DOCSLIB.ORG

Arachidonate 5-Lipoxygenase and Its Activating Protein: Prominent Hippocampal Expression and Role in Somatostatin Signaling

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Arachidonate 5-Lipoxygenase and Its Activating Protein: Prominent Hippocampal Expression and Role in Somatostatin Signaling UC Irvine UC Irvine Previously Published Works Title Arachidonate 5-lipoxygenase and its activating protein: prominent hippocampal expression and role in somatostatin signaling. Permalink https://escholarship.org/uc/item/5sg8x09h Journal Journal of neurochemistry, 66(1) ISSN 0022-3042 Authors Lammers, CH Schweitzer, P Facchinetti, P et al. Publication Date 1996 DOI 10.1046/j.1471-4159.1996.66010147.x License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Journal of Neurochemistry Lippincott—Raven Publishers, Philadelphia © 1996 International Society for Neurochemistry Arachidonate 5-Lipoxygenase and Its Activating Protein: Prominent Hippocampal Expression and Role in Somatostatin Signaling *C...H. Lammers, tP. Schweitzer, ~ Facchinetti, *J..M. Arrang, 1S. G. Madamba, tO. R. Siggins, and *tD. Piomelli * Unite de Neurobiologie et Pharmacologie de I ‘INSERM, Paris, France; and tScripps Research Institute, La Jolla; and ~Neurosciences Institute, San Diego, California, U.S.A. Abstract: 5-Lipoxygenase—activating protein (FLAP) is 2~ an 18-kDa integral membrane protein required, in periph- andpie cofactorsATP (Ford-Hutchinsonto become fullyet ai., active,1994).includingRises inCain- eral cells, for the activation of 5-lipoxygenase (5-LO) and tracellular Ca2~cause the transiocation of 5-LO from for the resulting synthesis of leukotrienes from arachi- cytosoi to membrane, where the enzyme interacts with donic acid. In the brain, the leukotrienes have been impli- an 18-kDa integral membrane protein, 5-lipoxygen- cated in several pathophysiological events and in the ase—activating protein (FLAP), required for leuko- electrophysiological effect of somatostatin, yet the cellu- triene biosynthesis in peripheral cells (Dixon et al., lar origin and role of these messenger molecules are still 1990; Miller et al., 1990; Abramovitz et al., 1993). poorly understood. In the present study, we used reverse Arachidonic acid metabolism via the 5-LO pathway transcriptase—polymerase chain reaction, in situ hybrid- ization, and immunohistochemistry to demonstrate that may play important roles in the CNS (for review, see 5-LO and FLAP are expressed in various regions of the Piomelli, 1994). In vitro, preparations of brain tissue rat brain, including hippocampus, cerebellum, primary 01- convert exogenous and endogenous arachidonic acid factory cortex, superficial neocortex, thalamus, hypothal- to leukotrienes and to other 5-LO products (Lindgren amus, and brainstem. Highest levels of expression were et al., 1984; Adesuyi et al., 1985; Shimizu et al., 1987). observed in cerebellum and hippocampus. In the latter In vivo, leukotriene biosynthesis is stimulated by the we demonstrate the colocalization of 5-La and FLAP in intracerebroventricular administration of platelet-acti- CAl pyramidal neurons. Moreover, electrophysiological vating factor and is associated with the induction of experiments show that selective inhibition of FLAP with seizure activity, ischemia, and intracranial tumors the compound MK-886 (0.25—1 1sM) prevents the so- (Simmet and Peskar, 1990; Hynes et al., 1991). More- matostatin-induced augmentation of the hippocampal K~ over, LTC M-current. Our results provide necessary evidence for the 4 exerts multiple actions on neural cells, such presence and signaling role of 5-LO and FLAP in central as prolonged excitation of cerebellar Purkinje neurons neurons and strongly support their proposed participa- (Palmer et al., 1981), stimulation of luteinizing hor- tion in somatostatin-receptor transmembrane signaling. mone release from anterior pituitary cells (Kiesel et Key Words: Arachidonic acid— Leukotrienes—Signal al., 1991), and enhancement of the M-current (IM) in transduction— Hippocampus. the hippocampal CAl field (Schweitzer et al., 1990, J. Neurochem. 66, 147—152 (1996). 1993). The ‘M is a noninactivating time- and voltage-depen- dent K~current (Brown and Adams, 1980) that, in The leukotrienes, a family of biologically active me- tabolites of arachidonic acid, are synthesized through Received April 20, 1995; final revised manuscript received July a sequence of enzymatic reactions initiated by 5-lipox- 10, 1995; accepted July 13, 1995. ygenase (5-LO), a cytosolic dioxygenase that cata- The present address of Dr. C-H. Lammers is Max Planck Institute for Psychiatry, Clinical Institute, Munich, Germany. lyzes both the initial oxidation of arachidonic acid to Address correspondence and reprint requests to Dr. D. Piomelli 5-hydroperoxy-6,8,1 1,14-eicosatetraenoic acid and its at Neurosciences Institute, 10640 John J. Hopkins Drive, San Diego, subsequent dehydration to leukotriene A4 (LTA4). CA 92121, U.S.A. LTA4 is short lived and may be rapidly transformed Abbreviations used: FLAP, 5-lipoxygenase—activating protein; either into LTC4, by LTC4-synthase, or into LTB4, 154, M-current, a noninactivating time- and voltage-dependent K~ current; 5-LO, 5-lipoxygenase; LT, leukotriene; PCR, polymerase by LTA4-hydrolase (Samuelsson et al., 1987). Unlike chain reaction; PLA2, phospholipase A2 RT, reverse transcriptase; other mammalian lipoxygenases, 5-LO requires multi- SDS, sodium dodecyl sulfate; SSC, standard saline citrate. /47 148 C.-H. LAMMERS ET AL. hippocampal pyramidal neurons, is reduced by musca- hybridizations were performed in the presence of 50%35S-la-for- rinic receptor agonists (Halliwell and Adams, 1982) beledmamideantisenseand 10 oligonucleotidesmM dithiothreitol,(baseusing89—109syntheticfor 5-LO and and augmented by the neuropeptide somatostatin —6 to 14 for FLAP). We used as control a missense oligonu- (Moore et al., 1988). Pharmacological evidence indi- cleotide (5 ‘-ACA TAT CTG ACT TCG AAT GCC-3’). In cates that a 5-LO metabolite of arachidonic acid medi- some experiments, distribution of 5-LO mRNA was con- ates the effect of somatostatin; ‘M enhancement by so- firmed by using a riboprobe prepared with a Promega ribo- matostatin is prevented by drugs that inhibit phospholi- probe kit from a Smal—BamHI DNA fragment correspond- pase A ing to nucleotides 1,417—1,735 of human 5-LO sequence 2 (PLA2) or 5-LO activities and mimicked by (Dixon et al., 1988), obtained by excision of a recombinant applications of exogenous arachidonic acid or LTC4 5-LO pUC 13 plasmid vector (generously provided by Dr. but not by application of LTB4 (Schweitzer et al., 1990, A. Ford-Hutchinson, Merck-Frosst, Canada) and subeloned 1993). in pGEM-4Z. We confirmed distribution of FLAP mRNA Although these studies suggest a signaling role for by using two 32P-labeled oligonucleotide probes, correspond- leukotrienes in the CNS, it is not known whether the ing to nucleotides 86—132 and 285—331 of the rat FLAP enzymatic machinery necessary for leukotriene biosyn- sequence (Dixon et al., 1990). thesis is expressed in neurons and under what circum- Immunohistochemistry stances it may become activated. Here, we report that After a 5-mm fixation with 4% paraformaldehyde, sec- 5-LO and FLAP are coexpressed in rat brain neurons tions were rinsed in phosphate-buffered saline solution, incu- and enriched in discrete regions of the CNS including bated for 12 hat 4°Cwith FLAP antiserum (a gift of Dr. the hippocampus. To test whether FLAP is physiologi- A. Ford-Hutchinson) at a 1:500 dilution, rinsed, incubated cally functional, and involved in somatostatin modula- with biotin-labeled anti-rabbit protein antiserum, treated with avidin/biotin/horseradish peroxidase complex and devel- tion of ‘M~ we used the compound MK-886, a potent and