EVALUATION OF DEHP-PLASTICIZER TOXICITY MECHANISMS

增塑剂在我们的生活中扮演着重要的角色，因为它们 物理性能、低成本和广泛的应用-包括 救命的医疗应用。有几个问题需要回答 回答是为了评估他们的安全性：1)肝素- DEHP对与人类相关的大鼠的致癌性，考虑到 这些物种对DEHP的代谢有何差异？和2)是 邻苯二甲酸酯的作用与DEHP相关的毒性 部分或其他毒性较低的邻苯二甲酸酯可被替代 为了DEHP？对DEHP毒性机理的认识 而它的生物转化应该有助于回答这些问题。 邻苯二甲酸二(2-乙基己基)酯是最常用的 增塑剂，一种已知的过氧化物酶增殖剂，以及一种可疑的 致癌物质。DEHP被食物和血液从塑料中滤出 产品，因此大多数美国人可能会接触到 大量的这种物质。喂食的大鼠和小鼠 DEHP患上了肝癌。过氧化物酶体的增殖 与癌症的发展有关。 拟议研究的广泛目标是调查 DEHP的生物转化和肝毒性。具体研究 将研究DEHP在大鼠体内的代谢，重点是 细胞色素P-450介导的omega和omega-1的作用 氧化、乙醛脱氢酶氧化和过氧化物酶-β- 氧化。邻苯二甲酸二乙酯代谢与代谢的关系 将检查肝过氧化物酶体的增殖情况。中的变化 体内毒性将与体外毒性的变化有关 为了阐明导致过氧化酶体的事件 扩散。这些研究可能定义潜在的地点 进行生化干预，降低潜在的健康风险。

Plasticizers have an important role in our life due to their physical properties, low cost, and wide applications-including lifesaving medical applications. Several questions need to be answered in order to evaluate their safety: 1) Is the hepato- carcinogenicity of DEHP in rats relevant to humans, considering the differences in metabolism of DEHP by these species? and 2) Are the toxicities associated with DEHP a function of the phthalate ester moiety or could other less toxic phthalate esters be substituted for DEHP? An understanding of the mechanism of toxicity of DEHP and its biotransformation should help answer these questions. DEHP, di-(2-ethylhexyl) phthalate, is the most commonly used plasticizer, a known peroxisome proliferator, and a suspected carcinogen. DEHP is leached from plastic by food and blood products, thus most of the U.S. population may be exposed to significant concentrations of this material. Rats and mice fed DEHP developed hepato carcinomas. Peroxisome proliferation has been associated with the development of carcinomas. The broad objective of the proposed research is to investigate the biotransformation and hepatotoxicity of DEHP. Specific studies will investigate the metabolism of DEHP in the rat, with emphasis on the role of cytochrome P-450-mediated omega and omega-1 oxidation, aldehyde dehydrogenase oxidations and peroxisomal beta- oxidation. The relationship between the metabolism of DEHP and hepatic peroxisome proliferation will be examined. The changes in in vivo toxicity will be related to changes in in vitro toxicity in an effort to elucidate the events leading to peroxisome proliferation. These studies may define potential sites for biochemical intervention to reduce the potential health risk.