MOLECULAR DETERMINANTS OF PEROXISOME PROLIFERATOR ACTION

过氧化物酶体增殖物诱导显著的肝脏增殖和 当给予啮齿动物时，会导致肝细胞癌。至少70岁 化学物质已被确定为过氧化物酶增殖物，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 氯苯氧乙酸除草剂、卤代烃溶剂和 一些降血脂的药物。人类暴露在过氧化物酶体内 增殖剂和啮齿动物致癌物DEHP被很好地记录下来 广泛用于制造聚氯乙烯塑料，以 使这些材质更加灵活。过氧化酶体的生物学效应 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(PPARpha)，类固醇/甲状腺激素受体的成员 配体依赖转录因子超家族。初步数据 已经获得的结果表明，一些过氧化物酶增殖剂 直接与重组人结合并诱导其构象变化 小鼠PPARpha(MPPARpha)。朝着分子描述的目标前进 过氧化物酶体增殖物的作用，本项目的目的是测试 假设：(1)工业邻苯二甲酸酯增塑剂 邻苯二甲酸二(2-乙基己基)酯及其初级代谢物单-(2- 邻苯二甲酸乙基己酯与mRRAPalpha直接相互作用；(2)配体结合 通过mPPARpha是一个两步过程，涉及配体识别和 随后的配体结合引起的受体构象变化 在形成独特的蛋白质相互作用界面的过程中 受体的配基结合域；(3)与 维甲酸X受体α(RXRpha)改变构象和功能 MPPARpha配体结合域的结合；(4)mPPARpha与 过氧化物酶体增殖物反应元件需要预先与 和(5)配体诱导的mPPARα构象变化 促进受体与不同的细胞蛋白相互作用 用来将受体连接到基本的转录机制。这个 该项目的长期目标是提供对 MPPARα介导的转录激活在过氧化物酶体中的作用 增殖与肝细胞癌。因为有可能 广泛接触人体，更好地理解机制(S) 过氧化物酶体增殖物的生物学效应的潜在原因是 在确定这些化合物构成的危险方面至关重要 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.