HYDROLYTIC ENZYMES IN THE METABOLISM OF TOXINS

Summary

Principal Investigator: Bruce D Hammock
Abstract: DESCRIPTION (provided by applicant): Evaluation of the risk of foreign compounds depends upon understanding the enzymes involved their degradation. A set of under-studied metabolic enzymes include the epoxide hydrolases in the ?/?-hydrolase fold family. These enzymes degrade epoxides by adding water. Some epoxides are reactive and highly mutagenic, and epoxides are commonly formed as metabolically labile functionalities by cytochrome P450s from variety of environmental chemicals. Not only are the levels of epoxide hydrolases variable in the human population, but they can be inhibited or induced by environmental chemicals and drugs. A central hypothesis is that epoxide hydrolases also have endogenous roles. We have established that the soluble epoxide hydrolase also acts on epoxides of arachidonic acid. These are key regulatory lipids. In fact, an inhibitor of the soluble epoxide hydrolase we made during the last grant period is in clinical trials to treat hypertension. Because the soluble epoxide hydrolase is involved in the regulation of blood pressure, inflammation and pain, it additionally represents a novel target for the action of xenobiotics. Similarly, inhibition of the microsomal epoxide hydrolase leads to acute xenobiotic toxicity. The knowledge of ?/?-fold enzymes will be expanded by completing two major objectives, and the tools developed here are critical to test a series of hypotheses regarding the endogenous role of the soluble epoxide hydrolase. Objective I addresses the structure and fundamental biochemistry of epoxide hydrolases with a major emphasis on the less studied soluble form. Objective II continues the development of a metabolomic profiling system to examine biologically active lipids in the arachidonate cascade and related pathways. Using this analytical platform as well as potent inhibitors and inducers of the enzyme, the role of the soluble epoxide hydrolase as a key enzyme in the arachidonate cascade and thus regulation of inflammation and pain will be evaluated. Along with 15% of the world's pharmaceuticals, common herbicides and personal care products are also known to act on the arachidonate cascade. For example we have found the common soap anti microbial, triclocarban, is a potent inhibitor of the soluble epoxide hydrolase and the endogenous peptide angiotensin along with PPAR? agonists are inducers. By addressing our objectives, knowledge will be expanded on the biochemistry and role in xenobiotic metabolism of epoxide hydrolases. The hypothesis of endogenous roles for epoxide hydrolases will be tested and the arachidonate cascade evaluated as a site of action for xenobiotics and nutraceuticals. PUBLIC HEALTH RELEVANCE: Epoxide hydrolase enzymes protect us against many environmental chemicals, and some of them also function to regulate our blood pressure, inflammation and pain. This study will identify new epoxide hydrolase targets for the action of drugs and nutraceuticals to improve health. This knowledge will also predict risk from environmental chemicals that increase or decrease the levels of epoxide hydrolases.
Funding Period: 1980-12-01 - 2013-12-31
more information: NIH RePORT

Top Publications

  1. pmc Cloning and characterization of two glutathione S-transferases from pyrethroid-resistant Culex pipiens
    Aman I Samra
    Department of Entomology, University of California, Davis, CA 95616, USA
    Pest Manag Sci 68:764-72. 2012
  2. pmc Development of pyrethroid-like fluorescent substrates for glutathione S-transferase
    Huazhang Huang
    Department of Entomology, University of California, Davis, CA 95616, USA
    Anal Biochem 431:77-83. 2012
  3. pmc Soluble epoxide hydrolase inhibition exhibits antihypertensive actions independently of nitric oxide in mice with renovascular hypertension
    Libor Kopkan
    Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
    Kidney Blood Press Res 35:595-607. 2012
  4. pmc Biologically active ester derivatives as potent inhibitors of the soluble epoxide hydrolase
    In Hae Kim
    Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA
    Bioorg Med Chem Lett 22:5889-92. 2012
  5. pmc Triclosan impairs excitation-contraction coupling and Ca2+ dynamics in striated muscle
    Gennady Cherednichenko
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 109:14158-63. 2012
  6. pmc Tetramethylenedisulfotetramine alters Ca²⁺ dynamics in cultured hippocampal neurons: mitigation by NMDA receptor blockade and GABA(A) receptor-positive modulation
    Zhengyu Cao
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, USA
    Toxicol Sci 130:362-72. 2012
  7. pmc Pharmacological inhibition of soluble epoxide hydrolase provides cardioprotection in hyperglycemic rats
    Kathleen Guglielmino
    Department of Pharmacology, University of California, Davis, CA 95616, USA
    Am J Physiol Heart Circ Physiol 303:H853-62. 2012
  8. pmc EH3 (ABHD9): the first member of a new epoxide hydrolase family with high activity for fatty acid epoxides
    Martina Decker
    Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland
    J Lipid Res 53:2038-45. 2012
  9. pmc Omics approaches in cystic fibrosis research: a focus on oxylipin profiling in airway secretions
    Jason P Eiserich
    Department of Internal Medicine, University of California, Davis, California, USA
    Ann N Y Acad Sci 1259:1-9. 2012
  10. pmc Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health
    Christophe Morisseau
    Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, California 95616, USA
    Annu Rev Pharmacol Toxicol 53:37-58. 2013

Research Grants

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013

Detail Information

Publications163 found, 100 shown here

  1. pmc Cloning and characterization of two glutathione S-transferases from pyrethroid-resistant Culex pipiens
    Aman I Samra
    Department of Entomology, University of California, Davis, CA 95616, USA
    Pest Manag Sci 68:764-72. 2012
    ..The Marin strain of Culex pipiens Say is a pyrethroid-resistant population that was collected in Marin County, California, in 2001 and subsequently maintained in the laboratory under regular permethrin exposure...
