The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

Kodani, Sean D.; Hammock, Bruce D.

doi:10.1124/dmd.115.063339

Cited by 67 publications

(63 citation statements)

References 167 publications

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“…EHs are ubiquitous and the hydration of epoxide substrates is energetically favored, with water as the only cosubstrate (Lacourciere and Armstrong, 1993;Hammock et al, 1994;Müller et al, 1997;Laughlin et al, 1998). In mammals, there are several EHs, including sEH, mEH, cholesterol EH, hepoxilin hydrolase, and leukotriene A4 EH (Kodani and Hammock, 2015). Among these EHs, sEH and mEH have been extensively characterized because of their potential clinical value and the involvement of mEH in the metabolism of xenobiotics (detoxification of cytotoxic, mutagenic, and carcinogenic intermediates) (Morisseau and Hammock, 2005;ElSherbeni and El-Kadi, 2014;Kodani and Hammock, 2015;Václavíková et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…In mammals, there are several EHs, including sEH, mEH, cholesterol EH, hepoxilin hydrolase, and leukotriene A4 EH (Kodani and Hammock, 2015). Among these EHs, sEH and mEH have been extensively characterized because of their potential clinical value and the involvement of mEH in the metabolism of xenobiotics (detoxification of cytotoxic, mutagenic, and carcinogenic intermediates) (Morisseau and Hammock, 2005;ElSherbeni and El-Kadi, 2014;Kodani and Hammock, 2015;Václavíková et al, 2015). The mEH is the key hepatic enzyme that catalyzes the hydration of numerous xenobiotics such as the epoxides of 1,3-butadiene, styrene, naphthalene, benzo(a)pyrene, phenantoin, and carbamazepine (El-Sherbeni and El-Kadi, 2014;Rosa et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

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Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

Hayes

Grönberg

et al. 2016

Drug Metabolism and Disposition

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Oxetane moieties are increasingly being used by the pharmaceutical industry as building blocks in drug candidates because of their pronounced ability to improve physicochemical parameters and metabolic stability of drug candidates. The enzymes that catalyze the biotransformation of the oxetane moiety are, however, not well studied. The in vitro metabolism of a spiro oxetane-containing compound AZD1979 [(3-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone] was studied and one of its metabolites, M1, attracted our interest because its formation was NAD(P)H independent. The focus of this work was to elucidate the structure of M1 and to understand the mechanism(s) of its formation. We established that M1 was formed via hydration and ring opening of the oxetanyl moiety of AZD1979. Incubations of AZD1979 using various human liver subcellular fractions revealed that the hydration reaction leading to M1 occurred mainly in the microsomal fraction. The underlying mechanism as a hydration, rather than an oxidation reaction, was supported by the incorporation of 18 O from H 2 18O into M1. Enzyme kinetics were performed probing the formation of M1 in human liver microsomes. The formation of M1 was substantially inhibited by progabide, a microsomal epoxide hydrolase inhibitor, but not by trans-4-[4-(1-adamantylcarbamoylamino)cyclohexyloxy]-benzoic acid, a soluble epoxide hydrolase inhibitor. On the basis of these results, we propose that microsomal epoxide hydrolase catalyzes the formation of M1. The substrate specificity of microsomal epoxide hydrolase should therefore be expanded to include not only epoxides but also the oxetanyl ring system present in AZD1979.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

Hayes

Grönberg

et al. 2016

Drug Metabolism and Disposition

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“…TPPU pretreatment significantly decreased the level of MPO and TNF-a in DCF-treated mice compared with mice treated with only DCF. This anti-inflammatory effect of sEHI was expected on the basis of previous observations (Schmelzer et al, 2005;Zhang et al, 2012;Kodani and Hammock, 2015). OME was also reported to decrease the levels of MPO and TNF-a in indomethacin-induced ulcers (Chatterjee et al, 2012;Yadav et al, 2013).…”

