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 detoxification of chemically reactive xenobiotic epoxides and for the processing of endogenous epoxides that act as signaling molecules. Here, we report the identification of two human epoxide hydrolases: 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 gastrointestinal tract. The recombinant enzyme shows a high turnover 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-acetylpiperidin-4-yl)-3-(4-(trifluoromethoxy)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 pharmacologic profile 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.
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
Martina
M
Decker
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
Magdalena
M
Adamska
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
Annette
A
Cronin
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
Francesca
F
Di Giallonardo
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
Julia
J
Burgener
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
Anne
A
Marowsky
Southwestern Medical Center, University of Texas, Dallas, TX 75390.
John R
JR
Falck
Entomology and Comprehensive Cancer Research Center, University of California, Davis, CA 95616; and.
Christophe
C
Morisseau
Entomology and Comprehensive Cancer Research Center, University of California, Davis, CA 95616; and.
Bruce D
BD
Hammock
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
Artiom
A
Gruzdev
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
Darryl C
DC
Zeldin
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland. Electronic address: arand@pharma.uzh.ch.
Michael
M
Arand
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D051379:Mice; D008810:Mice, Inbred C57BL; D010802:Phylogeny; D013229:Stearic Acids / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism
D004852:Epoxy Compounds; D013229:Stearic Acids; D015262:Xenobiotics; C013519:9,10-epoxystearic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; C577760:EPHX3 protein, human; C577761:EPHX4 protein, human; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid