Impact of Soluble Epoxide Hydrolase and Epoxyeicosanoids on Human Health

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. 37 A nn u. R ev . P ha rm ac ol . T ox ic ol . 2 01 3. 53 :3 758 . D ow nl oa de d fr om w w w . a nn ua lr ev ie w s. or g by U ni ve rs ity o f C al if or ni a D av is o n 01 /2 3/ 14 . F or p er so na l u se o nl y. PA53CH03-Hammock ARI 5 December 2012 12:44 EpFA: epoxy-fatty acid EET: epoxyeicosatrienoic acid sEH: soluble epoxide hydrolase DiHFA: 1,2-dihydroxy-fatty acid INTRODUCTION Arachidonic acid (ARA), an ω-6, 20-carbon polyunsaturated fatty acid, is at the center of a group of metabolic pathways, collectively termed the arachidonate cascade, that produces endogenous signaling molecules regulating multiple biological processes such as inflammation (Figure 1). Metabolic pathways for ω-3 fatty acid, such as eicosapentaenoic acid and docosahexaenoic acid, parallel and compete with the better described ARA cascade. A large proportion of the world’s pharmaceuticals target these lipid chemical mediators. Existing drugs target the cyclooxygenase (COX) and lipoxygenase (LOX) pathways of the ARA cascade (1, 2), which largely biosynthesize proinflammatory mediators (Figure 1), whereas the more recently discovered cytochrome P450 branch of the cascade has not been exploited as a pharmaceutical target. The P450 pathway produces both the proinflammatory, terminally hydroxylated metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) (3) and the anti-inflammatory epoxy-fatty acids (EpFAs) such as epoxyeicosatrienoic acids (EETs) from ARA (4, 5). P450 epoxidation retains the cis geometry of most natural fatty acids; however, this geometry can isomerize, and peroxidase-dependent pathways can lead to bioactive trans epoxides (6). EETs and other EpFAs have numerous actions (4, 5). Generally, EETs are chemical mediators that move biological processes toward a homeostatic or status quo condition. For example, EETs seem to encourage the resolution of inflammation rather than prevent it, in a manner similar to that exhibited by mediators in the LOX pathway (7). EETs reduce inflammation but are also analgesic, antifibrotic, and antihypertensive, acting in both autocrine and paracrine manners (4, 5). Linoleic acid is our major dietary fat, and its metabolites—including its inflammatory diols or DiHOMEs—are known to be biologically active (Figure 1) (8). The high ω-6 composition of the American diet is of concern, but because ω-3 lipids are increasingly entering the diet as value-added products, the study of the metabolites of ω-3 lipids is also crucial. This review focuses largely on EETs and EpFAs, which encompass the isomers of EETs and the corresponding ω-3 lipids (9). The detailed biology of EET action was recently reviewed elsewhere (5). There is likely an equilibrium between the P450-derived, largely anti-inflammatory EETs and the generally proinflammatory 20-HETE, and between antiand proinflammatory pathways in general. For example, when EET levels are increased in soluble epoxide hydrolase (sEH) knockout mice, 20-HETE levels increase presumably to counterbalance the increase in EETs (10). However, many physiological and pathophysiological states, including diabetes, pregnancy, obesity, and possibly even aging, shift such equilibrium in favor of more inflammatory pathways (3). Blocking the production of 20-HETE is likely to be beneficial in many disease states, but it has not resulted in promising therapeutics. However, the inhibition of 20-HETE production in combination with the stabilization of EETs appears to be a promising approach (11). Although EETs and other EpFAs are rapidly metabolized by numerous pathways including the sEH (discussed below), EETs have exceptionally high biological activity (5), making them attractive for some therapeutic applications such as ocular inflammation and organ baths. These beneficial biological effects of EETs illustrate the potential value of EET mimics (12). The optimization of EET mimics could be simplified by receptor-based screens, but the work to date has been based on mimicking the EET structure while blocking likely routes of metabolism, such as epoxide hydrolysis (13) and β-oxidation (14). Recently, an EET analog that also inhibits sEH was used as a biological probe (15). An advantage of this approach over sEH inhibition is that EET-like activity can be delivered to tissues where natural EET production is low. EETs are metabolized by a variety of pathways (5). However, sEH, which adds water across the epoxide to give the corresponding 1,2-dihydroxy-fatty acids (DiHFAs or diols), is the dominant pathway in many tissues (4). Thus, inhibition of this pathway will likely increase the EET 38 Morisseau · Hammock A nn u. R ev . P ha rm ac ol . T ox ic ol . 2 01 3. 53 :3 758 . D ow nl oa de d fr om w w w . a nn ua lr ev ie w s. or g by U ni ve rs ity o f C al if or ni a D av is o n 01 /2 3/ 14 . F or p er so na l u se o nl y. PA53CH03-Hammock ARI 5 December 2012 12:44