coupled or separable. The identification of CD resistant strain of rats will provide the opportunity to investigate if there is a genetic basis for the phenomena observed. Consequently, we propose to do a genetic analysis in crosses of susceptible (F344) and resistant (PVG) strains. The identification of specific loci for preneoplasia will be don using the amounts of 8-OHdG and positive foci. Future experiments, if our assumptions are correct, will strive to map the change, most likely utilizing molecular biology techniques. These studies will furnish new evidence for the participation of reactive oxygen free radicals in the process of cirrhosis and initiation/promotion during rat liver hepatocarcinogenesis.

我们使用了一种基于喂养大鼠的肝癌发生模型， 胆碱缺乏（CD）饮食，作为引发剂或作为促进剂。 该方法导致肝硬化的出现，并且由于在人类中60-90% 肝癌的发展在肝硬化，它可能允许是， 审查两者是否有共同的机制 流程. 与我们调查的长期目标一致， 也就是说，阐明肝癌发生的机制， 在伴随纤维化的情况下，发现 给予CD饮食24周的F344大鼠显示预期的 癌前病灶，此外，8- 羟基脱氧鸟苷（8-OHdG）。 这种DNA加合物，由反应性 给予足够的氧自由基，大鼠肝脏中的氧自由基通常较低 胆碱 应测量的适当治疗时间 然而，在治疗的动物中，尚不清楚。 因此，它将成为 必须评估在不同时间喂养的8-OHdG含量， CD减肥法。 我们还发现了PVG株的F344和两性 的大鼠对肿瘤前标志物的发展具有抗性， 肝硬化和8-OHdG值的变化。 我们的假设是 CD饮食诱导增加的氧自由基和氧化 损伤，8-OHdG积累。 如果不修复， 突变和/或缺失。 沿着DNA的改变， 变化导致细胞毒性和坏死， 增殖和纤维化。 为了支持这一论点， 8-OhdG上的抗氧化剂将与数量和大小一起确定 病灶和肝纤维化。 我们还将衡量 血清丙氨酸氨基转移酶和PCNA/Cycline的存在， 大鼠肝组织。 通过估计毒性和细胞复制， 我们将以这种方式，并结合前面的变量， 以解释毒性和8-OHdG水平是耦合的还是可分离的。 CD耐药大鼠品系的鉴定将为CD耐药大鼠的研究提供理论依据。 有机会调查这种现象是否有遗传基础 观察 因此，我们建议在杂交中进行遗传分析， 敏感株（F344）和抗性株（PVG）。 识别 将使用8-OHdG的量来确定癌前病变的特异性位点。 积极的焦点。 如果我们的假设是正确的， 将努力绘制这种变化，最有可能的是利用分子生物学 技术. 这些研究将提供新的证据， 活性氧自由基参与的过程 肝硬化和启动/促进大鼠肝癌发生过程中。