COOXIDATION OF XENOBIOTICS BY THE PROSTAGLANDIN SYNTHETASE

前列腺素合成酶对异种生物的共氧化

• 批准号: 3898124
• 负责人: T E ELING
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3898124
• 关键词: adduct; alkylation; benzopyrenes; chemical carcinogen; chemical carcinogenesis; chemical conjugate; cytochrome P450; cytotoxicity; detoxification; environment related neoplasm /cancer; environmental toxicology; enzyme mechanism; epoxides; fluorescent dye /probe; free radicals; glutathione; glutathione transferase; heterocyclic polycyclic compound; mutagen testing; mutagens; oxidation; peroxidases; prostaglandin endoperoxide synthase; toxin metabolism

The long range goal of this project is to study the oxidation of chemicals to toxic or carcinogenic metabolites by prostaglandin H synthase (PHS) and to demonstrate the importance of this enzyme system in chemical-induced toxicity or carcinogenesis. We have shown that aromatic amine carcinogens, are metabolized to mutagens by PHS. PHS dependent oxidation occurred by a free radical mechanism and resulted in the formation of DNA adducts which can be used as in vivo markers for PHS- dependent oxidation. We have further studied the formation of amine mutagens by PHS using bacterial tester systems having different levels of acetylase activity. Our data indicate that acetylase plays an important role in the formation of free radical mutagens from aromatic amines, including bladder carcinogen such as benzidine derivatives. We have also examined the interaction between bisulfite oxidation and the carcinogen benzo[a] pyrene (BP) =7,8-diol. Enhanced epoxidation is observed but the formation of sulfonates of BP-7,8-diol are seen in the reaction of sulfur trioxide anion radical with BP-7,8-diol. We further studied peroxidase catalyzed GSH conjugate formation and showed that this reaction occurs with a number of chemicals that contain a conjugated double bond adjacent to a aromatic ring. The reaction appears to be a general mechanism for conjugate formation. We have also shown that P-450 metabolites of BP will enhance this reaction which serves as a mechanism for detoxication of carcinogens. We have also started a new study on the dealkylation of aromatic amines by peroxidases using as model compounds the calcium ion indicator Quin-2 and its analogues. Our investigation of the activation of the heterocyclic aromatic compounds by PHS has continued. Our data suggest that PHS is a versatile enzyme system that can catalyze a variety of reactions which are important in the conversion of chemicals to carcinogenic metabolites in extra hepatic tissue.

本项目的长期目标是研究 前列腺素H的有毒或致癌代谢物 合成酶（PHS），并证明这种酶系统的重要性， 化学诱导毒性或致癌作用。我们已经证明芳香族 胺致癌物，通过PHS代谢为诱变剂。PHS依赖 氧化发生的自由基机制，并导致在 DNA加合物的形成，其可用作PHS的体内标记物- 依赖性氧化我们进一步研究了胺的形成 使用具有不同水平的诱变剂的细菌测试系统， 乙酰化酶活性我们的数据表明，乙酰化酶起着重要的作用， 在由芳香胺形成自由基诱变剂中的作用， 包括膀胱致癌物如联苯胺衍生物。我们还 研究了亚硫酸氢盐氧化和致癌物质之间的相互作用， 苯并[a]芘（BP）= 7，8-二醇。观察到增强的环氧化作用，但 BP-7，8-二醇的磺酸盐的形成是在硫的反应中观察到的 三氧化物阴离子自由基与BP-7，8-二醇。我们进一步研究了过氧化物酶 催化GSH结合物的形成，并表明该反应发生 与许多含有共轭双键的化学物质相邻， 连接到芳环上。该反应似乎是一个通用的机制， 共轭形成我们还表明，BP的P-450代谢产物将 增强这一反应，这是一种解毒机制， 致癌物质。我们还开始了一项关于 用钙离子作为模型化合物的过氧化物酶催化芳香胺 指示剂Quin-2及其类似物我们对激活的调查 的杂环芳香族化合物的PHS一直在继续。我们的数据 表明PHS是一种多功能酶系统，可以催化多种 在化学物质转化为 肝外组织中的致癌代谢物。