EH3 (ABHD9): the first member of a new epoxide hydrolase family with high activity for fatty acid epoxides

Epoxide hydrolases are a small superfamily of enzymes important for the detoxifi cation of chemically reactive xenobiotic epoxides and for the processing of endogenous epoxides that act as signaling molecules. Here, we report the identifi cation of two human epoxide hydro- lases: EH3 and EH4. They share 45% sequence identity, thus representing a new family of mammalian epoxide hydrolases. Quantitative RT-PCR from mouse tissue indicates strongest EH3 expression in lung, skin, and upper gastroin- testinal tract. The recombinant enzyme shows a high turn- over number with 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid (EET), as well as 9,10-epoxyoctadec-11-enoic acid (leukotoxin). It is inhibited by a subclass of N,N'-disubstituted urea derivatives, including 12-(3-adamantan-1-yl-ureido)- dodecanoic acid, 1-cyclohexyl-3-dodecylurea, and 1-(1-acetylpi- peridin-4-yl)-3-(4-(trifl uoromethoxy)phenyl)urea, compounds so far believed to be selective inhibitors of mammalian soluble epoxide hydrolase (sEH). Its sensitivity to this subset of sEH inhibitors may have implications on the phar- macologic profi le of these compounds. This is particularly relevant because sEH is a potential drug target, and clinical trials are under way exploring the value of sEH inhibitors in the treatment of hypertension and diabetes type II. — Decker, M., M. Adamska, A. Cronin, F. Di Giallonardo, J. Burgener, A. Marowsky, J. R. Falck, C. Morisseau, B. D. Hammock, A. Gruzdev, D. C. Zeldin, and M. Arand. EH3 (ABHD9): the fi rst member of a new epoxide hydrolase family with high activity for fatty acid epoxides. J. Lipid Res. 2012. 53: 2038-2045.