Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs)

doi:10.1016/j.prostaglandins.2006.05.004

Prostaglandins & Other Lipid Mediators

Volume 82, Issues 1–4, January 2007, Pages 42-49

https://doi.org/10.1016/j.prostaglandins.2006.05.004 Get rights and content

Abstract

Early on, intriguing biological activities were found associated with the EETs using in vitro systems. Although the EETs other than the 5,6-isomer, are quite stable chemically, they are quickly degraded enzymatically with the sEH accounting in many cases for much of the metabolism. This rapid degradation often made it difficult to associate biological effects with the administration of EETs and other lipid epoxides particularly in vivo. Thus, it is the power to inhibit the sEH that has facilitated the demonstration of many physiological processes associated with EETs and possibly other epoxy fatty acids. In the last few years it has become clear that major roles of the EETs include modulation of blood pressure and modulation of inflammatory cascades. There are a number of other physiological functions now associated with the EETs including angiogenesis, neurohormone release, cell proliferation, G protein signaling, modulation of ion channel activity, and a variety of effects associated with modulation of NFκB. More recently we observed a role of the EETs as modulated by sEHI in reducing non-neuropathic pain. The array of biological effects observed with sEHI illustrates the power of modulating the degradation of chemical mediators in addition to the modulation of their biosynthesis, receptor binding and signal transduction. Many of these biological effects can be modulated by sEHIs but also by the natural eicosanoids and their mimics all of which offer therapeutic potential.

Introduction

Over the last few years, the epoxides of arachidonic acid or epoxyeicosatrienoic acids (EETs) have been established as lipid mediators with important biological functions [1]. There are a variety of pathways involved in the degradation of these chemical mediators, but hydration of the epoxide to the corresponding 1,2-diols appears to be the major pathway [1], [2]. Interestingly the enzyme that carries out this reaction was first found while studying the metabolism of a terpenoid epoxide that mimicked the insect juvenile hormone [3]. The enzyme was termed cytosolic and later soluble epoxide hydrolase (sEH) because of its localization in the soluble (and peroxisomal) fractions of the cell [4], [5]. The human sEH is the product of EPXH-2, a single copy gene presents on chromosome 8 [6], [7]. Although multiple epoxide hydrolase enzymes are present in all living organisms [8], the human sEH is the subject of intense research due to emerging roles of its substrates in inflammation and hypertension [9], [10].

Section snippets

Structure and function of sEH

Following partial purification of the enzyme [11], [12] its substrate selectivity was examined. Unlike the better studied microsomal epoxide hydrolase the sEH hydrolyzed epoxides on acyclic systems. Although the sEH hydrated trisubstituted terpenoid epoxides with a low K_m, it showed the highest k_CAT for cis-1,2 disubstituted compounds [13]. However, both saturated and unsaturated fatty acid epoxides are excellent sEH substrates, especially the EETs [2], [12], [14], [15]. In the intervening 30

Novel aspects of sEH function: pain and inflammation

Because EETs and other lipid epoxides [15], [31] appear to be major chemical mediators we developed GLC–MS methods for their analysis [32]. With the availability of LC–MS technology we began to add a number of other analytes in the arachidonic acid cascade to our method [9], [33]. As expected, we observed that high level of sEH decreases EETs levels while increasing the corresponding diols, DHETs [25]. Analogously inhibiting sEH increases the epoxide to diol ratio in several animal models [9],

Synergistic interactions in the arachidonic acid cascade

Another surprising implication of the metabolic profiling was that the analgesic effect of inhibiting sEH correlated with decreased induction of COX-2 without affecting COX-1. Further work has shown that COX inhibitors can increase EETs concentrations and that a combination of these therapeutics can have an improved analgesic effect. COX inhibitors increase EETs levels dramatically enough that it is likely that at least some of the analgesic effects of non-steroidal anti-inflammatory drugs

EETs and receptors

Despite the fact that no specific EET receptor has yet been characterized, several studies suggest there are both intracellular and membrane bound EET high affinity binding sites [1]. Interestingly, when EETs were exogenously applied (100–300 mg/kg) to male rats, the animals displayed a unique set of behaviors including a short period of increased activity, exploratory behavior, grooming and chewing. In pursuit of a better understanding of the observed analgesic effects and other behavior we

Conclusion

The concepts presented here may have broader implication, with regard to both maintaining health and treating disease. Currently, over 15% of the world's pharmaceuticals influence the arachidonic acid cascade, and many of the key enzymes in the biosynthesis and degradation of lipid chemical mediators are major targets of the pharmaceutical industry. Thus any discussion of the arachidonic acid cascade is quite general. This cascade has been exploited for therapy for many years in terms of single

Acknowledgments

This work was supported by NIEHS Grant R37 ES02710, NIEHS Superfund Basic Research Program Grant P42 ES04699, NIEHS Center, P30 ES05707, NIEHS Center for Children's Environmental Health and Disease Prevention Grant P01 ES11269, and UCDMC Translational Technology Research Grant.

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ReviewSoluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs)

Abstract

Introduction

Section snippets

Structure and function of sEH

Novel aspects of sEH function: pain and inflammation

Synergistic interactions in the arachidonic acid cascade

EETs and receptors

Conclusion

Acknowledgments

Progress Lipid Res

Arch Biochem Biophys

Biochem Pharmacol

FEBS Lett

Arch Biochem Biophys

Biochem Biophys Res Commun

Prog Lipid Res

Comp Biochem Physiol

Biochem Biophys Res Commun

Anal Biochem

Arch Biochem Biophys

J Biol Chem

J Biol Chem

J Biol Chem

J Chromatogr A

J Lipid Res

Joint Bone Spine

Life Sci

Neuroscience

Mammalian metabolism and environmental degradation of the juvenoid 1-(4′-ethylphenoxy)-3,7-dimethyl-6,7-epoxy-trans-2-octene and related compounds

J Agric Food Chem

Soluble epoxide hyrolase is a therapeutic target for acute inflammation

Proc Natl Acad Sci USA

Review
Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs)