Inhibition of Microsomal Epoxide Hydrolases by Ureas, Amides, and Amines

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• 作者：Christophe Morisseau ; John W. Newman ; Deanna L. Dowdy ; Marvin H. Goodrow ; and Bruce D. Hammock
• 刊名：Chemical Research in Toxicology
• 出版年：2001
• 出版时间：April 2001
• 年：2001
• 卷：14
• 期：4
• 页码：409 - 415
• 全文大小：115K
• 年卷期：v.14,no.4(April 2001)
• ISSN：1520-5010

文摘

The microsomal epoxide hydrolase (mEH) plays a significant role in the metabolism ofxenobiotics such as polyaromatic toxicants. Additionally, polymorphism studies have underlineda potential role of this enzyme in relation to several diseases, such as emphysema, spontaneousabortion, and several forms of cancer. To provide new tools for studying the function of mEH,inhibition of this enzyme was investigated. Inhibition of recombinant rat and human mEHwas achieved using primary ureas, amides, and amines. Several of these compounds are morepotent than previously published inhibitors. Elaidamide, the most potent inhibitor that isobtained, has a K_i of 70 nM for recombinant rat mEH. This compound interacts with the enzymeforming a noncovalent complex, and blocks substrate turnover through an apparent mix ofcompetitive and noncompetitive inhibition kinetics. Furthermore, in insect cell culturesexpressing rat mEH, elaidamide enhances the toxicity effects of epoxide-containing xenobiotics.These inhibitors could be valuable tools for investigating the physiological and toxicologicalroles of mEH.