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: 4693293
• 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/4693293
• 关键词: acetylaminofluorene; azo compounds; benzanthracenes; benzopyrenes; 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; 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 aromatic amine carcinogen 2-aminofluorene (2-AF) is metabolized to free radical intermediates by PHS. The stable end products are azo-, nitro-fluorene and 2-aminodiffluorenylamine. 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.

该项目的长期目标是研究化学品的氧化