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PMID: 22798687 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Journal of lipid research ·Vol. 53 ·No. 10 ·2012-10-00 ·Pages 2038-2045

Decker M, Adamska M, Cronin A, Di Giallonardo F, Burgener J, Marowsky A, Falck JR, Morisseau C, Hammock BD, Gruzdev A, Zeldin DC, Arand M

Abstract

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.

MeSH Terms
8,11,14-Eicosatrienoic Acid/analogs & derivatives,metabolism Animals Epoxide Hydrolases/antagonists & inhibitors,chemistry,metabolism Epoxy Compounds/metabolism Humans Inactivation, Metabolic Mice Mice, Inbred C57BL Phylogeny Stearic Acids/metabolism Xenobiotics/metabolism
Chemicals
Epoxy Compounds Stearic Acids Xenobiotics 9,10-epoxystearic acid 14,15-epoxy-5,8,11-eicosatrienoic acid EPHX3 protein, human EPHX4 protein, human Epoxide Hydrolases 8,11,14-Eicosatrienoic Acid
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Decker Martina
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
Adamska Magdalena
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
Cronin Annette
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
Di Giallonardo Francesca
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
Burgener Julia
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
Marowsky Anne
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
Falck John R
Southwestern Medical Center, University of Texas, Dallas, TX 75390.
Morisseau Christophe
Entomology and Comprehensive Cancer Research Center, University of California, Davis, CA 95616; and.
Hammock Bruce D
Entomology and Comprehensive Cancer Research Center, University of California, Davis, CA 95616; and.
Gruzdev Artiom
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
Zeldin Darryl C
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
Arand Michael
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland. Electronic address: [email protected].
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Article Info
Journal
Journal of lipid research
Abbr.
J Lipid Res
ISSN
1539-7262
DOI
10.1194/jlr.M024448
Email
[email protected]
Published
2012-10-00
Epub
2012-00-12
Pages
2038-2045
Language
English
Region
United States
NLM ID
0376606
PMCID
PMC3435537
Subset
IM
Grants
NIGMS NIH HHS · GM-31278 · United States
NHLBI NIH HHS · R01 HL059699 · United States
NIDDK NIH HHS · P01 DK038226 · United States
NIGMS NIH HHS · R01 GM031278 · United States
NHLBI NIH HHS · R01-HL-059699 · United States
NIEHS NIH HHS · R01-ES-002710 · United States
NIEHS NIH HHS · R01 ES002710 · United States
External Links
PubMed source DOI: 10.1194/jlr.M024448 PMC Full Text View journal details
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