Characterization of a potent and selective inhibitor of soluble epoxide hydrolase

• Published in: The FASEB journal 2006-03, Vol.20 (4), p.A668-A668
• Main Authors: Morita, Kazuhiro, Ishimoto, Tsuyoshi, Iwahashi, Yuki, Sato, Mariko, Fujikawa, Naoto, Hirano, Hitomi, Ota, Tomomi, Muramatsu, Makoto, Miyata, Noriyuki
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.20.4.A668-c

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 IC50 values of 21.5 nM and 5.4 nM, respectively. In human liver cytosol, TUD also inhibited the conversion with IC50 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 IC50 value of 27.0 μM and it was about 500 times less potent than the IC50 for human recombinant sEH. However, TUD (10‐5M) had little or no significant effect on the activities of various enzymes and bindings for any receptors. TUD (10‐5M) 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.