selective FLAP inhibitor (Dixon et al., 1990). oped with diaminobenzidine for 5 mm. We find that the effect of somatostatin on ‘M in the Electrophysiology hippocampal slice preparation is abolished by MK- We performed intracellular recordings in rat hippocampal 886. Thus, our results provide strong support to a re- slices, as described previously (Schweitzer et al., 1993). In quirement of 5-LO and FLAP in transmembrane sig- brief, we cut transverse hippocampal slices (350—400 jim naling of somatostatin receptors in hippocampal neu- thick) and superfused them (2.0—4.0 mI/mm) with warm rons. (30—31°C),gassed (95% 02,5% C0 2) artificial CSF of the following composition (mM): NaCI 130, KC1 3.5, NaH2PO4 EXPERIMENTAL PROCEDURES 1.25, MgSO4 1.5, CaCl-, 2.0, NaHCO2 24, glucose 10. We Reverse transcriptase (RT) —polymerase chain dissolved MK-886 (a gift of Dr. A. Ford-Hutchinson) and reaction (PCR) analysis LTC4 (Biomol Research Laboratories, Plymouth Meeting, PA, U.S.A.) in 0.05% dimethyl sulfoxide, which alone had Poly (A) + mRNAs prepared from various regions of the no significant effect on ‘M~ We used sharp glass micropi- Wistar rat brain served as templates for eDNA synthesis pettes filled with 3 M KCI (tip resistances, 55—88 mIl) to using avian myeloblastosis virus RT (25 units, Boehringer). penetrate CA I pyramidal neurons for voltage clamp studies, We used the cDNAs obtained as templates to amplify, by using an Axoclamp preamplifier (Axon Instruments) in dis- PCR, DNA fragments corresponding to nucleotides —9 to continuous single-electrode voltage-clamp mode. We added 459 of rat FLAP sequence (Dixon et al., 1990) and nucleo- tetrodotoxin (0.5—1 pM) to block synaptic transmission and tides 442—1,028 of rat 5-LO sequence (Balcarek et al., Nat-dependent action potentials. We acquired current and 1988). PCR conditions were as follows: 92°C, 56°C,and voltage records by A/D sampling and acquisition software 72°C for I mm each; amplification of FLAP eDNA
Load more

Recommended publications
  • Role of 15-Lipoxygenase/15-Hydroxyeicosatetraenoic Acid in Hypoxia-Induced Pulmonary Hypertension
    J Physiol Sci (2012) 62:163–172 DOI 10.1007/s12576-012-0196-9 REVIEW Role of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in hypoxia-induced pulmonary hypertension Daling Zhu • Yajuan Ran Received: 29 September 2011 / Accepted: 25 January 2012 / Published online: 14 February 2012 Ó The Physiological Society of Japan and Springer 2012 Abstract Pulmonary arterial hypertension (PAH) is a Introduction rare disease with a complex aetiology characterized by elevated pulmonary artery resistance, which leads to right Pulmonary hypertension (PH) is a severe and frequently heart ventricular afterload and ultimately progressing to fatal disease characterized by elevated mean pulmonary right ventricular failure and often death. In addition to arterial (PA) pressure greater than 25 mmHg at rest or other factors, metabolites of arachidonic acid cascade play greater than 30 mmHg with exercise [1], and which con- an important role in the pulmonary vasculature, and dis- tributes to the morbidity and mortality of adult and pedi- ruption of signaling pathways of arachidonic acid plays a atric patients with various lung and heart diseases. central role in the pathogenesis of PAH. 15-Lipoxygenase According to the Venice Classification of Pulmonary (15-LO) is upregulated in pulmonary artery endothelial Hypertension in 2003, PH is currently classified into five cells and smooth muscle cells of PAH patients, and its categories as listed in Table 1. Importantly, many of these metabolite 15-hydroxyeicosatetraenoic acid (15-HETE) in diseases or conditions are associated with persistent or particular seems to play a central role in the contractile intermittent hypoxia, either globally or regionally, within machinery, and in the initiation and propagation of cell confined areas of the lung [2].
