MOLECULAR DETERMINANTS OF PEROXISOME PROLIFERATOR ACTION

过氧化物酶体增殖物引起显著的肝增殖， 肝细胞癌。至少七十 化学物质已被确定为过氧化物酶体增殖剂，包括 工业邻苯二甲酸酯增塑剂邻苯二甲酸二（2-乙基己基）酯（DEHP）， 氯苯氧乙酸除草剂、卤代烃溶剂和 一些抗高血压药。人体暴露于过氧化物酶体 增殖剂和啮齿动物致癌物DEHP是有据可查的， 广泛用于聚氯乙烯塑料的制造， 使这些材料更柔韧。过氧化物酶体的生物学效应 增殖物似乎是通过与特定的 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超家族。初步数据 表明某些过氧化物酶体增殖剂 直接结合并诱导重组体内的构象变化 小鼠PPARalpha（mPPARalpha）。朝着分子描述的目标 过氧化物酶体增殖剂的作用，这个项目的目的是测试 以下假设：（1）工业邻苯二甲酸酯类增塑剂 邻苯二甲酸二（2-乙基己基）酯及其主要代谢产物单（2- 邻苯二甲酸乙基己酯）直接与mRRAPalpha相互作用;（2）配体结合 通过mPPARalpha是一个两步过程，涉及配体识别和 随后配体结合诱导受体构象变化， 在形成一个独特的蛋白质相互作用的界面内， 受体的配体结合结构域;（3）异源二聚化， 类维生素A X受体α（RXR α）改变了构象和功能 （4）mPPARalpha配体结合域的结合; 过氧化物酶体增殖物反应元件需要预先与 RXR α;和（5）配体诱导的mPPARalpha构象变化 促进受体与不同细胞蛋白的相互作用， 用于将受体偶联到基本的转录机制上。的 该项目的长期目标是提供一个完整的了解 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。因为潜在的 广泛的人类接触，更好地了解机制 过氧化物酶体增殖物的潜在生物学效应将是 在确定这些化合物对环境造成的危害方面至关重要。 公共卫生

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.