Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs

Tsai, Hui‐Jen; Hwang, Sung Hee; Morisseau, Christophe; Yang, Jun; Jones, Paul D.; Kasagami, Takeo; Kim, In Hae; Hammock, Bruce D.

doi:10.1016/j.ejps.2010.03.018

Cited by 75 publications

(150 citation statements)

References 58 publications

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“…1, A and B). TPPU is a highly selective inhibitor of sEH with an IC 50 of 1.1 and 2.1 nM for murine and human sEH, respectively (Rose et al, 2010;Tsai et al, 2010;Liu et al, 2013). We previously demonstrated that sEH pharmacological inhibition does not alter sEH protein expression, and that prolonged sEH inhibition in mice appears to be quite benign (Luria et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

Soluble Epoxide Hydrolase Pharmacological Inhibition Ameliorates Experimental Acute Pancreatitis in Mice

Bettaieb

Chahed

Bachaalany

et al. 2015

Molecular Pharmacology

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Acute pancreatitis (AP) is an inflammatory disease, and is one of the most common gastrointestinal disorders worldwide. Soluble epoxide hydrolase (sEH; encoded by Ephx2) deficiency and pharmacological inhibition have beneficial effects in inflammatory diseases. Ephx2 whole-body deficiency mitigates experimental AP in mice, but the suitability of sEH pharmacological inhibition for treating AP remains to be determined. We investigated the effects of sEH pharmacological inhibition on cerulein-and arginine-induced AP using the selective sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), which was administered before and after induction of pancreatitis. Serum amylase and lipase levels were lower in TPPU-treated mice compared with controls. In addition, circulating levels and pancreatic mRNA of the inflammatory cytokines tumor necrosis factor-a, interleukin Il-1b, and Il-6 were reduced in TPPU-treated mice. Moreover, sEH pharmacological inhibition before and after induction of pancreatitis was associated with decreased cerulein-and arginine-induced nuclear factor-kB inflammatory response, endoplasmic reticulum stress, and cell death. sEH pharmacological inhibition before and after induction of pancreatitis mitigated cerulein-and arginineinduced AP. This work suggests that sEH pharmacological inhibition may be of therapeutic value in acute pancreatitis.

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Section: Resultsmentioning

confidence: 99%

Soluble Epoxide Hydrolase Pharmacological Inhibition Ameliorates Experimental Acute Pancreatitis in Mice

Bettaieb

Chahed

Bachaalany

et al. 2015

Molecular Pharmacology

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“…Thus, by the time one could isolate the sEH enzyme, the inhibitor would have diffused away from the catalytic site; however, the 10 mg/ kg/day dose used in this study results in blood levels above the IC 50 for t-TUCB, and t-TUCB increases the ratio of epoxides to diols for several oxylipin chemical mediators and reduces infl ammatory cytokines in the plasma even at 3 mg/kg in mice. These plasma epoxide-to-diol ratios have been demonstrated to be dose-related indicators of in vivo sEH target engagement in a number of species, including mice ( 57-59 ), rats ( 60,61 ), dogs ( 62 ), and monkeys ( 63 ).…”

Section: Discussionmentioning

confidence: 99%

Metabolic products of soluble epoxide hydrolase are essential for monocyte chemotaxis to MCP-1 in vitro and in vivo

Kundu

Roome

Bhattacharjee

et al. 2013

Journal of Lipid Research

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Monocyte migration from peripheral blood into infl ammatory sites is a complex phenomenon that occurs during acute and chronic infl ammatory diseases such as peritonitis, atherosclerosis, rheumatoid arthritis, and infl ammatory bowel disease. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is one of the key chemokines that regulate migration and infi ltration of monocytes in response to infl ammatory conditions by attracting monocytes toward MCP-1 in a gradient-dependent manner ( 1, 2 ). MCP-1 expression has been demonstrated to be elevated in a number of different diseases, including atherosclerosis ( 3 ). In vivo studies with MCP-1-or MCP-1 receptor-defi cient mice have shown the reduction of atherosclerotic plaque size, supporting the relevance of MCP-1 in atherogenesis ( 4, 5 ).The cellular effect of MCP-1 is mediated through interaction with its receptor, CCR2 ( 6 ). Our laboratory has identifi ed several critical signaling pathways that are activated downstream of this receptor and regulate monocyte chemotaxis to MCP-1 both in vitro and in vivo ( 2,7,8 ).Abstract Monocyte chemoattractant protein-1 (MCP-1)-induced monocyte chemotaxis is a major event in infl ammatory disease. Our prior studies have demonstrated that MCP-1-dependent chemotaxis requires release of arachidonic acid (AA) by activated cytosolic phospholipase A 2 (cPLA 2 ). Here we investigated the involvement of AA metabolites in chemotaxis. Neither cyclooxygenase nor lipoxygenase pathways were required, whereas pharmacologic inhibitors of both the cytochrome-P450 (CYP) and the soluble epoxide hydrolase (sEH) pathways blocked monocyte chemotaxis to MCP-1. To verify specifi city, we demonstrated that the CYP and sEH products epoxyeiscosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs), respectively, restored chemotaxis in the presence of the inhibitors, indicating that sEH-derived products are essential for MCP-1-driven chemotaxis. Importantly, DHETs also rescued chemotaxis in cPLA 2 -defi cient monocytes and monocytes with blocked Erk1/2 activity, because Erk controls cPLA 2 activation. The in vitro fi ndings regarding the involvement of CYP/sEH pathways were further validated in vivo using two complementary approaches measuring MCP-1-dependent chemotaxis in mice. These observations reveal the importance of sEH in MCP-1-regulated monocyte chemotaxis and may explain the observed therapeutic value of sEH inhibitors in treatment of infl ammatory diseases, cardiovascular diseases, pain, and even carcinogenesis. Their effectiveness, often attributed to increasing EET levels, is probably infl uenced by the impairment of DHET formation and inhibition of chemotaxis. -Kundu, S

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“…The 14,15-, 11,12-EET or vehicle were administered intraperitoneally via osmotic minipump (Alzet) at a dose of 15 μg·kg −1 ·d −1 . TUPS was synthesized as described (24,25), and TUPS was completely dissolved in PEG 400 at a concentration of 10 mg/mL and mixed into Vanicream to obtain a 0.1% (wt:vol) formulated cream. The sEHi (TUPS) was administered orally by gavage in an aqueous solution of 10% (vol/vol) DMSO in 0.5% methylcellulose (10 mg·kg −1 ·d −1 ) or as a 0.1% cream applied topically; control mice received vehicle.…”

Section: Methodsmentioning

confidence: 99%

“…We first studied compounds that increase EETs by inhibiting sEH, the main metabolizing enzyme of EETs. Notably, several structurally distinct sEH inhibitors (sEHis) are being evaluated for clinical indications (3,24,25). Systemic administration of the sEHi 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS, UC1709) increased liver regeneration by 38% compared with vehicle-treated mice (Fig.…”

Section: Pharmacological Manipulation Of Eets and Their Action In Organmentioning

confidence: 99%

Epoxyeicosanoids promote organ and tissue regeneration

Panigrahy

Kalish

Huang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.

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Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs

Cited by 75 publications

References 58 publications

Soluble Epoxide Hydrolase Pharmacological Inhibition Ameliorates Experimental Acute Pancreatitis in Mice

Soluble Epoxide Hydrolase Pharmacological Inhibition Ameliorates Experimental Acute Pancreatitis in Mice

Metabolic products of soluble epoxide hydrolase are essential for monocyte chemotaxis to MCP-1 in vitro and in vivo

Epoxyeicosanoids promote organ and tissue regeneration

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