Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health

Abstract

The presence of epoxyeicosatrienoic acids (EETs) in tissues and their metabolism by soluble epoxide hydrolase (sEH) to 1,2-diols were first reported 30 years ago. However, appreciation of their importance in cell biology and physiology has greatly accelerated over the past decade with the discovery of metabolically stable inhibitors of sEH, the commercial availability of EETs, and the development of analytical methods for the quantification of EETs and their diols. Numerous roles of EETs in regulatory biology now are clear, and the value of sEH inhibition in various animal models of disease has been demonstrated. Here, we review these results and discuss how the pharmacological stabilization of EETs and other natural epoxy-fatty acids could lead to possible disease therapies.

Figure 1

Overview of the arachidonic acid cascade emphasizing the conversion of largely anti-inflammatory epoxides to their corresponding 1,2-diols by the soluble epoxide hydrolase. Abbreviations: ARA, arachidonic acid; CoA, coenzyme A; COX, cyclooxygenase; CYP450, cytochrome P450; DHA, docosahexaenoic acid; DHET, dihydroxyeicosatrienoic acid; DiHDPE, dihydroxydocosapentaenoic acid; DiHETE, dihydroxyeicosatetraenoic acid; DiHOME, dihydroxyoctadecenoic acid; EET, epoxyeicosatrienoic acid; EPA, eicosapentaenoic acid; EpDPE, epoxydocosapentaenoic acid; EpETE, epoxyeicosatetraenoic acid; EpOME, epoxyoctadecenoic acid; HETE, hydroxyeicosatetraenoic acid; LA, linoleic acid; LOX, lipoxygenase; PLA2, phospholipase A2; sEH, soluble epoxide hydrolase.

Figure 2

Structure and commonly used acronyms of soluble epoxide hydrolase inhibitors used in biological assays, animal models of diseases, and clinical trials. References for compounds: 1 (53); 2 (55); 3–5, 7 (56); 6 (57); 8 (58); 9 (59); 10 (60); 11, 12 (61); 13 (62); and 14 (63). Abbreviations: AEPU, 1-adamantanyl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl]}urea; APAU, 1-(1-acetypiperidin-4-yl)-3-adamantanylurea; AUDA, 12-(3-adamantan-1-yl-ureido) dodecanoic acid; t-CUPM, trans-4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-cyclohexyloxy}-pyridine-2-carboxylic acid methylamide; TPPU, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea; t-TUCB, trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid.

Figure 3

(a) Role of epoxy-fatty acids (EpFAs) in inflammation. (b) Effects of soluble epoxide hydrolase inhibitors (sEHIs). Abbreviations: COX, cyclooxygenase; DiHFA, 1,2-dihydroxy-fatty acid; FA, fatty acid; IKK, IκB kinase; IL, interleukin; iNOS, inducible nitric oxide synthase; LKT, leukotriene; LOX, lipoxygenase; NF-κB, nuclear factor κB; NO, nitric oxide; PG, prostaglandin; PLA2, phospholipase A2; PPAR, peroxisome proliferator-activated receptor; sEH, soluble epoxide hydrolase; TNF-α, tumor necrosis factor-α; VCAM-1, vascular cell adhesion molecule-1.

Figure 4

(a) Effect of a soluble epoxide hydrolase inhibitor (sEHI), APAU (Figure 2, compound 3), in a lipopolysaccharide (LPS)-induced inflammatory pain model (82, 88). (b) Effect of sEHIs in a streptozocin-induced type 1 diabetes neuropathic pain model (89). APAU is compared with celecoxib (which reduces inflammatory pain) and gabapentin (which reduces neuropathic pain). Nociceptive responses were measured with a von Frey apparatus and electronic aesthesiometer before the induction of diabetes or before the injection of LPS. Rats (n = 6 per group) were treated with the tested drugs 60 min prior to 10-μg intraplantar LPS injection in the inflammatory pain model; pretreatment was not possible for the neuropathic pain model. The measurements were taken at 2 h postinjection and are reported as a percent of the pretreatment naive baseline (no pain). All compounds were formulated in PEG400 vehicle and administered by subcutaneous injection. Asterisk indicates that compared to the vehicle control, the treatment significantly reduced the pain (p < 0.01). Abbreviation: APAU, 1-(1-acetypiperidin-4-yl)-3-adamantanylurea.