A novel activity of microsomal epoxide hydrolase: Metabolism of the endocannabinoid 2-arachidonoylglycerol

Kasem Nithipatikom, Michael P. Endsley, Adam W. Pfeiffer, J R Falck, William B. Campbell

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Microsomal epoxide hydrolase (EPHX1, EC 3.3.2.9) is a highly abundant α/β-hydrolase enzyme that is known for its catalytical epoxide hydrolase activity. A wide range of EPHX1 functions have been demonstrated including xenobiotic metabolism; however, characterization of its endogenous substrates is limited. In this study, we present evidence that EPHX1 metabolizes the abundant endocannabinoid 2-arachidonoylglycerol (2-AG) to free arachidonic acid (AA) and glycerol. The EPHX1 metabolism of 2-AG was demonstrated using commercially available EPHX1 microsomes as well as PC-3 cells overexpressing EPHX1. Conversely, EPHX1 siRNA markedly reduced the EPHX1 expression and 2-AG metabolism in HepG2 cells and LNCaP cells. A selective EPHX1 inhibitor, 10-hydroxystearamide, inhibited 2-AG metabolism and hydrolysis of a well-known EPHX1 substrate, cis-stilbene oxide. Among the inhibitors studied, a serine hydrolase inhibitor, methoxy-arachidonyl fluorophosphate, was the most potent inhibitor of 2-AG metabolism by EPHX1 microsomes. These results demonstrate that 2-AG is an endogenous substrate for EPHX1, a potential role of EPHX1 in the endocannabinoid signaling and a new AA biosynthetic pathway.

Original languageEnglish (US)
Pages (from-to)2093-2102
Number of pages10
JournalJournal of Lipid Research
Volume55
Issue number10
DOIs
StatePublished - Oct 1 2014

Fingerprint

Epoxide Hydrolases
Endocannabinoids
Metabolism
fluorophosphate
Hydrolases
Microsomes
Arachidonic Acid
Substrates
Biosynthetic Pathways
Hep G2 Cells
Xenobiotics
Glycerol
Serine
Small Interfering RNA
2-arachidonylglycerol
Hydrolysis
Enzymes

Keywords

  • Anandamide
  • Arachidonic acid
  • Prostate carcinoma cells

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

A novel activity of microsomal epoxide hydrolase : Metabolism of the endocannabinoid 2-arachidonoylglycerol. / Nithipatikom, Kasem; Endsley, Michael P.; Pfeiffer, Adam W.; Falck, J R; Campbell, William B.

In: Journal of Lipid Research, Vol. 55, No. 10, 01.10.2014, p. 2093-2102.

Research output: Contribution to journalArticle

Nithipatikom, Kasem ; Endsley, Michael P. ; Pfeiffer, Adam W. ; Falck, J R ; Campbell, William B. / A novel activity of microsomal epoxide hydrolase : Metabolism of the endocannabinoid 2-arachidonoylglycerol. In: Journal of Lipid Research. 2014 ; Vol. 55, No. 10. pp. 2093-2102.
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