Section: Resultsmentioning

confidence: 65%

“…Anti-inflammatory effects of EETs have been reported by numerous authors (Node et al, 1999;Chiamvimonvat et al, 2007;Thomson et al, 2012;Kodani and Hammock, 2015). Inhibition or gene deletion of sEH exert anti-inflammatory effects in different animal models and are associated with an increase in endogenous epoxy fatty acids or the ratio of epoxy/ dihydroxy derivatives (Schmelzer et al, 2005;Liu et al, 2010b;Zhang et al, 2012Zhang et al, , 2013Askari et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…This study illustrates the potential value of sEHI as an alternative to OME and related proton pump inhibitors in management of intestinal ulcers induced by NSAIDs. Since sEH inhibitors dramatically synergize the analgesic and anti-inflammatory effects of NSAIDs (Schmelzer et al, 2005;Liu et al, 2010b), they could be combined with NSAIDs both to synergize efficacy and reduce side effects of NSAIDs (Schmelzer et al, 2005;Liu et al, 2010a, b;Kodani and Hammock, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers

Goswami

Wan

Yang

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Proton pump inhibitors such as omeprazole (OME) reduce the severity of gastrointestinal (GI) ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs) but can also increase the chance of dysbiosis. The aim of this study was to test the hypothesis that preventive use of a soluble epoxide hydrolase inhibitor (sEHI) such as TPPU can decrease NSAID-induced ulcers by increasing anti-inflammatory epoxyeicosatrienoic acids (EETs). Dose-[10, 30, and 100 mg/kg, by mouth (PO)] and time-dependent (6 and 18 hours) ulcerative effects of diclofenac sodium (DCF, an NSAID) were studied in the small intestine of Swiss Webster mice. Dose-dependent effects of TPPU (0.001-0.1 mg/kg per day for 7 days, in drinking water) were evaluated in DCF-induced intestinal toxicity and compared with OME (20 mg/kg, PO). In addition, the effect of treatment was studied on levels of Hb in blood, EETs in plasma, inflammatory markers such as myeloperoxidase (MPO) in intestinal tissue homogenates, and tissue necrosis factor-a (TNF-a) in serum. DCF dose dependently induced ulcers that were associated with both a significant (P , 0.05) loss of Hb and an increase in the level of MPO and TNF-a, with severity of ulceration highest at 18 hours. Pretreatment with TPPU dose dependently prevented ulcer formation by DCF, increased the levels of epoxy fatty acids, including EETs, and TPPU's efficacy was comparable to OME. TPPU significantly (P , 0.05) reversed the effect of DCF on the level of Hb, MPO, and TNF-a. Thus sEHI might be useful in the management of NSAID-induced ulcers.

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Activating endogenous resolution pathways by soluble epoxide hydrolase inhibitors for the management of COVID‐19

Manickam

Meenakshisundaram²,

Pillaiyar

2021

Archiv der Pharmazie

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Anti‐inflammatory, specialized proresolving mediators such as resolvins, protectins, maresins, and lipoxins derived from polyunsaturated acids may play a potential role in lung diseases as they protect different organs in animal disease models. Polyunsaturated fatty acids are an important resource for epoxy fatty acids (EET, EEQ, and EDP) that mediate a broad array of anti‐inflammatory and proresolving mechanisms, such as mitigation of the cytokine storm. However, epoxy fatty acids are rapidly metabolized by soluble epoxide hydrolase (sEH). In animal studies, administration of sEH inhibitors (sEHIs) increases epoxy fatty acid levels, reduces lung inflammation, and improves lung function, making it a viable COVID‐19 treatment approach. Thus, using sEHIs to activate endogenous resolution pathways might be a novel method to minimize organ damage in severe cases and improve outcomes in COVID‐19 patients. This review focuses on the use of sEH inhibitors to activate endogenous resolution mechanisms for the treatment of COVID‐19.

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The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

Cited by 67 publications

References 167 publications

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers

Activating endogenous resolution pathways by soluble epoxide hydrolase inhibitors for the management of COVID‐19

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