MOLECULAR DETERMINANTS OF PEROXISOME PROLIFERATOR ACTION

过氧化物酶体增殖作用的分子决定因素

• 批准号: 6564406
• 负责人: MARK E LEID
• 金额: $ 17.85万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564406
• 关键词: diethylhexylphthalate; environmental toxicology; genetic transcription; nuclear magnetic resonance spectroscopy; receptor binding; receptor coupling; retinoid binding proteins; steroid hormone receptor; toxicant interaction; toxin metabolism

Peroxisome proliferators elicit marked hepatic proliferation and hepatocellular carcinoma when administered to rodents. At least seventy chemicals have been identified as peroxisome proliferators including the industrial phthalate ester plasticizer di-(2-ethylhexyl)phthalate (DEHP), chlorphenoxyacetic acid herbicides, halogenated hydrocarbon solvents and some anti-hyperlipidemic drugs. Human exposure to the peroxisome proliferating agents and rodent carcinogen DEHP is well documented as it is used extensively in the manufacture of polyvinylchloride plastics to render these materials more flexible. Biological effects of peroxisome proliferators appear to be mediated via an interaction with a specific intracellular receptor protein, peroxisome proliferator-activated receptor alpha (PPARalpha), a member of the steroid/thyroid hormone receptor superfamily of ligand-dependent transcription factors. Preliminary data have been obtained suggesting that some peroxisome proliferating agents bind directly to and induce conformational changes within recombinant mouse PPARalpha (mPPARalpha). Toward the goal of a molecular description of peroxisome proliferator action, the object of this project is to test the following hypothesis: (1) the industrial phthalate ester plasticizer di-(2-ethylhexyl)phthalate and its primary metabolite mono-(2- ethylhexyl)phthalate interact directly with mRRAPalpha; (2) ligand binding by mPPARalpha is a two-step process involving ligand recognition and a subsequent ligand binding-induced receptor conformational change resulting in the formation of a unique protein interaction interface within the ligand binding domain of the receptor; (3) heterodimerization with retinoid X receptor alpha (RXRalpha) alters the conformation and function of the mPPARalpha ligand binding domain; (4) binding of mPPARalpha to peroxisome proliferator response elements requires prior dimerization with RXRalpha; and (5) ligand-induced mPPARalpha conformational changes promotes interaction of the receptor with distinct cellular proteins that serve to couple the receptor to the basic transcriptional machinery. The long-term goal of this project is to provide a complete understanding of the role of mPPARalpha-mediated transcriptional activation in peroxisome proliferation and hepatocellular carcinoma. Because of the potential for wide-spread human exposure, a better understanding of the mechanism(s) underlying the biological effects of peroxisome proliferators will be of critical importance in determining the hazard that these compounds pose to public health.

过氧化物酶体增生剂引起的标志性肝扩散和 肝细胞癌递给啮齿动物。至少七十 化学药品已被确定为过氧化物酶体增生剂，包括 工业邻苯二甲酸酯增塑剂Di-（2-乙基己基）邻苯二甲酸酯（DEHP）， 氯氧基乙酸除草剂，卤素溶剂和 一些抗血脂药物。人类暴露于过氧化物酶体 增殖剂和啮齿动物致癌剂有充分的文献记载 广泛用于生产聚氯乙烯塑料 使这些材料更灵活。过氧化物酶体的生物学作用 扩散剂似乎是通过与特定的相互作用介导的 细胞内受体蛋白，过氧化物酶体增殖物激活受体 α（pparalpha），类固醇/甲状腺激素受体的成员 配体依赖性转录因子的超家族。初步数据 已经获得了一些过氧化物酶体增殖剂 直接结合并诱导重组内的构象变化 小鼠pParalpha（mpparalpha）。达到分子描述的目标 在过氧化物酶体增殖物动作中，该项目的目的是测试 以下假设：（1）工业邻苯二甲酸酯增塑剂 di-（2-乙基己基）邻苯二甲酸酯及其原代代谢物一单元（2-） 乙二醇直接与Mrrapalpha相互作用； （2）配体结合 Mpparalpha是一个两步的过程，涉及配体识别和 随后的配体结合诱导的受体构象变化导致 在形成独特的蛋白质相互作用接口中 受体的配体结合结构域； （3）与 类视黄素X受体α（rxralpha）改变构象和功能 mpparalpha配体结合结构域； （4）mpparalpha与 过氧化物酶体增生剂响应元素需要事先二聚 rxralpha; （5）配体诱导的mpparalpha构象变化 促进受体与不同的细胞蛋白的相互作用 将受体与基本的转录机械相结合。这 该项目的长期目标是提供对 Mpparalpha介导的转录激活在过氧化物酶体中的作用 增殖和肝细胞癌。因为有潜力 广泛的人类暴露，更好地理解机制 过氧化物酶体增殖物的生物学作用将是 确定这些化合物对 公共卫生。