PROMOTION OF LIVER CARCINOGENESIS BY OROTIC ACID

乳清酸促进肝癌发生

• 批准号: 2089221
• 负责人: DITTAKAVI S SARMA
• 金额: $ 10.59万
• 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 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2089221
• 关键词: DNA replication; chemical carcinogen; chemical carcinogenesis; complementary DNA; epidermal growth factor; hepatocellular carcinoma; laboratory rat; liver cells; messenger RNA; nuclear runoff assay; orotate; ribonucleotide reductase; tumor promoters

The present proposal examines the hypothesis that orotic acid induces liver tumor promotion by creating differential mito-inhibitory environment in the surrounding liver while permitting the initiated hepatocytes to respond to growth stimuli to form hepatic foci and nodules. During the past grant period, it was observed that orotic acid is mito-inhibitory to hepatocytes both in vitro and in vivo. Further, hepatic nodules appear to be relatively resistant to the mito-inhibitory effect of orotic acid. Based on these recent preliminary observations the following three specific aims are proposed. (1) To determine the site at which orotic acid exerts its mito-inhibitory effect; (2) to determine the mechanism by which hepatic nodules become resistant to the mito-inhibitory effect of orotic acid; and (3) to determine whether orotic acid induced mito-inhibitory environment when coupled with a liver cell proliferative stimulus will exert a rapid promoting effect. In the first specific aim we will determine whether ribonucleosidedliphosphate reductase (RNR) is one target site of the mito- inhibitory effect of orotic acid. The effect of orotic acid on the regulation of the activity and expression of RNR will be examined both in vitro in isolated primary hepatocytes exposed to EGF and in vivo in the liver following partial hepatectomy (PH). The inhibitory effect of orotic acid will be correlated with the imbalances in nucleotide and deoxynucleotide pools induced in hepatocytes by orotic acid. The second specific aim examines the question whether the resistance of hepatic nodules to the mito-inhibitory effects of orotic acid is due to a defect in the (i) uptake and/or metabolism of orotic acid to uridylic acid and/or (ii) due to an altered RNR i.e. less sensitive to the effects of imbalances in nucleotide/deoxynucleotide pools. Both in vitro experiments using hepatocytes from nodules and in vivo experiments using rats bearing nodules will be employed. In the third specific aim, rats will be initiated with diethylnitrosamine and subjected to orotic acid induced mito-inhibitory environment coupled with PH to determine whether such a protocol selectively and rapidly promote the growth of hepatocytes to form foci and hepatic nodules. Since nucleotide pools and RNR are normal cellular constituents, it was tempting to speculate that orotic acid model of liver tumor promotion has the potential to be extended to other organs as well.

目前的建议检验了奥罗巴酸诱导肝脏的假说。 在肿瘤细胞中创造不同的有丝分裂抑制环境促进肿瘤 包围肝脏，同时允许启动的肝细胞对 生长刺激物形成肝脏病灶和结节。在过去的拨款期间 期间，观察到冬凌草酸对肝细胞有丝分裂抑制作用。 在体外和体内都有。此外，肝脏结节似乎是 相对抵抗奥罗里酸的有丝分裂抑制作用。基座 关于最近的这些初步观察，以下三个具体目标 都被提出了。(1)确定奥罗里酸的作用部位 丝裂原抑制作用；(2)确定肝纤维化的机制。 根瘤对冬虫夏酸的有丝分裂抑制作用产生抵抗力； (3)确定冬凌草酸是否诱导有丝分裂抑制环境 当与肝细胞增殖刺激相结合时，将产生快速的 促进作用。 在第一个具体目标中，我们将确定 核糖核苷二磷酸还原酶(RNR)是核糖核苷二磷酸还原酶的靶点之一。 奥罗里酸的抑制作用。冬凌草酸对小鼠肾小球滤过率的影响 RNR活性和表达的调节将在以下两个方面进行研究 体外培养的原代肝细胞暴露于EGF和体内的 肝部分切除术(PH)后的肝脏。口臭的抑制作用 酸将与核苷酸的不平衡和 冬凌草酸致肝细胞脱氧核酸池。第二 特定目的考察肝组织的阻力是否 结节对有丝分裂抑制作用的影响是由于 (I)摄取和/或代谢口香酸为尿酸和/或 (2)由于RNR的改变，即对不平衡的影响不那么敏感 在核苷酸/脱氧核苷酸池中。这两项体外实验都使用了 结节来源的肝细胞及荷瘤大鼠的体内实验 将会被雇佣。在第三个具体目标中，老鼠将被启动 二乙基亚硝胺和口香酸诱导的有丝分裂抑制 环境与PH值的耦合，以确定这样的协议是否 选择性和快速地促进肝细胞生长，形成病灶和 肝脏结节。 由于核苷酸池和RNR是正常的细胞成分，所以 很容易推测，促进肝脏肿瘤的冬凌草酸模型 也有可能扩展到其他器官。

项目成果

Ethionine in the analysis of the possible separate roles of methionine and choline deficiencies in carcinogenesis.

乙硫氨酸用于分析甲硫氨酸和胆碱缺乏在致癌过程中可能的单独作用。

• DOI: 10.1007/978-1-4613-1835-4_21
• 发表时间: 1986
• 期刊: Advances in experimental medicine and biology
• 作者: Ghoshal,AK;Sarma,DS;Farber,E
• 通讯作者: Farber,E

In vitro and in vivo response of hepatocytes from hepatic nodules to the mitoinhibitory effects of phenobarbital.

肝结节肝细胞对苯巴比妥有丝分裂抑制作用的体外和体内反应。

• DOI: 10.1093/carcin/15.9.1963
• 发表时间: 1994
• 期刊: Carcinogenesis
• 影响因子: 4.7
• 作者: Manjeshwar,S;Laconi,E;Sheikh,A;Rao,PM;Rajalakshmi,S;Sarma,DS
• 通讯作者: Sarma,DS

Increasing the interval between initiation and the onset of exposure to orotic acid decreases its promoting effect on rat liver carcinogenesis.

增加乳清酸暴露与开始暴露之间的间隔会降低其对大鼠肝癌发生的促进作用。

• DOI: 10.1093/carcin/14.8.1701
• 发表时间: 1993
• 期刊: Carcinogenesis
• 影响因子: 4.7
• 作者: Laconi,E;Vasudevan,S;Rao,PM;Rajalakshmi,S;Pani,P;Sarma,DS
• 通讯作者: Sarma,DS

Diploid growth pattern of hepatocellular tumours induced by various carcinogenic treatments.

• DOI: 10.1093/carcin/12.2.325
• 发表时间: 1991-02
• 期刊: Carcinogenesis
• 影响因子: 4.7
• 作者: P. Schwarze;G. Sæter;D. Armstrong;R. Cameron;E. Laconi;D. Sarma;V. Préat;P. Seglen

Inhibition of DNA synthesis by phenobarbital in primary cultures of hepatocytes from normal rat liver and from hepatic nodules.

苯巴比妥对正常大鼠肝脏和肝结节肝细胞原代培养物中 DNA 合成的抑制作用。

• DOI: 10.1093/carcin/13.12.2287
• 发表时间: 1992
• 期刊: Carcinogenesis
• 影响因子: 4.7
• 作者: Manjeshwar,S;Rao,PM;Rajalakshmi,S;Sarma,DS
• 通讯作者: Sarma,DS