Inhibition of cytosolic epoxide hydrolase by trans-3-phenylglycidols

Eric C. Dietze, Eiichi Kuwano, Josefina Casas, Bruce D. Hammock

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The inhibition of murine cytosolic epoxide hydrolase has been studied with both racemic and enantiomerically pure trans-3-phenylglycidols. These compounds are the first enantioselective, slow binding inhibitors of cytosolic epoxide hydrolase. The (2S,3S)-3-phenylglycidol enantiomer was always a better inhibitor than the (2R,3R)-enantiomer. When the I50 values of (2S,3S)- and (2R,3R)-3-(4-nitrophenyl) glycidol were compared, the (2S,3S)-enantiomer was at least a 750-fold better inhibitor (I50 = 1.6 μM) than the (2R,3R)-enantiomer (I50 = 1200 μM), and it was the most potent inhibitor tested in the 3-phenylglycidol series. If the hydroxyl group of the glycidol was masked or converted to another functionality, the potency of the inhibitor decreased and the (2S,3S)-enantiomer was not necessarily the better inhibitor. In addition, trans-3-phenylglycidols demonstrated slow binding inhibition of cytosolic epoxide hydrolase. Inhibitors without a hydroxyl group, or with a blocked hydroxyl group, were not slow binding inhibitors. These results suggested that the hydroxyl group was important in both enantioselectivity and time dependence of inhibition of cytosolic epoxide hydrolase by trans-3-phenylglycidols. The hydration pattern of (2S,3S)- and (2R,3R)-2,3-epoxy-3-(4-nitrophenyl)glycidol by cytosolic epoxide hydrolase also differed. When incorporation of [18O] from water catalyzed by cytosolic epoxide hydrolase was measured, the (2S,3S)-enantiomer gave 12% incorporation into the benzylic carbon and the (2R,3R)-enantiometer gave 40% incorporation into the benzylic carbon. Finally, trans-3-phenylglycidols were found to be poor inhibitors of microsomal epoxide hydrolase.

Original languageEnglish (US)
Pages (from-to)1163-1175
Number of pages13
JournalBiochemical Pharmacology
Volume42
Issue number6
DOIs
StatePublished - Aug 22 1991

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Epoxide Hydrolases
glycidol
Enantiomers
Hydroxyl Radical
Carbon
Enantioselectivity
phenylglycidol
Hydration
Water

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibition of cytosolic epoxide hydrolase by trans-3-phenylglycidols. / Dietze, Eric C.; Kuwano, Eiichi; Casas, Josefina; Hammock, Bruce D.

In: Biochemical Pharmacology, Vol. 42, No. 6, 22.08.1991, p. 1163-1175.

Research output: Contribution to journalArticle

Dietze, Eric C. ; Kuwano, Eiichi ; Casas, Josefina ; Hammock, Bruce D. / Inhibition of cytosolic epoxide hydrolase by trans-3-phenylglycidols. In: Biochemical Pharmacology. 1991 ; Vol. 42, No. 6. pp. 1163-1175.
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