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A Novel Activity of Microsomal Epoxide Hydrolase: Metabolism of the Endocannabinoid 2-arachidonoylglycerol

A Novel Activity of Microsomal Epoxide Hydrolase: Metabolism of the Endocannabinoid 2-arachidonoylglycerol

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

J Lipid Res. 2014 Oct;55(10):2093-102.

PMID: 24958911

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1622426156	Serine Hydrolase Inhibitor-10		1622426-15-6	Price

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