ENZYME INDUCERS EFFECT ON LIVER PRENEOPLASTIC LESIONS

化学致癌是一个多步骤的过程，可以受到影响。 受各种外生和内生因素的影响。大多数研究都在检查 环境和饮食物质对致癌物质的影响 进程的重点是第一步的变化--启动。然而， 越来越多的证据表明，饮食和环境化学物质 它们是有效的生物转化酶诱导剂，也可以改变 致癌过程的后期阶段。似乎有很多人 非遗传毒性致癌物可能会以这种方式起作用。与我们的 对酶诱导在启动过程中作用的认识 致癌方面，人们对两者之间的关系知之甚少 酶诱导和启动后事件，如肿瘤促进和 进步。多年来，人们已经认识到，相同的酶 负责外源物质生物转化的系统也会代谢 内源性物质，尤指类固醇激素。它也是众所周知的 细胞内各种内源性激素的浓度 可以显著改变细胞的生长和分化、过程 密切参与肿瘤的促进和进展。长距离的 这项研究的目的是了解环境和饮食 影响化学品发展和进步的因素 致癌，尤其是“启动后”事件，如肿瘤 晋升和进步。这笔赠款的主要目标是 调查肿瘤之间是否存在因果关系 无遗传毒性的“环境”致癌物和 它们诱导或不诱导特定的细胞色素同工酶的能力 P-450在不同癌前病变和正常组织中的表达。我们打算 使用两种不同的“短期”改变的病灶/结节模型 广泛使用的细胞色素P450的诱导反应性 利用DEN和AAF诱导病灶和结节的“Solt-Farber”模型 (SF-HHNS)，以及黄曲霉毒素引起的改变的病灶和结节模型 BL.本研究的具体目的是：一、评价机制(S) 通过短期刺激Solt-Farber结核扩张的方式 用苯巴比妥治疗；2.确定其他PB型诱导剂 例如2，2‘，4，4’-四氯联苯和DDT，或3-MC型诱导剂 作为3，3‘，4，4’四氯联苯和TCDD，产生类似的戏剧性 SF-HHN的扩展，以及诱导物是否只作用于特定的 “诱导反应性”改变的病灶/结节群体 特定的P450。3.确定：a)苯巴比妥膨胀是否 SF-HHN要求甲状腺或性激素水平正常；b) SF-HHN是否有更多的激素结合形式和/或其各自 受体；c)微粒体羟化活性是否 睾酮或雌二醇、脱碘和/或葡萄糖醛酸苷 SF-HHN对T3的结合活性低于SF-HHN 周围组织；4.确定具体的改变的轮廓 细胞色素P-450在SF-HHN中的免疫组织化学和原位研究 特异性抗体与特异性寡核苷酸的杂交 探测器。

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.