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Israel Journal of Veterinary Medicine  Vol. 69 (2)  June 2014 55 Soluble Epoxide Hydrolase Inhibitors
INTRODUCTION
Pets are treated as members of the family and pet owners de-
mand the same level of care they expect for themselves. Tis
change in attitude has led to a rapid evolution in the feld of
pharmacology with a trend towards the development of more
efective and innovative veterinary therapies with higher po-
tency, more rapid speed of action and fewer side efects (1).
Treatment of pain and infammation are important con-
siderations in human medicine. Likewise, in veterinary medi-
cine in recent years, pain has been shown to dramatically af-
fect animal welfare and production, and interest in the feld
of analgesia is increasing (2). Furthermore, veterinary phar-
macology still has a limited drug armamentarium and hu-
man drugs are increasingly being investigated for veterinary
use. It has only been in recent years that analgesics have been
marketed exclusively for veterinary patients. Terefore, it is
pivotal that new human drugs and therapies be tested also
in veterinary species (1).
Te two main classes of drugs used to reduce pain in ani-
mals are opioids and nonsteriodal anti-infammatory drugs
(NSAIDs). Recently, some of the novel molecules in these
classes marketed for the human feld have been successfully
tested on veterinary species (3-5). In the last few years, many
researchers have directed attention towards arachidonic acid
(AA) metabolism and in particular, to the cytochrome P450
(CYP450) enzymes. Tese have been referred to as the third
pathway of AA metabolism, in addition to cyclooxygenases
(COX) and lipoxygenases (LOX) (6).
All AA metabolites, which encompass the prostanoids,
leukotrienes and epoxy fatty acids (Figure 1), are bioactive
lipids that play a positive or negative role in infammation
and pain, specifcally under pathological conditions. Te al-
logeneic and pro-infammatory prostanoids and leukotrienes
drive and maintain infammation, while the anti-infamma-
tory and analgesic epoxy fatty acids epoxyeicosatrienoic acids
(EETs) reduce and resolve infammation (7).
Soluble Epoxide Hydrolase Inhibitors: New Molecules with Potential
for Use in Veterinary Medicine
Lee, H.K.,
1§
De Vito, V.
2§
and Giorgi, M.
2
*
1
College of Veterinary Medicine, Chungnam National University, Daejeon, South Korea.
2
Department of Veterinary Sciences, University of Pisa, Via Livornese (lato monte) 56122, San Piero a Grado, Pisa, Italy.
§
Tese authors equally contributed to the study.
* Corresponding Author: M. Giorgi ChemD MsPharmacol. Tel: +39 (0)50 2210154. Email: mario.giorgi@unipi.it.
ABSTRACT
Treatments for infammation and pain are important consideration in human and veterinary medicine. Te
classical drugs for treatments of infammation and pain act by inhibition of cyclooxygenase and lypoxygenase
pathways. However, there is still a need to develop new veterinary drugs and trials to apply human drugs
to the veterinary feld in order to increase the veterinary drug armamentarium. However, it is pivotal to
experimentally test human drugs and therapies in veterinary species before veterinary clinical applications.
Te soluble epoxide hydrolase inhibitors (sEHIs), are novel active ingredients shown to have a number of
benefcial efects. Tis has been especially demonstrated in many animal models in relation to infammation
and pain. Te present review reports the state of the art of soluble epoxide hydrolase inhibitors and suggests
their potential use in veterinary medicine.
Keywords: Soluble epoxide hydrolase, epoxyeicosatrienoic acids, infammation, pain.
Review Articles
Israel Journal of Veterinary Medicine  Vol. 69 (2)  June 2014 Lee, H.K. 56
Compared to the well-recognized products of the COX
and LOX branches of the AA cascade, the EETs gener-
ated by CYPs were only discovered in the early 1980s (7).
EETs have various benefcial biological efects: not only
do they have anti-infammatory and analgesic actions but
they also have protective efects on the cardiovascular sys-
tem and kidney as recently reported in the literature (8-19)
(Table 1).
Table 1: Functions of EETs
Functions References
Efect on sodium ion channel 8
Increases in intracellular Ca
2+
9
Activation of K
ATP
ion channel
10
Ca
2+
signalling 11, 12
Activation of BK
Ca
ion channel
13
Myocardiocyte contraction 14
Efect on heart ischemia 15
Inhibition of PGE2 16
Inhibition of IκB kinase (IKK) 17
Mitogenesis 18
Fibrinolysis 19
EETs are metabolized by various pathways, however the
main pathway of their metabolism is through conversion
to the corresponding 1,2 diols (dihydroxyeicosatrienoates,
DHETs), has a less bioactive molecular structure that is char-
acterized by a pro-infammatory action.
