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Characterization of a potent and selective inhibitor of soluble epoxide hydrolase
Author(s) -
Morita Kazuhiro,
Ishimoto Tsuyoshi,
Iwahashi Yuki,
Sato Mariko,
Fujikawa Naoto,
Hirano Hitomi,
Ota Tomomi,
Muramatsu Makoto,
Miyata Noriyuki
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a668-c
Subject(s) - epoxide hydrolase 2 , epoxygenase , chemistry , epoxyeicosatrienoic acid , ic50 , microsome , arachidonic acid , epoxide hydrolase , pharmacology , biochemistry , cytochrome p450 , curcumin , enzyme , in vitro , biology
Epoxyeicosatrienoic acids (EETs) are the major arachidonic acid products of cytochrome P‐450 epoxygenase and further metabolized by soluble epoxide hydrolase (sEH) to their corresponding dihydroxyeicosatrienoic acids. EETs have a vasorelaxant activity in cerebral, coronary and renal circulations and are thought to be potential candidates for endothelium‐derived hyperpolarizing factor. Hydrolysis of EETs by sEH diminishes these biological activities. The present study characterized the inhibitory profile of Thienyl Urea Derivative (TUD), a new potent and selective inhibitor of sEH. TUD potently inhibited the conversion of 14,15‐EET and 11,12‐EET to their corresponding diols by cytosolic fraction of rat kidney with IC 50 values of 21.5 nM and 5.4 nM, respectively. In human liver cytosol, TUD also inhibited the conversion with IC 50 values of 88.3 nM and 7.5 nM, respectively. Higher concentration of TUD inhibited the conversion of cis‐stilbene oxide to trans‐stilbene dihydrodiol by human microsomal epoxide hydrolase with an IC 50 value of 27.0 μM and it was about 500 times less potent than the IC 50 for human recombinant sEH. However, TUD (10 ‐5 M) had little or no significant effect on the activities of various enzymes and bindings for any receptors. TUD (10 ‐5 M) significantly augmented the 14,15‐EET‐induced vasorelaxation in isolated rat aorta. These results indicate TUD is a potent and selective inhibitor of sEH, and may have a therapeutic potential for vascular diseases such as hypertension and cardiovascular diseases.