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: 3965314
• 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/3965314
• 关键词: acetylaminofluorene; azo compounds; benzanthracenes; benzopyrenes; biophysics; biotransformation; carbopolycyclic compound; chemical carcinogen; cyclic amine; cytochrome P450; cytotoxicity; diol; eicosanoid metabolism; environment related neoplasm /cancer; environmental toxicology; epoxides; free radicals; human tissue; lung; molecular biology; mutagen testing; neoplastic transformation; physical chemical interaction; prostaglandin endoperoxide synthase; respiratory toxin; thin layer chromatography; tissue /cell culture; toxin metabolism

The long range goal of this project is to study the oxidation of chemicals to toxic metabolites by prostaglandin synthetase (PHS) and to demonstrate the significance of this system in chemically induced toxicity or carcinogenesis. We have shown that PHS converts both polycyclic hydrocarbons and aromatic amines to mutagens as measured by bacterial tester systems. Other in vitro studies have demonstrated the formation of electrophilic metabolites that react with macromolecules. Benzo(a)pyrene-7,8-diol is metabolized to an anti-diol epoxide by PHS. We have compared PHS and NADPH-dependent metabolism in mouse skin epidermal cells. The atomatic amine carcinogen 2-aminofluorene (a-AF) is metabolized to free radical intermediates by PHS. The stable end products are azo-, nitrofluorene and 2-aminodifluorenylamine. We have studied the formation of phenolic 2-AF adducts and obtained evidence that 2-AF is oxidized to several free radicals or free radical derived products (nitrenium ion). These radicals may not only be responsible for covalent binding to DNA but also may indeed be the proximate carcinogenic and mutagenic agents. We have also studied the formation of 2-AF DNA adducts catalyzed by PHS. Several unique 2-AF-DNA adducts were detected. We have also shown that 2-napthylamine is oxidized to unique metabolites by PHS and demonstrated a free radical mechanism for the formation of styrene-GSH adducts. Our studies indicate that PHS activates chemicals to ultimate carcinogenic metabolites which may be of importance in the initiation of tumors in extrahepatic tissue. Thus PHS is an enzyme system that, like cytochrome P-450, is important in the metabolism of xenobiotics.

这个项目的长期目标是研究化学品的氧化 前列腺素合成酶（PHS）的毒性代谢产物，并证明 该系统在化学诱导毒性中的重要性， 致癌作用 我们已经表明，PHS转换多环 碳氢化合物和芳香胺致突变剂， 测试系统 其他体外研究已经证明了 与大分子反应的亲电代谢物。 苯并（a）芘-7，8-二醇通过PHS代谢为抗二醇环氧化物。 我们 比较了小鼠皮肤表皮中PHS和NADPH依赖性代谢 细胞 原子胺致癌物2-氨基芴（a-AF） 自由基中间体。 稳定的终产物是偶氮， 硝基芴和2-氨基二芴胺。 我们研究了 的酚2-AF加合物和获得的证据表明，2-AF被氧化， 几种自由基或自由基衍生产物（氮离子）。 这些自由基可能不仅负责与DNA的共价结合， 也可能是最接近的致癌和致突变剂。 我们 还研究了PHS催化的2-AF DNA加合物的形成。 检测到几种独特的2-AF-DNA加合物。 我们还表明， 2-萘胺被PHS氧化成独特的代谢物，并证明了 苯乙烯-GSH加合物形成的自由基机制。 我们 研究表明，PHS激活化学物质，最终致癌 代谢物，这可能是重要的，在启动肿瘤， 肝外组织 因此，PHS是一种酶系统， P-450在外源性物质的代谢中起重要作用。