EFFECT OF ENZYME INDUCERS ON LIVER PRENEOPLASTIC LESIONS

酶诱导剂对肝脏癌前病变的影响

• 批准号: 3251676
• 负责人: David L Eaton
• 金额: $ 18.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-05-01 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3251676
• 关键词: DNA replication; acetylaminofluorene; aflatoxins; biotransformation; biphenyl compounds; carcinogenesis inhibitor; chemical binding; chemical carcinogen; chemical carcinogenesis; cocarcinogen; cytochrome P450; disease /disorder model; environment related neoplasm /cancer; enzyme induction /repression; estradiol; glucuronides; hepatectomy; hepatocellular carcinoma; hepatotoxin; hydroxylation; hyperplasia; in situ hybridization; isozymes; laboratory rat; liver disorder; microsomes; nutrition aspect of cancer; nutrition related tag; phenobarbital; preneoplastic state; testosterone; toxin metabolism; tumor promoters

Chemical carcinogenesis is a multi-step process which can be influenced by variety of exogenous and endogenous factors. Most studies examining the effects of environmental and dietary substances on the carcinogenic process have focused on changes in the first step - initiation. However, there is increasing evidence that dietary and environmental chemicals which are effective biotransformation enzyme inducers may also modify later stages of the carcinogenic process. It appears that many non-genotoxic carcinogens may act in this manner. Compared to our understanding of the role of enzyme induction in the initiation step of carcinogenesis, relatively little is known about the relationship between enzyme induction and post-initiation events such as tumor promotion and progression. It has been recognized for many years that the same enzyme system responsible for biotransformation of xenobiotics also metabolize endogenous substances, especially steroid hormones. It is also known that the intracellular concentration of a variety of endogenous hormones can substantially alter cell growth and differentiation, processes intimately involved in tumor promotion and progression. The long range objective of this study is to understand how environmental and dietary factors influence the development and progression of chemical carcinogenesis, especially "post-initiation" events such as tumor promotion and progression. The primary goal of this grant is to investigate whether there is a causal connection between the tumor promoting abilities of non-genotoxic "environmental" carcinogens and their ability to induce, or not induce, specific isoenzymes of cytochrome P-450 in different preneoplastic lesions and normal tissue. We intend to use two "short-term" altered foci / nodule models which vary in their responsiveness to induction of cytochromes P450: the widely used "Solt-Farber" model which uses DEN and AAF to induce foci and nodules (SF-HHNs), and an altered foci and nodule model produce with aflatoxin Bl. The specific aims of this study are to: I.Evaluate the mechanism(s) by which Solt-Farber nodules are stimulated to expand by short-term treatment with phenobarbital; 2. Determine whether other PBtype inducers such as 2,2',4,4'-tetrachlorobiphenyl and DDT, or 3-MC-type inducers such as 3,3',4,4'tetrachlorobiphenyl and TCDD, produce a similar dramatic expansion of SF-HHNs, and whether an inducer only acts on specific foci/nodule populations which have an altered "induction responsiveness" of specific P450s. 3. Determine: a) whether phenobarbital expansion of SF-HHN requires the presence normal levels of thyroid or sex hormones; b) whether SF-HHNs have more bound forms of hormones and/or their respective receptors; c) whether microsomal hydroxylation activities toward testosterone or estradiol, and deiodination and/or glucuronide conjugation activities toward T3 are lower in SF-HHNs than the surrounding tissue; 4. Determine the profile of alterations in specific cytochromes P-450 in SF-HHN, using immunohistology and in situ hybridization with specific antibodies and specific oligonucleotide probes.

化学致癌是一个多步骤的过程， 受各种内外因素的影响。 大多数研究 环境和饮食物质对致癌物质的影响 过程中的变化集中在第一步-启动。 然而，在这方面， 越来越多的证据表明，饮食和环境化学品 其是有效的生物转化酶诱导剂， 致癌过程的后期阶段。 似乎许多 非遗传毒性致癌物可能以这种方式起作用。 比起我们 了解酶诱导在启动步骤中的作用， 致癌作用，相对较少的是知道之间的关系， 酶诱导和启动后事件，如肿瘤促进， 进展 多年来人们已经认识到， 负责异生物质生物转化系统也代谢 内源性物质，特别是类固醇激素。 另据了解 细胞内各种内源性激素的浓度 可以显著改变细胞生长和分化， 与肿瘤的促进和发展密切相关。 远程 这项研究的目的是了解环境和饮食 影响化学工业发展和进步的因素 致癌作用，特别是“后启动”事件，如肿瘤 晋升和进步。 该补助金的主要目标是 调查肿瘤与癌症之间是否存在因果关系 促进非遗传毒性“环境”致癌物质的能力， 它们诱导或不诱导细胞色素特异性同工酶的能力 不同癌前病变和正常组织中的P-450。 我们打算 使用两种“短期”改变的病灶/结节模型， 对细胞色素P450诱导的反应：广泛使用的 使用DEN和AAF诱导病灶和结节的“Solt-Farber”模型 （SF-HHN），以及改变的病灶和结节模型产生黄曲霉毒素 Bl. 本研究的具体目的是： 通过这种方法，Solt-Farber结节被短期刺激而扩张， 苯巴比妥治疗; 2.确定是否有其他PB型诱导剂 例如2，2 ′，4，4 ′-四氯联苯和DDT，或3-MC型诱导剂，例如 如3，3 '，4，4'-四氯联苯和TCDD， SF-HHN的扩增，以及诱导剂是否仅作用于特异性 具有改变的“诱导反应性”的病灶/结节群 具体的P450 3.确定：a）苯巴比妥是否扩张 SF-HHN需要存在正常水平的甲状腺激素或性激素; B） SF-HHN是否具有更多结合形式的激素和/或它们各自的 受体; c）微粒体羟基化活性是否朝向 睾酮或雌二醇，以及脱碘和/或葡糖苷酸 SF-HHN中对T3的缀合活性低于 周围组织; 4.确定特定基因组中 SF-HHN中细胞色素P-450，使用免疫组织学和原位 特异性抗体和特异性寡核苷酸杂交 probes.