  2. pmc Development of pyrethroid-like fluorescent substrates for glutathione S-transferase
    Huazhang Huang
    Department of Entomology, University of California, Davis, CA 95616, USA
    Anal Biochem 431:77-83. 2012
    ....
  3. pmc Soluble epoxide hydrolase inhibition exhibits antihypertensive actions independently of nitric oxide in mice with renovascular hypertension
    Libor Kopkan
    Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
    Kidney Blood Press Res 35:595-607. 2012
    ..The present study was performed to examine whether the blood pressure (BP)-lowering effects of soluble epoxide hydrolase (sEH) inhibition in two-kidney, one-clip (2K1C) Goldblatt hypertension are nitric oxide (NO) dependent...
  4. pmc Biologically active ester derivatives as potent inhibitors of the soluble epoxide hydrolase
    In Hae Kim
    Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA
    Bioorg Med Chem Lett 22:5889-92. 2012
    ..Modifications around the ester function enhanced in vitro metabolic stability of the ester inhibitors up to 32-fold without a decrease in inhibition potency. Further, several compounds had improved physical properties...
  5. pmc Triclosan impairs excitation-contraction coupling and Ca2+ dynamics in striated muscle
    Gennady Cherednichenko
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 109:14158-63. 2012
    ....
  6. pmc Tetramethylenedisulfotetramine alters Ca²⁺ dynamics in cultured hippocampal neurons: mitigation by NMDA receptor blockade and GABA(A) receptor-positive modulation
    Zhengyu Cao
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, USA
    Toxicol Sci 130:362-72. 2012
    ..These rapid throughput in vitro assays may assist in the identification of single agents or combinations that have utility in the treatment of TETS intoxication...
  7. pmc Pharmacological inhibition of soluble epoxide hydrolase provides cardioprotection in hyperglycemic rats
    Kathleen Guglielmino
    Department of Pharmacology, University of California, Davis, CA 95616, USA
    Am J Physiol Heart Circ Physiol 303:H853-62. 2012
    ..The results suggest that sEH/EETs may be an effective therapeutic target for cardioprotection in insulin resistance and diabetes...
  8. pmc EH3 (ABHD9): the first member of a new epoxide hydrolase family with high activity for fatty acid epoxides
    Martina Decker
    Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland
    J Lipid Res 53:2038-45. 2012
    ..This is particularly relevant because sEH is a potential drug target, and clinical trials are under way exploring the value of sEH inhibitors in the treatment of hypertension and diabetes type II...
  9. pmc Omics approaches in cystic fibrosis research: a focus on oxylipin profiling in airway secretions
    Jason P Eiserich
    Department of Internal Medicine, University of California, Davis, California, USA
    Ann N Y Acad Sci 1259:1-9. 2012
    ..Finally, the utility of oxylipin metabolic profiling in directing optimal therapeutic approaches and determining the efficacy of various interventions is discussed...
  10. pmc Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health
    Christophe Morisseau
    Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, California 95616, USA
    Annu Rev Pharmacol Toxicol 53:37-58. 2013
    ..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...
  11. pmc Hepoxilin A(3) facilitates neutrophilic breach of lipoxygenase-expressing airway epithelial barriers
    David L Tamang
    Mucosal Immunology Laboratory, Massachusetts General Hospital, Charlestown, MA 02129, USA
    J Immunol 189:4960-9. 2012
    ..Data generated from multiple models in this study provide further evidence that hepoxilin A(3) is produced in response to lung pathogenic bacteria and functions to drive neutrophils across epithelial barriers...
  12. pmc Comparative efficacy of 3 soluble epoxide hydrolase inhibitors in rat neuropathic and inflammatory pain models
    Karen Wagner
    Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, One Shields Ave, Davis, CA 95616, USA
    Eur J Pharmacol 700:93-101. 2013
    ..Because of their ability to block diabetic neuropathic pain sEH inhibition is a promising new approach to treat chronic pain conditions...
  13. pmc Beneficial effects of inhibition of soluble epoxide hydrolase on glucose homeostasis and islet damage in a streptozotocin-induced diabetic mouse model
    Lingdan Chen
    Department of Physiology, Georgia Health Sciences University, Augusta, GA 30912, USA
    Prostaglandins Other Lipid Mediat 104:42-8. 2013
    ..These studies provide pharmacological evidence that inhibiting sEH activity provides significant protection against islet β-cell damage and improves glucose homeostasis in STZ-induced diabetes...
  14. pmc Synthesis and structure-activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors
    Stevan Pecic
    Department of Medicine, Columbia University, 650 W 168th Street, BB1029, New York, NY 10032, USA
    Bioorg Med Chem Lett 23:417-21. 2013
    ....
  15. pmc Förster resonance energy transfer competitive displacement assay for human soluble epoxide hydrolase
    Kin Sing Stephen Lee
    Department of Entomology and UCD Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
    Anal Biochem 434:259-68. 2013
    ..This assay provides additional data to evaluate the potency of sEH inhibitors...
