Inhibition of microsomal epoxide hydrolases by ureas, amides, and amines

Christophe Morisseau, John W. Newman, Deanna L. Dowdy, Marvin H. Goodrow, Bruce D. Hammock

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46 Scopus citations

Abstract

The microsomal epoxide hydrolase (mEH) plays a significant role in the metabolism of xenobiotics such as polyaromatic toxicants. Additionally, polymorphism studies have underlined a potential role of this enzyme in relation to several diseases, such as emphysema, spontaneous abortion, 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 mEH was achieved using primary ureas, amides, and amines. Several of these compounds are more potent than previously published inhibitors. Elaidamide, the most potent inhibitor that is obtained, has a Ki of 70 nM for recombinant rat mEH. This compound interacts with the enzyme forming a noncovalent complex, and blocks substrate turnover through an apparent mix of competitive and noncompetitive inhibition kinetics. Furthermore, in insect cell cultures expressing rat mEH, elaidamide enhances the toxicity effects of epoxide-containing xenobiotics. These inhibitors could be valuable tools for investigating the physiological and toxicological roles of mEH.

Original languageEnglish (US)
Pages (from-to)409-415
Number of pages7
JournalChemical Research in Toxicology
Volume14
Issue number4
DOIs
StatePublished - 2001

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ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Morisseau, C., Newman, J. W., Dowdy, D. L., Goodrow, M. H., & Hammock, B. D. (2001). Inhibition of microsomal epoxide hydrolases by ureas, amides, and amines. Chemical Research in Toxicology, 14(4), 409-415. https://doi.org/10.1021/tx0001732