Te enzyme that carries out this reaction is the soluble ep-
oxide hydrolase (sEH), and its inhibition could stabilize EET
levels with expected benefcial biological efects (Figure 1).
Te purposes of this review are: 1) to report the current
status of preclinical studies on drugs inhibiting the soluble
epoxide hydrolases (sEH) enzyme; 2) to evaluate the use of
these novel active ingredients in veterinary medicine so that
they can be used in the near future, thus increasing the vet-
erinary drug inventory.
ARACHIDONIC ACID CASCADE
AND CYP450 PATHWAY
Figure 1 shows the arachidonic acid cascade and its metabo-
lism to eicosanoid mediators via three pathways, namely the
COX, LOX and CYP450 pathways. CYP enzymes, which
are mainly expressed in the liver, gut and kidney, are responsi-
ble for the metabolism of xenobiotics and many pharmaceu-
ticals, but they also utilize endogenous compounds as sub-
strates, such as cholesterol and fatty acids (6). Arachidonic
acid, as shown the Figure 2, is not the only endogenous CYP
substrate. CYP enzymes are also able to generate epoxides
from n-6 fatty acids, linoleic acid and n-3 fatty acids, eicosa-
pentaenoic acid (EPA) and docosahexaenoic acid (DHA).
Biological activity has been attributed to almost all of these
CYP derivatives, however, the specifc enzymes involved
in the conversion of linoleic acid, EPA, and DHA are less
well studied than those that metabolize AA (6).Via unique
mechanisms, CYP450 metabolises EETs by incorporating
them into phospholipids, chain shortening, chain elongation,
hydroxylation and other pathways, however, the dominant
pathway is the hydration of the epoxides to the correspond-
ing 1,2-diols by soluble epoxide hydrolases (sEH) (20). sEH
is a member of the epoxide hydrolases class which, in turn
belongs to a sub-category of a broad group of hydrolytic en-
zymes that include esterases, proteases, dehalogenases and
lipases (21).
In mammalian species, there are at least fve epoxide
hydrolase forms characterized by two diferent domains:
N-terminal and C-terminal. Te biological role of these do-
mains is not yet well known but the C-terminal domain is an
α/β hydrolase fold structure and is responsible for the epoxide
hydrolase activity that catalyzes the hydration of chemically
reactive epoxides to their corresponding diol products (21).
In conclusion, EETs have an important role especially in
vascular, renal, and cardiac systems and modulated gene ex-
pression. Tey also induce vasorelaxation which likewise, has
anti-infammatory efects (22), but they are quickly metabo-
lize by the sEH enzyme into corresponding less bioactive di-
ols (20), reducing the benefcial efects of EETs. Terefore,
the addition of sEH could be an efcient way to increase
EET levels and to maintain their benefcial efects.
THE BIOLOGICAL EFFECTS OF SEHIS
As mentioned above, increasing EETs by sEHIs maintains
their benefcial autocrine and paracrine efects. A number of
studies concerning sEHIs have been carried out in diferent
animal models (Table 2) to confrm this efect. sEHIs could
be useful in the treatment of hypertension, atherosclerosis,
pulmonary diseases, infammation, and pain. However, the
most studied and attractive targets are related to the treat-
ment of infammation, pain and cardiovascular diseases.
Review Article
Israel Journal of Veterinary Medicine  Vol. 69 (2)  June 2014 57 Soluble Epoxide Hydrolase Inhibitors
Figure 2: Endogenous CYP
substrate arachidonic acid,
linoleic acid, eicosapentae-
noic acid (EPA) and docosa-
hexaenoic acid (DHA), their
epoxydation by converting
into epoxyeicosatrienoic acid
(EET), epoxyoctadecenoic
acid (EpOME), epoxyeicosa-
tetraenoic acid (EEQ), epoxy-
docosapentaenoic acid (EDP),
and metabolism of epoxides
generated to the correspond-
ing diols, by the epoxide hy-
drolase (sEH), dihidroxye-
icosatrienoic acid (DHET),
dihydroxyoctadecenoic acid
(DiHOME), dihidroxyeicosa-
tetraenoic acid (DHEQ) and
dihydroxydocosapentaenoic
acid (DHDP).