  16. pmc Development of an HTS assay for EPHX2 phosphatase activity and screening of nontargeted libraries
    Christophe Morisseau
    Department of Entomology and UCD Comprehensive Cancer Center, CA 95616, USA
    Anal Biochem 434:105-11. 2013
    ..Ebselen binds to the N-terminal domain of sEH (K(I)=550 nM) and chemically reacts with the enzyme to quickly and irreversibly inhibit Nterm-phos, and subsequently Cterm-EH, and thus represents a new class of sEH inhibitor...
  17. pmc Soluble epoxide hydrolase inhibitor, TUPS, protects against isoprenaline-induced cardiac hypertrophy
    Hassan N Althurwi
    Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
    Br J Pharmacol 168:1794-807. 2013
    ..Therefore, it is important to examine whether the inhibition of sEH by 1-(1-methanesulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS) will protect against isoprenaline-induced cardiac hypertrophy...
  18. pmc Metabolic products of soluble epoxide hydrolase are essential for monocyte chemotaxis to MCP-1 in vitro and in vivo
    Suman Kundu
    Department of Cell Biology, and Research Core Services, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
    J Lipid Res 54:436-47. 2013
    ..Their effectiveness, often attributed to increasing EET levels, is probably influenced by the impairment of DHET formation and inhibition of chemotaxis...
  19. pmc Upregulation of soluble epoxide hydrolase in proximal tubular cells mediated proteinuria-induced renal damage
    Qian Wang
    Dept of Physiology and Pathophysiology, Peking Univ Health Science Center, Beijing, China
    Am J Physiol Renal Physiol 304:F168-76. 2013
    ....
  20. pmc Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes
    Bora Inceoglu
    Department of Entomology, University of California Davis and UC Davis Cancer Center, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 109:11390-5. 2012
    ..Overall, these results argue that further efforts in understanding the spectrum of effects of EpFAs will yield novel opportunities in treating neuropathic pain...
  21. pmc Food in an evolutionary context: insights from mother's milk
    Katie Hinde
    Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA
    J Sci Food Agric 92:2219-23. 2012
    ..Here we present emerging transdisciplinary research 'decoding' mother's milk from humans and other mammals. We further discuss how insights from mother's milk have important implications for food science and human health...
  22. pmc Reduction of inflammatory bowel disease-induced tumor development in IL-10 knockout mice with soluble epoxide hydrolase gene deficiency
    Wanying Zhang
    Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
    Mol Carcinog 52:726-38. 2013
    ..These results indicate that sEH plays an important role in IBD and its-induced carcinogenesis and could serve as a highly potential target of chemoprevention and treatment for IBD...
  23. pmc Allergic asthmatics show divergent lipid mediator profiles from healthy controls both at baseline and following birch pollen provocation
    Susanna L Lundström
    Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
    PLoS ONE 7:e33780. 2012
    ..Progression of allergic inflammation is driven by T-helper type 2 (Th2) mediators and is associated with alterations in the levels of lipid mediators...
  24. pmc Bifidobacteria isolated from infants and cultured on human milk oligosaccharides affect intestinal epithelial function
    Maciej Chichlowski
    Foods for Health Institute, University of California, Davis, USA
    J Pediatr Gastroenterol Nutr 55:321-7. 2012
    ..Our objective was to test the hypothesis that growth of selected bifidobacteria on HMO stimulates the intestinal epithelium...
  25. pmc Homocysteine upregulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo
    Donghong Zhang
    Cardiovascular Research Center, Shantou University Medical College, Guangdong, China
    Circ Res 110:808-17. 2012
    ..Soluble epoxide hydrolase (sEH) is a major enzyme that hydrolyzes epoxyeicosatrienoic acids and attenuates their cardiovascular protective effects. Whether homocysteine (Hcy) regulates sEH and the underlying mechanism remains elusive...
  26. pmc Characterization of seizures induced by acute and repeated exposure to tetramethylenedisulfotetramine
    Dorota Zolkowska
    Department of Neurology, School of Medicine, University of California Davis, Sacramento, California, USA
    J Pharmacol Exp Ther 341:435-46. 2012
    ....
  27. pmc Inhibition of soluble epoxide hydrolase by cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension
    Jan Neckar
    Department of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    Clin Sci (Lond) 122:513-25. 2012
    ..These findings indicate that chronic inhibition of sEH exhibits antihypertensive and cardioprotective actions in this transgenic model of angiotensin II-dependent hypertension...
  28. pmc Development of monoclonal antibodies to human microsomal epoxide hydrolase and analysis of "preneoplastic antigen"-like molecules
    Hongying Duan
    Department of Microbiology, Faculty of Medicine, Saitama Medical University, Moroyama cho, Iruma gun, Saitama 350 0495, Japan
    Toxicol Appl Pharmacol 260:17-26. 2012
    ..These antibodies and antigen detection methods may be useful to study pathological changes of mEH in various human diseases...
  29. pmc Monoclonal antibodies reveal multiple forms of expression of human microsomal epoxide hydrolase
    Hongying Duan
    Department of Microbiology, Faculty of Medicine, Saitama Medical University, Moroyama cho, Iruma gun, Saitama 350 0495, Japan
    Toxicol Appl Pharmacol 260:27-34. 2012
    ..These findings show the multiple mode of expression of mEH which may be possibly related to the multiple roles that mEH plays in different cells...
  30. pmc A potent soluble epoxide hydrolase inhibitor, t-AUCB, acts through PPARγ to modulate the function of endothelial progenitor cells from patients with acute myocardial infarction
    Dan Yan Xu
    Department of Cardiology, Second Xiangya Hospital, Central South University, Changsha 410011, PR China
    Int J Cardiol 167:1298-304. 2013
    ..In this work, we investigated whether increasing EETs with the sEH inhibitor t-AUCB would increase angiogenesis related function in endothelial progenitor cells (EPCs) from patients with acute myocardial infarction (AMI)...
  31. pmc Inhibition of soluble epoxide hydrolase limits niacin-induced vasodilation in mice
    Ahmet B Inceoglu
    Department of Entomology, University of California, Davis, CA, USA
    J Cardiovasc Pharmacol 60:70-5. 2012
    ..Arachidonic acid is also metabolized by the cytochrome P450 system, which is regulated, in part, by the enzyme soluble epoxide hydrolase (sEH)...
  32. pmc Role of epoxide hydrolases in lipid metabolism
    Christophe Morisseau
    Department of Entomology and U C D Comprehensive Cancer Center, One Shields Avenue, University of California, Davis, CA 95616, USA
    Biochimie 95:91-5. 2013
    ..This review will discuss the biological activity of key lipid epoxides in mammals. In addition, the use of EH specific inhibitors will be highlighted as possible therapeutic disease interventions...
  33. pmc Metabolism of the antibacterial triclocarban by human epidermal keratinocytes to yield protein adducts
    Nils Helge Schebb
    Institute of Food Toxicology and Chemical Analysis, University of Veterinary Medicine Hannover, Hannover 30173, Germany
    J Biochem Mol Toxicol 26:230-4. 2012
    ..Exploiting the sensitivity of the method, we demonstrated that a substantial portion of triclocarban forms adducts with keratinocyte protein under the P450 inducing conditions employed...
  34. pmc Cardiac-generated prostanoids mediate cardiac myocyte apoptosis after myocardial ischaemia
    Hong Qiu
    Division of Cardiovascular Medicine, Department of Internal Medicine, University of California Davis, One Shields Avenue, Davis, CA 95616, USA
    Cardiovasc Res 95:336-45. 2012
    ..However, the key question that remains unanswered is whether cardiac-generated eicosanoids are the cause or the consequence of cardiac cell damage in MI...
  35. pmc Multiple precursor ion scanning of gangliosides and sulfatides with a reversed-phase microfluidic chip and quadrupole time-of-flight mass spectrometry
    Hyeyoung Lee
    Department of Food Science and Technology, University of California, Davis, California 95616, United States
    Anal Chem 84:5905-12. 2012
    ..Accurate mass measurements and chromatography unveiled the degree of unsaturation and hydroxylation in the ceramide lipid tails...
  36. pmc Soluble epoxide hydrolase regulates hematopoietic progenitor cell function via generation of fatty acid diols
    Timo Frömel
    Institute for Vascular Signalling, Goethe University, Frankfurt am Main D 60596, Germany
    Proc Natl Acad Sci U S A 109:9995-10000. 2012
    ..Thus, sEH activity is required for optimal progenitor cell proliferation, whereas long-term sEH inhibition is detrimental to progenitor cell proliferation, mobilization, and vascular repair...
  37. pmc Enhancement of vitamin D metabolites in the eye following vitamin D3 supplementation and UV-B irradiation
    Yanping Lin
    Department of Entomology and Cancer Center, University of California, Davis, CA, USA
    Curr Eye Res 37:871-8. 2012
    ..We also determined if the corneal epithelium can synthesize vitamin D following UV-B exposure...
  38. pmc Soluble epoxide hydrolase gene deficiency or inhibition attenuates chronic active inflammatory bowel disease in IL-10(-/-) mice
    Wanying Zhang
    Department of Pathology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611, USA
    Dig Dis Sci 57:2580-91. 2012
    ..Soluble epoxide hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids (EETs) into their much less active dihydroxy derivatives dihydroxyeicosatrienoic acids. Thus, targeting sEH would be important for inflammation...
  39. pmc Metabolomic profiling of regulatory lipid mediators in sputum from adult cystic fibrosis patients
    Jun Yang
    Department of Entomology, University of California at Davis, Davis, CA 95616, USA
    Free Radic Biol Med 53:160-71. 2012
    ....
  40. pmc Cloning and characterization of a microsomal epoxide hydrolase from Heliothis virescens
    Shizuo G Kamita
    Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
    Insect Biochem Mol Biol 43:219-28. 2013
    ..The ability of Hv-mEH1 to rapidly hydrolyze 1,2-disubstituted epoxides suggests that it may play roles in the metabolism of fatty acid epoxides such as those that are commonly found in the diet of Heliothis...
  41. pmc Substituted phenyl groups improve the pharmacokinetic profile and anti-inflammatory effect of urea-based soluble epoxide hydrolase inhibitors in murine models
    Jun Yan Liu
    Department of Entomology and UCD Comprehensive Cancer Center, University of California, Davis, CA 95615, USA
    Eur J Pharm Sci 48:619-27. 2013
    ..This indicates a new strategy for development of sEHIs for further study toward clinical trials...
  42. pmc A novel p21 attenuator which is structurally related to sorafenib
    Hiromi I Wettersten
    Division of Nephrology, Department of Internal Medicine, University of California, Davis, Davis, CA, USA
    Cancer Biol Ther 14:278-85. 2013
    ..Thus, this novel p21 inhibitor will be indispensable for exploring the function of p21, and upon further study may be translatable to the clinic...
  43. pmc Structure-activity relationships of substituted oxyoxalamides as inhibitors of the human soluble epoxide hydrolase
    In Hae Kim
    Department of Applied Bioscience, Faculty of Agriculture, Ehime University, 3 5 7 Tarumi, Matsuyama, Ehime 790 8566, Japan
    Bioorg Med Chem 22:1163-75. 2014
    ....
  44. pmc Modulation of blood oxylipin levels by long-chain omega-3 fatty acid supplementation in hyper- and normolipidemic men
    Jan Philipp Schuchardt
    Institute of Food Science and Human Nutrition, Leibniz University Hannover, Germany Electronic address
    Prostaglandins Leukot Essent Fatty Acids 90:27-37. 2014
    ..So far, the effect of an increased dietary LC n-3 PUFA intake on hydroxy, epoxy, and dihydroxy FA levels has not been investigated in subjects with mild combined hyperlipidemia...
  45. pmc Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer
    Guodong Zhang
    Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616, United States Department of Food Science, University of Massachusetts, Amherst, MA 01003, United States
    Prog Lipid Res 53:108-23. 2014
    ..Pharmacological inhibitors of sEH that stabilize endogenous EpFAs are being considered for human clinical uses. Here we review the biology of ω-3 and ω-6 EpFAs on inflammation, pain, angiogenesis and tumorigenesis. ..
  46. pmc Soluble epoxide hydrolase deficiency inhibits dextran sulfate sodium-induced colitis and carcinogenesis in mice
    Wanying Zhang
    Northwestern University, Feinberg School of Medicine 303 E Chicago Avenue, Chicago, IL 60611, U S A Tel 1 3125030645
    Anticancer Res 33:5261-71. 2013
    ..These results indicate that sEH plays an important role in the development of colitis and in inducing carcinogenesis. ..
  47. pmc Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase
    Ting Chen
    Hematology Laboratory for Translational Research, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, United States
    J Med Chem 56:9457-70. 2013
    ..We consider these compounds to represent lead candidates for the development of potent and specific HRI activators. ..
  48. pmc Treatment of mice with 2,3,7,8-Tetrachlorodibenzo-p-dioxin markedly increases the levels of a number of cytochrome P450 metabolites of omega-3 polyunsaturated fatty acids in the liver and lung
    Jun Yang
    Department of Entomology and Comprehensive Cancer Center, University of California, USA
    J Toxicol Sci 38:833-6. 2013
    ....
  49. pmc Individual variation in lipidomic profiles of healthy subjects in response to omega-3 Fatty acids
    Malin L Nording
    Computational Life Science Cluster CLIC, Department of Chemistry, Umea University, Umea, Sweden Department of Entomology, University of California Davis, Davis, California, United States of America
    PLoS ONE 8:e76575. 2013
    ..This may be due to individual variability in response. We used a multi-platform lipidomic approach to investigate both the consistent and inconsistent responses of individuals comprehensively to a defined ω3 intervention...
  50. pmc Soluble epoxide hydrolase inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid is neuroprotective in rat model of ischemic stroke
    Jafar Sadik B Shaik
    Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania
    Am J Physiol Heart Circ Physiol 305:H1605-13. 2013
    ..1μM: 58 ± 5.11% vs. t-AUCB0.5μM: 39.9 ± 5.8%). These findings suggest that t-AUCB may exert its neuroprotective effects by affecting multiple components of neurovascular unit including neurons, astrocytes, and microvascular flow...
  51. pmc Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren-2 transgenic hypertensive rats
    Petr Kujal
    Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Charles University, Prague, Czech Republic Department of Pathology, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic
    Clin Exp Pharmacol Physiol 41:227-37. 2014
    ....
  52. pmc Novel sorafenib-based structural analogues: in-vitro anticancer evaluation of t-MTUCB and t-AUCMB
    Aaron T Wecksler
    Departments of aEntomology and Nematology bNeurobiology, Physiology and Behavior, University of California Davis, Davis cUC Davis Comprehensive Cancer Center dDepartment of Internal Medicine, Davis Medical Center, Division of Nephrology, University of California eDepartment of Biochemistry and Molecular Medicine, University of California Davis School of Medicine fUS Department of Veterans Affairs Medical Center, Sacramento, California, USA
    Anticancer Drugs 25:433-46. 2014
    ....
  53. pmc Opposite effects of gene deficiency and pharmacological inhibition of soluble epoxide hydrolase on cardiac fibrosis
    Lijuan Li
    Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China
    PLoS ONE 9:e94092. 2014
    ..Thus, compared with pharmacological inhibition of sEH, EPHX2 deletion caused the shift in arachidonic acid metabolism, which may led to pathological cardiac remodeling, especially cardiac fibrosis...
  54. pmc Soluble epoxide hydrolase inhibitor, t-TUCB, protects against myocardial ischaemic injury in rats
    Ayush Shrestha
    Department of Pharmacology, JSS College of Pharmacy A Constituent College of JSS University, Mysore, Ootacamund, Tamilnadu, India
    J Pharm Pharmacol 66:1251-8. 2014
    ..To determine the protective role of a soluble epoxide hydrolase(sEH) inhibitor, trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido] cyclohexyloxy} benzoic acid (t-TUCB), in isoproterenol (ISO)-induced myocardial ischaemic injury in vivo...
  55. pmc An omega-3 epoxide of docosahexaenoic acid lowers blood pressure in angiotensin-II-dependent hypertension
    Arzu Ulu
    Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA and School of Veterinary Medicine, Anatomy, Physiology and Cell Biology, University of California, Davis, CA
    J Cardiovasc Pharmacol 64:87-99. 2014
    ....
  56. pmc Symmetric adamantyl-diureas as soluble epoxide hydrolase inhibitors
    Vladimir Burmistrov
    Department of Chemistry and General Chemical Technology, Volzhsky Polytechnic Institute branch Volgograd State Technical University, Volzhsky, Russia Volgograd State Technical University, Volgograd, Russia
    Bioorg Med Chem Lett 24:2193-7. 2014
    ..5 nM) with a strong binding to sEH (Ki=3.1 nM) and a moderately long residence time on the enzyme (koff=1.05 × 10(-3) s(-1); t1/2=11 min)...
  57. pmc Increase of EPA-derived hydroxy, epoxy and dihydroxy fatty acid levels in human plasma after a single dose of long-chain omega-3 PUFA
    Jan Philipp Schuchardt
    Institute of Food Science and Human Nutrition, Leibniz University of Hannover, Germany Electronic address
    Prostaglandins Other Lipid Mediat 109:23-31. 2014
    ..In order to investigate the kinetics of changes in oxylipin levels in response to LC n-3 PUFA ingestion, we conducted a single dose treatment study with healthy subjects...
  58. pmc Synthesis and functional survey of new Tacrine analogs modified with nitroxides or their precursors
    Tamas Kalai
    Institute of Organic and Medicinal Chemistry, University of Pecs, H 7624 Pecs, Szigeti St 12 Pécs, Hungary
    Eur J Med Chem 77:343-50. 2014
    ....
  59. pmc Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure
    Dong Sun
    Department of Physiology, New York Medical College, Valhalla, New York
    Am J Physiol Heart Circ Physiol 306:H1146-53. 2014
    ..In conclusion, the increased EET bioavailability, as a function of deficiency/inhibition of sEH, potentiates vasodilator responses that counteract pressure-induced vasoconstriction to lower blood pressure...
  60. pmc Preparation of 20-HETE using multifunctional enzyme type 2-negative Starmerella bombicola
    Inge Van Bogaert
    Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium
    J Lipid Res 54:3215-9. 2013
    ....
  61. pmc Epoxyeicosanoids promote organ and tissue regeneration
    Dipak Panigrahy
    Vascular Biology Program and Department of Surgery, Boston Children s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 110:13528-33. 2013
    ..Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis. ..
  62. pmc Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis
    Guodong Zhang
    Department of Entomology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 110:6530-5. 2013
    ..These results designate epoxyeicosatrienoic acids and EDPs as unique endogenous mediators of an angiogenic switch to regulate tumorigenesis and implicate a unique mechanistic linkage between omega-3 and omega-6 fatty acids and cancers...
  63. pmc Use of a soluble epoxide hydrolase inhibitor as an adjunctive analgesic in a horse with laminitis
    Alonso G P Guedes
    Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
    Vet Anaesth Analg 40:440-8. 2013
    ....
  64. pmc Carbon turnover in the water-soluble protein of the adult human lens
    Daniel N Stewart
    Department of Chemistry, University of California, One Shields Avenue, Davis, CA, USA
    Mol Vis 19:463-75. 2013
    ....
  65. pmc Rationally designed multitarget agents against inflammation and pain
    S H Hwang
    Department of Entomology and Comprehensive Cancer Center, University of California, Davis, One Shields Avenue, Davis, CA 95616 8584, USA
    Curr Med Chem 20:1783-99. 2013
    ....
  66. pmc Soluble epoxide hydrolase inhibition and peroxisome proliferator activated receptor γ agonist improve vascular function and decrease renal injury in hypertensive obese rats
    John D Imig
    Department of Pharmacology and Toxicology and Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
    Exp Biol Med (Maywood) 237:1402-12. 2012
    ..These results indicate that even though sEHi or PPARγ agonist have benefits when used individually, the combination is more beneficial for the multidisease features in cardiometabolic syndrome...
  67. pmc Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME
    Zuzana Honetschlägerová
    Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
    J Hypertens 31:321-32. 2013
    ..The present study was performed to investigate in a model of malignant hypertension if the antihypertensive actions of soluble epoxide hydrolase (sEH) inhibition are nitric oxide (NO)-dependent...
  68. pmc Soluble epoxide hydrolase deficiency or inhibition attenuates diet-induced endoplasmic reticulum stress in liver and adipose tissue
    Ahmed Bettaieb
    Department of Nutrition, University of California, Davis, California 95616, USA
    J Biol Chem 288:14189-99. 2013
    ..In summary, these findings demonstrate that sEH is a physiological modulator of ER stress and a potential target for mitigating complications associated with obesity...
  69. pmc Therapeutic activity of inhibition of the soluble epoxide hydrolase in a mouse model of scrapie
    Giorgio Poli
    Department of Veterinary Science and Public Health, Faculty of Veterinary Medicine, University of Milan, Milan, Italy
    Life Sci 92:1145-50. 2013
    ..Stabilization of these bioactive lipids by inhibiting their degradation mediated by the soluble epoxide hydrolase (sEH) results in potent anti-inflammatory effects in multiple disease models...
  70. pmc Nutritional lipidomics: molecular metabolism, analytics, and diagnostics
    Jennifer T Smilowitz
    Foods for Health Institute, University of California, Davis, CA 95616, USA
    Mol Nutr Food Res 57:1319-35. 2013
    ..Additionally, lipidomics must tackle the task of assigning the functions of lipids as signaling molecules, nutrient sensors, and intermediates of metabolic pathways. ..
  71. pmc Niemann-pick type C2 deficiency in human fibroblasts confers robust and selective activation of prostaglandin E2 biosynthesis
    Andrey Frolov
    Division of Rheumatology, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky 40536, USA
    J Biol Chem 288:23696-703. 2013
    ....
  72. pmc Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors
    Sung Hee Hwang
    Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, One Shields Avenue, Davis, CA 95616 8584, USA
    Bioorg Med Chem Lett 23:3732-7. 2013
    ..The data presented suggest a potential rational approach to control the angiogenic responses stemming from sEH inhibition...
  73. pmc Characterization of Hovi-mEH1, a microsomal epoxide hydrolase from the glassy-winged sharpshooter Homalodisca vitripennis
    Shizuo G Kamita
    Department of Entomology, University of California, Davis, CA, USA
    Arch Insect Biochem Physiol 83:171-9. 2013
    ..On the basis of biochemical, phylogenetic, and transcriptome analyses, we hypothesize that Hovi-mEH1 is a biologically relevant JH-metabolizing enzyme in H. vitripennis...
  74. pmc Comparison of free serum oxylipin concentrations in hyper- vs. normolipidemic men
    Jan Philipp Schuchardt
    Institute of Food Science and Human Nutrition, Leibniz University Hannover, Germany
    Prostaglandins Leukot Essent Fatty Acids 89:19-29. 2013
    ..Given that the synthesis of EPA from other n-3 FA in humans is low; this suggests that oxylipin levels can be directly influenced by the diet...
  75. pmc Inhibition of soluble epoxide hydrolase by fulvestrant and sulfoxides
    Christophe Morisseau
    Department of Entomology and UCD Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA
    Bioorg Med Chem Lett 23:3818-21. 2013
    ..We found that fulvestrant, an anticancer agent, is a potent (KI=26 nM) competitive inhibitor of sEH. From this observation, we found that alkyl-sulfoxides represent a new kind of pharmacophore for the inhibition of sEH...
  76. pmc Anti-inflammatory effects of ω-3 polyunsaturated fatty acids and soluble epoxide hydrolase inhibitors in angiotensin-II-dependent hypertension
    Arzu Ulu
    Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA
    J Cardiovasc Pharmacol 62:285-97. 2013
    ....
  77. ncbi Comparison of the effects of long-chain omega-3 fatty acid supplementation on plasma levels of free and esterified oxylipins
    Nils Helge Schebb
    Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Germany Electronic address
    Prostaglandins Other Lipid Mediat 113:21-9. 2014
    ..In this study, we compared the impact of twelve weeks of LC n-3 PUFA supplementation on the patterns of free and total (sum of esterified and free) hydroxy, epoxy and dihydroxy FAs...
  78. pmc Whole blood is the sample matrix of choice for monitoring systemic triclocarban levels
    Nils Helge Schebb
    Institute of Toxicology and Chemical Analysis, University of Veterinary Medicine, Hannover, Germany
    Chemosphere 87:825-7. 2012
    ..Utilizing whole blood sampling, a low but significant absorption of TCC from soap during showering is demonstrated for a small group of human subjects...
  79. pmc Attenuation of vascular smooth muscle cell proliferation by 1-cyclohexyl-3-dodecyl urea is independent of soluble epoxide hydrolase inhibition
    Benjamin B Davis
    Division of Nephrology, Department of Internal Medicine, University of California, Davis, 95616, USA
    J Pharmacol Exp Ther 316:815-21. 2006
    ..In addition, our results show that caution should be used when attempting to infer conclusions of EET biology based solely on the effects these inhibitors in tissue culture models, especially when used at micromolar concentrations...
  80. pmc Naturally occurring monoepoxides of eicosapentaenoic acid and docosahexaenoic acid are bioactive antihyperalgesic lipids
    Christophe Morisseau
    Department of Entomology and Cancer Center, School of Medicine, University of California, Davis, CA 95616, USA
    J Lipid Res 51:3481-90. 2010
    ..Consequently, the DHA and eicosapentaenoic acid epoxides may be responsible for some of the beneficial effects associated with dietary n-3 fatty acid intake...
  81. pmc Bioassays of compounds with potential juvenoid activity on Drosophila melanogaster: juvenile hormone III, bisepoxide juvenile hormone III and methyl farnesoates
    Lawrence G Harshman
    School of Biological Sciences, University of Nebraska Lincoln, Lincoln, NE 68588, United States
    J Insect Physiol 56:1465-70. 2010
    ..One possible explanation for the results is that methyl farnesoate is active as a hormone in larval stages, but has little activity at the pupal stage where only juvenile hormone has a major effect...
