Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues.

Christophe Morisseau,Shizuo G Kamita,Jun Yang,Sean D Kodani,Bruce D Hammock,Kin Sing Stephen Lee

doi:10.3390/ijms22094993

Christophe Morisseau, Shizuo G Kamita + Show 4 more

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https://doi.org/10.3390/ijms22094993

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Abstract

Epoxy-fatty acids (EpFAs) are endogenous lipid mediators that have a large breadth of biological activities, including the regulation of blood pressure, inflammation, angiogenesis, and pain perception. For the past 20 years, soluble epoxide hydrolase (sEH) has been recognized as the primary enzyme for degrading EpFAs in vivo. The sEH converts EpFAs to the generally less biologically active 1,2-diols, which are quickly eliminated from the body. Thus, inhibitors of sEH are being developed as potential drug therapeutics for various diseases including neuropathic pain. Recent findings suggest that other epoxide hydrolases (EHs) such as microsomal epoxide hydrolase (mEH) and epoxide hydrolase-3 (EH3) can contribute significantly to the in vivo metabolism of EpFAs. In this study, we used two complementary approaches to probe the relative importance of sEH, mEH, and EH3 in 15 human tissue extracts: hydrolysis of 14,15-EET and 13,14-EDP using selective inhibitors and protein quantification. The sEH hydrolyzed the majority of EpFAs in all of the tissues investigated, mEH hydrolyzed a significant portion of EpFAs in several tissues, whereas no significant role in EpFAs metabolism was observed for EH3. Our findings indicate that residual mEH activity could limit the therapeutic efficacy of sEH inhibition in certain organs.

Highlights

For the past two decades, epoxy-fatty acids have emerged as important endogenous bioactive regulators of several cellular functions that have implications in numerous
A mixture of Epoxy-fatty acids (EpFAs) with various fatty acid backbones and regioisomers exists inside the cells
The pattern of hydrolysis appears to be globally similar in all of the tissues, with 13,14-EDP being the most metabolized, and represents a mixture of the profiles obtained with the recombinant soluble epoxide hydrolase (sEH) and microsomal epoxide hydrolase (mEH)

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Poly-unsaturated fatty acids (PUFA) are major structural constituents of cellular membranes, influencing their fluidity and the environment of membrane proteins. PUFAs act as a substrate reservoir for the formation of oxidized metabolites, which are bioactive lipid mediators [1,2]. The best understood of these metabolites are those produced by cyclooxygenases and lipoxygenases [3]. For the past three decades, cytochrome P450 (CYP450) metabolism has increasingly been seen as important for producing both hydroxy- and epoxy-metabolites which are highly active signaling molecules [4,5]

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