Figure 1: Arachidonic acid
cascade and its major path-
ways metabolism. Arachidonic
acid is metabolized by cyclo-
oxygenase (COX) and lipox-
ygenase (LOX) enzymes into
predominantly pro-infam-
matory metabolites which are
prostanoids and leukotrienes,
respectively. Te third path-
way involves the cytochrome
P450 enzymes that metabolize
arachidonic acid into anti-in-
fammatory metabolites epoxy
eicosatrienoic acid (EETs).
EETs are rapidly metabo-
lized by the epoxide hydrolase
(sEH) to their corresponding
diols dihydroxyeicosatrienoic
acids (DHETs). sEH inhibi-
tors (sEHI) block this degra-
dation and stabilize EET lev-
els while reducing DHETs.
Review Article
Israel Journal of Veterinary Medicine  Vol. 69 (2)  June 2014 Lee, H.K. 58
Table 2: Various pharmacological efects of sEHIs
Pharmacological Efects Species References
Anti-hypertensive efect Mouse 26
Rat 27, 28
Myocardial protective efect Mouse 46, 47
Anti-atherosclerosis efect Mouse 48
Pulmonary vasoconstrictive efect Mouse 33
Renal vasodilatory efect Rat 49
Anti-infammatory efect Mouse 35, 38
Rat 39, 43
Analgesic efect Rat 43, 50
Horse 45
Several sEHIs have been widely used and evaluated for
their biological efects in animal models. Te frst sEHIs
discovered were substituted chalcone oxides: these demon-
strated low efcacies in vivo (23). When the newer urea-
and carbamate-based compounds were discovered, they
showed a better metabolic stability and safety profle than
their predecessors (24). However, none of these compounds
have been launched on the market as yet, as a thorough
evaluation of their therapeutic efectiveness and safety pro-
fle is lacking.
Cardiovascular efects
Vasodilation is a one of the major biological efects of the
EETs (25). A number of investigators have demonstrated
that sEHIs could be used to improve hypertension. Tese
active ingredients have been shown to reduce hypertension
in many animal models, with an efcacy similar to angio-
tensin II (26), deoxycorticosterone (27), salt and high fat
diet (28). It has been reported that sEHIs reduce pulmonary
vascular remodeling and delay pulmonary hypertension in
monocrotaline induced pulmonary hypertension in rats (25).
Imig et al. (29) demonstrated that the sEHI drug NCND
(N-cyclohexyl-N-dodecyl urea) reduced arterial blood pres-
sure in angiotensin II hypertensive animals. Moreover, other
works showed protective efects of sEHIs against cardiovas-
cular diseases. It has been reported that EETs reduce adverse
efects of stress on mitochondrial potassium channels (30).
Wang et al. (31) suggested that sEHIs showed a potential
therapeutic efect in the treatment of atherosclerosis. Te
reduction of low-density lipoprotein and elevation of high
density lipoprotein cholesterols were correlated with the an-
ti-atherosclerotic efects of sEHI. In wild-type mice, sEHI
(AUDA-BE, (12-(3-adamantan-1-yl-ureido)-dodecanoic
acid butyl ester)) reduced infarct size after regional myocar-
dial ischemia-reperfusion injury in vivo (32) while Xu et al.
(33), showed that sEHIs reversed cardiac hypertrophy using
a murine model of pressure induced cardiac hypertrophy.
Anti-infammatory efect
sEHIs appear to exert their anti-infammatory efect through
stabilization of EET levels. A number of investigators have
demonstrated that EETs reduce infammation. Node et al.
(17) demonstrated that physiological concentrations of EETs
or overexpression of CYP2J2 decreased cytokine-induced
endothelial cell adhesion molecule expression, and EETs pre-
vented leukocyte adhesion to the vascular wall by a mecha-
nism involving inhibition of transcription factor NF-κB and
IκB kinase (IKK). NF-κB plays a key role in cytokine medi-
ated infammation and could be inactive while bound to IκB.
Tus, sEHIs indirectly maintain NF-κB in the inactive state
correlated with inhibition of IKK. Furthermore, inhibition of
sEH enzymes led to increased anti-infammatory properties
related to regulation of cytokines (17).
Several studies have evaluated the anti-infammatory ef-
fect of sEHIs in diferent infammatory disease models. Te
endotoxin-induced model is a common form of the septi-
cemic model (34); lipopolysaccharide (LPS), also known as
endotoxin, is the primary Gram-negative bacteria surface an-
tigen which causes a number of pathophysiological changes
associated with eliciting immunologic responses including
leukocyte activation, cytokine production and enhanced pro-
infammatory gene expression. In the LPS induced infam-
mation model in mice, the sEHI (AUDA-BE, (2-(3-ada-
mantan-1-yl-ureido)-dodecanoic acid butyl ester)) decreased
the production of nitric oxide metabolites and pro-infam-
matory cytokines and prevented mortality (35). In another
study, the sEHI (t-AUCB) signifcantly reduced plasma lev-
els of pro-infammatory cytokines such as TNF-α and IL-6
at 24 h after treatment in the LPS-treated murine model
(36).