  82. pmc Inhibition or deletion of soluble epoxide hydrolase prevents hyperglycemia, promotes insulin secretion, and reduces islet apoptosis
    Pengcheng Luo
    Department of Physiology, Medical College of Georgia, Augusta, Georgia 30912, USA
    J Pharmacol Exp Ther 334:430-8. 2010
    ..These results show not only that sEH KO and its inhibition prevent hyperglycemia in diabetes, but also that sEH KO enhances islet GSIS through the amplifying pathway and decreases islet cell apoptosis in diabetes...
  83. pmc Soluble epoxide hydrolase inhibitors and heart failure
    Hong Qiu
    Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, CA, USA Department of Veterans Affairs, Northern California Health Care System Mather, CA, USA Department of Entomology and UC Davis Cancer Center, University of California, Davis, CA, USA
    Cardiovasc Ther 29:99-111. 2011
    ..The data published to date support the notion that sEH inhibitors may represent a promising therapeutic approach for combating detrimental cardiac remodeling and HF. ..
  84. pmc Soluble epoxide hydrolase in atherosclerosis
    Yi Xin Jim Wang
    Arete Therapeutics Inc, 7000 Shoreline Court, Suite 201, South San Francisco, CA 94080, USA
    Curr Atheroscler Rep 12:174-83. 2010
    ..The broad spectrum of biological action of EETs and sEHIs with multiple biological beneficial actions provides a promising new class of therapeutics for atherosclerosis and other cardiovascular diseases...
  85. pmc Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs
    Hsing Ju Tsai
    Department of Entomology and Cancer Center, University of California, Davis, CA 95616, USA
    Eur J Pharm Sci 40:222-38. 2010
    ..Such compounds may also be a valuable lead for the development of veterinary therapeutics...
  86. pmc Function of phenylalanine 259 and threonine 314 within the substrate binding pocket of the juvenile hormone esterase of Manduca sexta
    Shizuo G Kamita
    Department of Entomology, UC Davis Cancer Center, USA
    Biochemistry 49:3733-42. 2010
    ..Our findings also demonstrate that chemical bond strength does not necessarily correlate with how reactive the bond will be to metabolism...
  87. pmc Impact of epoxyeicosatrienoic acids in lung ischemia-reperfusion injury
    Mary I Townsley
    Department of Physiology, Center for Lung Biology, University of South Alabama, Mobile, AL 36688, USA
    Microcirculation 17:137-46. 2010
    ..In this study, we tested whether EETs would be protective in lung ischemia-reperfusion injury...
  88. pmc Reactivity versus steric effects in fluorinated ketones as esterase inhibitors: a quantum mechanical and molecular dynamics study
    Josep Rayo
    Department of Biological Chemistry and Molecular Modeling, IQAC CSIC, Jordi Girona 18 26, 08034, Barcelona, Spain
    J Mol Model 16:1753-64. 2010
    ..Overall, the results sustain a subtle balance between reactivity and steric effects in modulating the inhibitory activity of TFMK inhibitors...
  89. pmc Human milk glycobiome and its impact on the infant gastrointestinal microbiota
    Angela M Zivkovic
    Foods for Health Institute, Department of Food Science and Technology, University of California, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 108:4653-8. 2011
    ....
  90. pmc Immunoassays and biosensors for monitoring environmental and human exposure to pyrethroid insecticides
    Ki Chang Ahn
    Department of Entomology, University of California, Davis, Davis, California 95616, United States
    J Agric Food Chem 59:2792-802. 2011
    ..These new technologies alone and in combination result in an improved ability to both determine if effective levels of pyrethroids are being used in the field and evaluate possible contamination...
  91. pmc Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension
    Zuzana Honetschlägerová
    Department of Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
    J Physiol 589:207-19. 2011
    ..These data suggest that the oral administration of c-AUCB displays antihypertensive effects in Ren-2 transgenic rats with inducible malignant hypertension via an improvement of renal function...
  92. pmc Incorporation of piperazino functionality into 1,3-disubstituted urea as the tertiary pharmacophore affording potent inhibitors of soluble epoxide hydrolase with improved pharmacokinetic properties
    Shao Xu Huang
    State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
    J Med Chem 53:8376-86. 2010
    ..0 nM against human sEH enzyme. ..
  93. pmc Epoxygenated fatty acids and soluble epoxide hydrolase inhibition: novel mediators of pain reduction
    Karen Wagner
    Department of Entomology and University of California Davis Cancer Center, University of California Davis, Davis, California 95616, United States
    J Agric Food Chem 59:2816-24. 2011
    ..This paper provides a brief history of the discovery of the sEH enzyme and argues that inhibitors of sEH through several independent mechanisms display pain-reducing effects...
  94. pmc Electrochemistry-mass spectrometry unveils the formation of reactive triclocarban metabolites
    A Baumann
    Institute of Inorganic and Analytical Chemistry, University of Munster, Munster, Germany
    Drug Metab Dispos 38:2130-8. 2010
    ..Moreover, the occurrence of reactive metabolites is compared with findings from earlier in vivo studies and their relevance in vivo is argued...
  95. pmc Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events
    Jun Yan Liu
    Department of Entomology and University of California Davis Cancer Center, University of California, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 107:17017-22. 2010
    ....
  96. pmc 1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain
    Tristan E Rose
    Department of Entomology and University of California Davis Cancer Center, University of California, One Shields Avenue, Davis, California 95616, USA
    J Med Chem 53:7067-75. 2010
    ..This novel sEH inhibitor showed a 1000-fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mechanical withdrawal threshold using the in vivo carrageenan induced inflammatory pain model...

Research Grants30

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..