EFFECTS OF DEHP ON LIVER

DEHP 对肝脏的影响

• 批准号: 3251446
• 负责人: Richard T. Okita
• 金额: $ 11.57万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-05-01 至 1993-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3251446
• 关键词: RNA biosynthesis; affinity chromatography; cytochrome P450; detoxification; diethylhexylphthalate; enzyme induction /repression; enzyme mechanism; fatty acid metabolism; guinea pigs; hamsters; hepatotoxin; high performance liquid chromatography; human tissue; hydrogen peroxide; hydroxylation; laboratory rabbit; laboratory rat; lipid peroxides; liver function; liver metabolism; liver pharmacology; membrane lipids; messenger RNA; microsomes; peroxidation; phospholipids; spectrometry; ultracentrifugation

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.

许多结构不同的化合物引起过氧化物酶体和内质网 啮齿类动物肝脏中的网状增生。 伴随着这种肥大的是 蛋白质浓度和酶活性的变化，包括： 微粒体脂肪酸ω-羟化酶 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。 化学物质诱导这些 细胞器被分类为过氧化物酶体增殖物，包括 氯贝特，降血脂剂，和邻苯二甲酸二乙基己酯（DEHP）， 塑料的普通添加剂，使其具有弹性。 的研究 过氧化物酶体增殖物的健康危害是重要的，除了 肝脏肥大和酶的变化，它们产生肝细胞 癌 动物物种的反应存在显着差异 过氧化物酶体增殖剂对啮齿类动物的反应最强烈。 已经 很难确定人类是否对过氧化物酶体也有反应 扩散者。 由于过氧化物酶体增殖物是由 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物 已经被提议了。 由于邻苯二甲酸酯可容易地从 塑料材料并污染它们所接触的样品 重要的是要了解它们的生物效应， 增塑剂用于食品容器、保健品、玩具， 家庭用品。 在这项拨款申请中，大鼠肝脏中的酶反应 将研究DEHP处理后的变化。 的影响 将研究脂肪酸结合蛋白对酶促反应的影响， 这种蛋白质通过DEHP处理而增加。 蛋白质的身份 将研究与DEHP结合的这种受体， 不同动物的反应。 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， 代谢过氧化氢和活性化合物及其 抑制可能是肝毒性的原因。 的抑制作用 将研究DEHP对这些酶的影响。 脂肪酸组成的变化 在DEHP给药后检测到肝微粒体， 将测定其它细胞器的脂肪酸组成。 的 ω-水解脂肪酸的细胞色素P-450的诱导， 过氧化物酶体增殖物和P-450所特有的， 将表征ω-羟基化反应。

项目成果

Cytochrome P450 3A conjugation to ubiquitin in a process distinct from classical ubiquitination pathway.

细胞色素 P450 3A 与泛素的结合过程不同于经典的泛素化途径。

• DOI: 10.1124/mol.61.4.892
• 发表时间: 2002
• 期刊: Molecular pharmacology
• 影响因子: 3.6
• 作者: Zangar,RC;Kimzey,AL;Okita,JR;Wunschel,DS;Edwards,RJ;Kim,H;Okita,RT
• 通讯作者: Okita,RT

Improved separation and immunodetection of rat cytochrome P450 4A forms in liver and kidney.

• 发表时间: 1997-08
• 期刊: Drug metabolism and disposition: the biological fate of chemicals
• 作者: J. Okita;S. Johnson;P. J. Castle;S. Dezellem;R. Okita

Oleamide Reduces Mitochondrial Dysfunction and Toxicity in Rat Cortical Slices Through the Combined Action of Cannabinoid Receptors Activation and Induction of Antioxidant Activity.

油酰胺通过大麻素受体激活和抗氧化活性诱导的联合作用，减少大鼠皮质切片的线粒体功能障碍和毒性。

• DOI: 10.1007/s12640-022-00575-7
• 发表时间: 2022
• 期刊: Neurotoxicity research
• 影响因子: 3.7
• 作者: Reyes-Soto,CarolinaY;Villaseca-Flores,Mariana;Ovalle-Noguez,EnidA;Nava-Osorio,Jade;Galván-Arzate,Sonia;Rangel-López,Edgar;Maya-López,Marisol;Retana-Márquez,Socorro;Túnez,Isaac;Tinkov,AlexeyA;Ke,Tao;Aschner,Michael;Santamaría,Ab
• 通讯作者: Santamaría,Ab

Prostaglandin-metabolizing enzymes during pregnancy: characterization of NAD(+)-dependent prostaglandin dehydrogenase, carbonyl reductase, and cytochrome P450-dependent prostaglandin omega-hydroxylase.

• DOI: 10.3109/10409239609106581
• 发表时间: 1996-04
• 期刊: Critical reviews in biochemistry and molecular biology
• 影响因子: 6.5
• 作者: R T Okita;Janice Rice Okita

Modification of lipoperoxidative effects of dichloroacetate and trichloroacetate is associated with peroxisome proliferation.

二氯乙酸盐和三氯乙酸盐的脂质过氧化作用的改变与过氧化物酶体增殖相关。

• DOI: 10.1016/0300-483x(94)02926-l
• 发表时间: 1995
• 期刊: Toxicology
• 影响因子: 4.5
• 作者: Austin,EW;Okita,JR;Okita,RT;Larson,JL;Bull,RJ
• 通讯作者: Bull,RJ