ETHIONINE CARCINOGENESIS

乙硫氨酸致癌

• 批准号: 3164124
• 负责人: RAY COX
• 金额: $ 6.33万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-09-01 至 1986-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3164124
• 关键词: DNA repair; alkylating agents; alkylation; chemical carcinogen; chemical carcinogenesis; chemical related neoplasm /cancer; chromatin; density gradient ultracentrifugation; hepatectomy; heterochromatin; ion exchange chromatography; liver; liver neoplasms; liver regeneration; neoplasm /cancer genetics; nitrosamines; physical chemical interaction; preneoplastic state; radiotracer; scintillation spectrometry; tissue /cell culture

Ethionine, a methionine analog, is a hepatocarcinogen in the rat. One of the major metabolites of ethionine is S-adenosylethionine (AdoEth), which is an analog of S-adenosylmethionine (AdoMet). AdoEth accumulates in the hepatic tissue of rats when given acutely or chronically and has been suspected to play a major role in ethionine carcinogenesis. We plan to study the synthesis and cellular distribution of AdoMet and AdoEth in various carcinogenic models. The tissue specificity will be examined in the rat. Species differences will be studied using the rat, hamster, mouse, and guinea pig. The synthesis of AdoEth will also be examined in animals fed a choline-devoid-0.05% ethionine diet. It has also been demonstrated from our laboratory that ethionine via AdoEth inhibits DNA and protein methylases producing a hypomethylated state. DNA and protein methylation will be studied in vivo by giving [3H-methyl]-methionine, in vitro with an enzymatic assay for the methylase enzymes, and by the use of restriction endonucleases. Ethionine is not carcinogenic to the hamster, therefore a comparative study of the rat and hamster should give a better understanding of the need for hypomethylated DNA and/or protein in carcinogenesis. The overall long term objective of this work is to decipher in a stepwise manner the biochemical mechanism of chemical carcinogenesis. The immediate work involves ethionine carcinogenesis as the working model.

乙硫氨酸是一种蛋氨酸类似物，是大鼠的肝癌致癌物。其中之一 乙硫氨酸的主要代谢物是S-腺苷硫氨酸(ADOEth)，它是 是S-腺苷甲硫氨酸(ADOMet)的类似物。ADOEth累积在 急性或慢性给药时大鼠的肝组织 怀疑在乙硫氨酸致癌过程中起主要作用。我们计划 ADOMet和ADOEth的合成及细胞分布研究 各种致癌模型。组织特异性将在 那只老鼠。物种差异将用老鼠、仓鼠、 老鼠和豚鼠。ADOEth的合成也将在 动物饲喂不含胆碱-0.05%乙硫氨酸的饮食。它也一直是 从我们的实验室证明，乙硫氨酸通过ADOEth抑制DNA和 产生低甲基化状态的蛋白质甲基酶。DNA和蛋白质 甲基化将在体内进行研究，给[~3H-甲基]-蛋氨酸，在 体外用酶法检测甲基酶，并通过使用 限制性内切酶。乙硫氨酸对仓鼠没有致癌作用， 因此，对老鼠和仓鼠的比较研究应该会给出更好的 了解人类对低甲基化DNA和/或蛋白质的需求 致癌。这项工作的总体长期目标是 循序渐进地破译化学物质的生化机理 致癌。眼下的工作涉及乙硫氨酸致癌，因为 工作模式。