As mentioned above, EETs are converted to DHETs cor-
responding diols, and the blockage of this conversion by sE-
HIs has an important role in reducing infammation. LPS,
in particular increases the conversion into diols, decreasing
the ratio of epoxides to diols. Blood epoxide and diol lev-
els in normal animals treated with sEHIs are lower than
those in infammatory animals (37). Tis was clearly shown
Review Article
Israel Journal of Veterinary Medicine  Vol. 69 (2)  June 2014 59 Soluble Epoxide Hydrolase Inhibitors
by Liu et al. (38) in LPS-treated mice where sEHIs such as
AUDA-BE, signifcantly reduced the production of diols
and increased the ratio of epoxides to diols. Tus, sEHIs have
been shown to have therapeutic efcacy in the treatment of
endotoxin induced infammation.
Moreover, in tobacco smoke-exposed rats, the sEHIs
(AUDA-nBE, AUDA n-butyl ester) facilitated a decrease
in bronchoalveolar infammatory cells, including signifcant
reductions in alveolar macrophages, neutrophils, and lym-
phocytes (39). Additionally, co-administration with EETs
further reduced the number of bronchoalveolar infamma-
tory cells (39).
In summary, the anti-infammatory efects of sEHIs have
been shown to result through multiple pathways. sEHIs re-
duce the production of cytokines and pro-infammatory lipid
mediators. Stabilizing EETs by sEHIs led to down regula-
tion of other enzymes such as COX-2 and 5-LOX in the AA
cascade. In addition, the co-administration of NSAIDs and
sEHIs produced an antinociceptive efect in an infammatory
pain model. Indeed a synergistic action in reducing predomi-
nantly infammatory eicosanoids like prostaglandin PGE2
has been shown (37). Hence, it was speculated that COX
inhibitors can increase EET levels and that stabilized EETs
can improve anti-infammatory efects (40). Tis is in agree-
ment with results from the infammatory rat model, where
co-administration of a sEHI with a low dose of celecoxib
(a COX-2 selective inhibitor) was highly efective against
infammation (41). Moreover, co-administration of sEHIs
and COX inhibitors reduced the side efects of the COX in-
hibitor, improving their safety. Tus, the sEHIs should allow
reducing the dose of COX inhibitors required for the treat-
ment of infammation.
Infammatory pain
EETs dramatically reduce PGE2 levels, a cytokine with a
central role in infammation and pain, therefore, sEHIs could
be used in cases of infammatory pain to reduce production
of painful mediators of infammation. Tis is in line with the
analgesic efect showed in animal models.
sEHI showed similar efcacy and a 1000 fold increase
in potency compared to morphine in infammatory pain
models (42). According to Inceoglu et al (43), topical appli-
cation of sEHIs efectively attenuates thermal hyperalgesia
and mechanical allodynia in LPS-treated rats. Moreover,
co-administration of EETs with a sEHI showed an addi-
tive increase in anti-hyperalgesia and sEHIs were dem-
onstrated as acting in both peripheral and central nerves
systems (44).
Veterinary applications
In the feld of veterinary medicine, the frst application of
sEHI was conducted in 2013.Tis study tested if the sEHI
(t-TUCB, trans-4-{4-[3-(4-trifuoromethoxy- phenyl)-
ureido]-cyclohexyloxy}-benzoic acid) might reduce severe
infammatory pain in a horse afected by laminitis (45). Te
patient in this study was a horse treated for laminitis for
a 7-day period using diferent NSAIDs and gabapentin.
Treatments with these classical drugs were not efective and
euthanasia was being considered for humane reasons. On day
8, a sEHI was added to the treatment protocol. After the frst
dose, the horse began to walk spontaneously, had a good ap-
petite with remarkable reduction in pain scores and no side
efects were reported (45).
In conclusion, the studies presented in this review are
quite persuasive in demonstrating that sEHIs may have
potential applications in the treatment of several diseases.
Moreover, a recent study has also demonstrated efectiveness
of these drugs in veterinary medicine (45). Hopefully, this is
the frst of many sets of data to be generated regarding the
successful treatment of pain in animals. Tese new active in-
gredients could be particularly applicable in animals sensitive
to the common anti-infammatory drugs.
