EFFECTS OF DEHP ON LIVER

许多结构不同的化合物会引起过氧化酶体和内质 啮齿动物肝脏网状结构的增殖。伴随着这种肥大的是 蛋白质浓度和酶活性的变化包括： 微体脂肪酸欧米伽羟基酶；过氧化氢酶；过氧体脂肪 酸性β-氧化系统；脂肪酸结合蛋白；谷胱甘肽 过氧化物酶和谷胱甘肽转移酶。导致这些变化的化学物质 细胞器被归类为过氧化物酶体增殖物，包括 降血脂药氯贝特和邻苯二甲酸二乙基己酯(DEHP) 常见的塑料添加剂，使其具有柔韧性。对中国传统文化的研究 过氧化物酶增殖物对健康的危害除了 肝脏肥大和酶的变化，它们会产生肝细胞 癌症。动物物种的反应有明显的差异 对过氧化物体增殖物与啮齿动物的反应最强。一直以来 很难确定人类是否也对过氧化物酶体有反应 扩散者。由于过氧化物酶体增殖物由 在结构上不同的化合物，很难解释 它们共同的感应特性。共同受体的概念 可作为直接诱导物的蛋白质或常见内源性产品 已经被提出了。由于邻苯二甲酸酯很容易从 塑料材料，并污染它们接触的样品 对于，了解它们的生物学效应是很重要的，因为 增塑剂用于食品容器、保健品、玩具和 家居用品。在这项拨款提案中，大鼠肝脏中的酶反应 被DEHP处理改变的那些将被研究。美国政府的影响 脂肪酸结合蛋白对酶反应的影响将被研究为 这种蛋白质被DEHP处理后增加。蛋白质的同一性 将研究与DEHP结合的受体可能解释 在动物物种中有不同的反应。DEHP治疗抑制了两种 重要的肝酶，谷胱甘肽过氧化物酶和转移酶， 过氧化氢和活性化合物的代谢及其作用 抑制可能是肝脏毒性的原因。它的抑制作用 将研究DEHP对这些酶的作用。脂肪酸组成的变化 在注射DEHP后检测到肝微粒体的数量和 其他细胞器的脂肪酸组成将被测定。这个 欧米伽脂肪酸对细胞色素P-450的诱导作用 过氧化物酶体增殖物和P-450所独有的催化各种 欧米伽-羟基化反应将被表征。

A number of structurally diverse compounds cause peroxisome and endoplasmic reticulum proliferation in rodent liver. Accompanying this hypertrophy are changes in protein concentrations and enzymatic activities including: the microsomal fatty acid omega-hydroxylase; catalase; the peroxisomal fatty acid beta-oxidation system; the fatty acid binding protein; glutathione peroxidase; and glutathione transferase. Chemicals that induce these organelles are classified as peroxisome proliferators and include clofibrate, a hypolipidemic agent, and diethylhexyl phthalate (DEHP), a common additive of plastics which gives it flexibility. The study of the health hazards of peroxisome proliferators is important for, besides the liver hypertrophy and enzyme changes, they produce hepatocellular carcinomas. There are marked differences in the response of animal species to peroxisome proliferators with rodents the most responsive. It has been difficult to ascertain whether humans also respond to peroxisome proliferators. Since peroxisome proliferators are comprised of structurally divergent compounds, it has been difficult to account for their common induction properties. The concept of a common receptor protein or common endogenous product that may act as the immediate inducer has been proposed. Since phthalate esters may readily migrate from the plastic materials and contaminate the samples that they are in contact with, it is important to understand their biological effects, as plasticizers are used in food containers, health care products, toys, and household goods. In this grant proposal, enzymatic reactions in rat liver that are altered by DEHP-treatment will be studied. The effect of the fatty acid binding protein on enzymatic reactions will be investigated as this protein is increased by DEHP-treatment. The identity of the protein that binds DEHP will be studied for this receptor may account for the different responses in animal species. DEHP-treatment inhibits two important liver enzymes, the glutathione peroxidase and transferase, that metabolize hydrogen peroxide and reactive chemical compounds and their inhibition may account for the hepatotoxicity. The inhibitory effects of DEHP on these enzymes will be studied. Changes in fatty acid composition of liver microsomes have been detected after DEHP administration and the fatty acid composition of other organelles will be determined. The induction of the cytochrome P-450 that omega-hydrolates fatty acids is unique to peroxisome proliferators and the P-450s that catalyze various omega-hydroxylation reactions will be characterized.