STUDIES ON THE HALOGENATED AROMATIC HYDROCARBONS

卤代芳烃的研究

• 批准号: 3249616
• 负责人: ALAN P. POLAND
• 金额: $ 28.14万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-09-01 至 1991-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3249616
• 关键词: affinity chromatography; chemical carcinogen; chemical structure function; chemical synthesis; chlorine; dioxins; drug metabolism; drug receptors; enzyme induction /repression; enzyme mechanism; gas chromatography; gel electrophoresis; gene expression; halobiphenyl /halotriphenyl compound; hamsters; laboratory mouse; laboratory rat; mathematical model; phenobarbital; radioimmunoassay; radiotracer; scintillation cameras; species difference; stereochemistry; teratogens; tissue /cell culture; tritium; tumor promoters

Many organic compounds, when administered to laboratory animals, induce a number of hepatic enzyme activities. Several patterns of enzyme induction, i.e. distinctive pleiotropic responses are produced by xenobiotics, and these compounds can be classified on this basis. We are interested in three classes of xenobiotics: 1) 2,3,7,8-tetrachlorodibenzo-p-dioxins (TCDD) and related halogenated aromatic hydrocarbons; 2) phenobarbital and phenobarbital-like inducers; and 3) 2(3)-tert-butyl-4-hydroxyanisole (BHA). The induction of the microsomal monooxygenase, aryl hydrocarbon hydroxylase (AHH) activity, and other coordinately expressed enzymes, and the characteristic toxic responses of TCDD, appear to be mediated through the stereospecific binding of TCDD to a cytosol receptor, the product of the Ah locus. We plan to study the properties of this receptor, the pleiotropic responses it mediates, and how this is related to the toxicity of TCDD. We plan to characterize the phenobarbital response and compare the responses produced by a potent new phenobarbital-like agonist. Using this radiolabeled phenobarbital-like agonist, we propose to search in vitro for a binding species, that has the properties expected of the putative receptor for phenobarbital. BHA induces hepatic epoxide hydratase and glutathione-S-transferase activities. We plan to examine related compounds and establish a structure-activity relationship. We propose to screen mice for genetic polymorphism in their responses to BHA or in the structural genes expressed by this compound.

许多有机化合物，当给予实验动物时，会引起许多 肝酶活性。 酶诱导的几种模式，即 异生素产生独特的多效性反应，并且这些 化合物可以在此基础上进行分类。 我们对三门课感兴趣 外源物质：1) 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 及相关物质 卤代芳香烃； 2) 苯巴比妥和苯巴比妥样药物 诱导剂； 3)2(3)-叔丁基-4-羟基苯甲醚(BHA)。 微粒体单加氧酶、芳烃羟化酶的诱导 （AHH）活性和其他协调表达的酶，以及特征 TCDD 的毒性反应似乎是通过立体特异性介导的 TCDD 与胞质受体（Ah 基因座的产物）的结合。 我们计划 研究这种受体的特性，它介导的多效性反应， 以及这与 TCDD 的毒性有何关系。 我们计划描述苯巴比妥反应的特征并比较反应 由一种有效的新型苯巴比妥样激动剂产生。 使用这种放射性标记 苯巴比妥样激动剂，我们建议在体外寻找结合物种， 具有苯巴比妥推定受体的预期特性。 BHA 诱导肝环氧化物水合酶和谷胱甘肽-S-转移酶活性。 我们计划检查相关化合物并建立结构活性 关系。 我们建议筛选小鼠的基因多态性 对 BHA 或该化合物表达的结构基因的反应。