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.

化学癌变是一个多步过程，可以受到影响 通过各种外源和内源性因素。 大多数研究研究 环境和饮食物质对致癌性的影响 过程重点是第一步的变化 - 启动。 然而， 越来越多的证据表明饮食和环境化学品 哪些是有效的生物转化酶诱导剂也可能会修改 致癌过程的后期。 看来很多 非生物毒性致癌物可能以这种方式起作用。 与我们相比 了解酶诱导在开始步骤中的作用 致癌作用，对 酶诱导和发射后事件，例如肿瘤促进和 进展。 多年来已经认识到相同的酶 负责异种生物生物转化的系统也代谢 内源性物质，尤其是类固醇激素。 这也已知 各种内源激素的细胞内浓度 可以显着改变细胞的生长和分化，过程 密切参与肿瘤促进和进展。 远距离 这项研究的目的是了解环境和饮食 因素影响化学的发展和进展 致癌事件，尤其是肿瘤之类的“生气后”事件 促进和进展。 这笔赠款的主要目标是 调查肿瘤之间是否有因果关系 促进非生物毒性“环境”致癌能力和 它们诱导或不诱导细胞色素的特异性同工酶的能力 在不同的肿瘤病变和正常组织中的P-450。 我们打算 使用两个“短期”更改的焦点 /结节模型，它们的不同 对诱导细胞色素P450的响应：广泛使用的 使用DEN和AAF诱导焦点和结节的“ Solt-Farber”模型 （SF-HHNS），以及用黄曲霉毒素产生的焦点和结节模型改变 bl。 这项研究的具体目的是：i.对 刺激溶液 - 弗伯蛋白结节以短期扩展 用苯巴比妥治疗； 2。确定其他PBTYPE诱导剂是否 例如2,2'，4,4'-tetrachlorobiphenyl和DDT，或3-MC型诱导剂这样 AS 3,3'，4,4'tetrachlorobiphenyl和TCDD，产生类似的戏剧性 SF-HHNS的扩展以及诱导剂是否仅对特定作用 焦点/结节种群的“诱导响应能力”改变了 特定的P450。 3。确定：a）苯巴比妥扩张是否 SF-HHN需要存在正常水平的甲状腺或性激素。 b） SF-HHNS是否具有更多的荷尔蒙形式和/或它们的荷尔蒙形式 受体； c）微粒体羟基化活性是否 睾丸激素或雌二醇以及去牙剂和/或葡萄糖醛酸化合物 在SF-HHNS中，针对T3的共轭活动低于 周围的组织； 4。确定特定变化的轮廓 SF-HHN中的细胞色素P-450，使用免疫组织学和原位 与特定抗体和特定寡核苷酸的杂交 探针。