CONFLI CT OF I NTERESTS
None of the authors has any fnancial or personal relation-
ship that could inappropriately infuence the content of the
paper.
ACKNOWLEDGEMENTS
Authors acknowledge Dr. H. Owen (University of Queensland,
Australia) for the English editing of the manuscript.
Review Article
Israel Journal of Veterinary Medicine  Vol. 69 (2)  June 2014 Lee, H.K. 60
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36. Liu, J.Y., Yang, J., Inceoglu, B., Qiu, H., Ulu, A., Hwang, S.H.,
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epoxide hydrolase enhances the anti-infammatory efects of as-
pirin and 5-lipoxygenase activation protein inhibitor in a murine
model. Biochem. Pharmacol. 79: 880–887, 2010.
37. Schmelzer, K.R., Inceoglu, B., Kubala, L., Kim, I.H., Jinks, S.L.
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38. Liu, J.Y., Tsai, H.J., Hwang, S.H., Jones, P.D., Morisseau, C. and
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epoxide hydrolase inhibitors for use in a murine model of infam-
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39. Smith, K.R., Pinkerton, K.E., Watanabe, T., Pedersen, T.L., Ma,
S.J. and Hammock, B.D.: Attenuation of tobacco smoke-induced
lung infammation by treatment with a soluble epoxide hydro-
lase inhibitor. Proc. Natl. Acad. Sci. USA. 102: 2186–2191, 2005.
40. Inceoglu, B., Schmelzer, K.R., Morisseau, C., Jinks, S.L. and
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novel biological functions of epoxyeicosatrienoic acids (EETs).
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41. Hwang, S.H., Wagner, K. and Morisseau, C.: Synthesis and
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42. Rose, T.E., Morisseau, C., Liu, J.Y., Inceoglu, B., Jones, P.D., San-
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urea inhibitors of human and murine soluble epoxide hydrolase:
structure-activity relationships, pharmacokinetics, and reduction
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43. Inceoglu, B., Jinks, S.L., Schmelzer, K.R., Waite, T., Kim, I.H.
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44. Wagner, K., Inceoglu, B., Gill, S.S. and Hammock, B.D.: Epoxy-
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45. Guedes, A.G.P., Morisseau, C., Sole, A., Soares, J.H.N., Ulu, A.,
Dong, H. and Hammock, B.D.: Use of a soluble epoxide hydro-
lase inhibitor as an adjunctive analgesic in a horse with laminitis.
Vet. Anaesth. Analg. 40: 440-448, 2013.
46. Zhang, L.N., Vincelette. J., Cheng, Y., Mehra, U., Chen, D.,
Anandan, S.K., Gless, R., Webb, H.K. and Wang, Y.X.: Inhibi-
tion of soluble epoxide hydrolase attenuated atherosclerosis, ab-
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47. Keseru, B., Barbosa-Sicard, E., Popp, R., Fisslthaler, B., Dietrich,
A., Gudermann, T., Hammock, B.D., Falck, J.R., Weissmann,
N, Busse, R. and Fleming, I.: Epoxyeicosatrienoic acids and the
soluble epoxide hydrolase are determinants of pulmonary artery
pressure and the acute hypoxic pulmonary vasoconstrictor re-
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48. Li, N., Liu, J.Y., Timofeyev, V., Qiu, H., Hwang, S.H., Tuteja, D.,
Lu, L., Yang, J., Mochida, H., Low, R., Hammock, B.D. and Chia-
mvimonvat, N.: Benefcial efects of soluble epoxide hydrolase in-
hibitors in myocardial infarction model: insight gained using me-
tabolomics approaches. J. Mol. Cell. Cardiol. 47: 835-845, 2009.
49. Carroll, M.A., Doumad, A.B., Li, J., Cheng, M.K., Falck, J.R.
and McGif, J.C.: Adenosine2A receptor vasodilation of rat pre-
glomerular microvessels is mediated by EETs that activate the
cAMP/PKA pathway. Am. J. Physiol. Renal. Physiol. 291: 155-
161, 2006.
50. Inceoglu, B., Jinks, S.L., Ulu, A., Hegedus, C.M., Georgi, K.,
Schmelzer, K.R., Wagnera, K., Jones, P.D., Morisseau, C. and
Hammock, B.D.: Soluble epoxide hydrolase and epoxyeicosatrie-
noic acids modulate two distinct analgesic pathways. Proc. Natl.
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Review Article