    [Show full text]
  • Eicosanoids in Carcinogenesis
    4open 2019, 2,9 © B.L.D.M. Brücher and I.S. Jamall, Published by EDP Sciences 2019 https://doi.org/10.1051/fopen/2018008 Special issue: Disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer” Available online at: Guest Editor: Obul R. Bandapalli www.4open-sciences.org REVIEW ARTICLE Eicosanoids in carcinogenesis Björn L.D.M. Brücher1,2,3,*, Ijaz S. Jamall1,2,4 1 Theodor-Billroth-Academy®, Germany, USA 2 INCORE, International Consortium of Research Excellence of the Theodor-Billroth-Academy®, Germany, USA 3 Department of Surgery, Carl-Thiem-Klinikum, Cottbus, Germany 4 Risk-Based Decisions Inc., Sacramento, CA, USA Received 21 March 2018, Accepted 16 December 2018 Abstract- - Inflammation is the body’s reaction to pathogenic (biological or chemical) stimuli and covers a burgeoning list of compounds and pathways that act in concert to maintain the health of the organism. Eicosanoids and related fatty acid derivatives can be formed from arachidonic acid and other polyenoic fatty acids via the cyclooxygenase and lipoxygenase pathways generating a variety of pro- and anti-inflammatory mediators, such as prostaglandins, leukotrienes, lipoxins, resolvins and others. The cytochrome P450 pathway leads to the formation of hydroxy fatty acids, such as 20-hydroxyeicosatetraenoic acid, and epoxy eicosanoids. Free radical reactions induced by reactive oxygen and/or nitrogen free radical species lead to oxygenated lipids such as isoprostanes or isolevuglandins which also exhibit pro-inflammatory activities. Eicosanoids and their metabolites play fundamental endocrine, autocrine and paracrine roles in both physiological and pathological signaling in various diseases. These molecules induce various unsaturated fatty acid dependent signaling pathways that influence crosstalk, alter cell–cell interactions, and result in a wide spectrum of cellular dysfunctions including those of the tissue microenvironment.
    [Show full text]
  • Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid
    Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 231 _____________________________ _____________________________ Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid Cloning, Expression and Catalytic Properties of CYP4F8 and CYP4F21 BY JOHAN BYLUND ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2000 Dissertation for the Degree of Doctor of Philosophy (Faculty of Pharmacy) in Pharmaceutical Pharmacology presented at Uppsala University in 2000 ABSTRACT Bylund, J. 2000. Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid: Cloning, Expression and Catalytic Properties of CYP4F8 and CYP4F21. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from Faculty of Pharmacy 231 50 pp. Uppsala. ISBN 91-554-4784-8. Cytochrome P450 (P450 or CYP) is an enzyme system involved in the oxygenation of a wide range of endogenous compounds as well as foreign chemicals and drugs. This thesis describes investigations of P450-catalyzed oxygenation of prostaglandins, linoleic and arachidonic acids. The formation of bisallylic hydroxy metabolites of linoleic and arachidonic acids was studied with human recombinant P450s and with human liver microsomes. Several P450 enzymes catalyzed the formation of bisallylic hydroxy metabolites. Inhibition studies and stereochemical analysis of metabolites suggest that the enzyme CYP1A2 may contribute to the biosynthesis of bisallylic hydroxy fatty acid metabolites in adult human liver microsomes. 19R-Hydroxy-PGE and 20-hydroxy-PGE are major components of human and ovine semen, respectively. They are formed in the seminal vesicles, but the mechanism of their biosynthesis is unknown. Reverse transcription-polymerase chain reaction using degenerate primers for mammalian CYP4 family genes, revealed expression of two novel P450 genes in human and ovine seminal vesicles.
    [Show full text]
  • Eicosanoids Mediate Insect Nodulation Responses to Bacterial Infections (Cyclooxygenase/Lipoxygenase/Phospholipase A2/Manduca Sexta/Serratia Marcescens) JON S
    Proc. Natl. Acad. Sci. USA Vol. 91, pp. 12418-12422, December 1994 Physiology Eicosanoids mediate insect nodulation responses to bacterial infections (cyclooxygenase/lipoxygenase/phospholipase A2/Manduca sexta/Serratia marcescens) JON S. MILLER, TUANH NGUYEN, AND DAVID W. STANLEY-SAMUELSON* Insect Biochemistry/Physiology Laboratory, Department of Entomology, University of Nebraska, Lincoln, NE 68583-0816 Communicated by Wendell L. Roelofs, September 12, 1994 (receivedfor review August 11, 1993) ABSTRACT We propose that nodule formation is medi- inhibiting eicosanoid biosynthesis. On the basis of these ated by eicosanoids in insects. Nodulation is the temporally and findings, we proposed that eicosanoid products of the cyclo- quantitatively predominant cellular defense response to bac- oxygenase and lipoxygenase pathways are involved in insect terial infection in insects and other invertebrates. Inhibition of immune responses to bacterial infections. Because most of eicosanoid biosynthesis in larvae of the tobacco hornworn our experiments were done during the first hour postinfection Manduca sexta immediately prior to intrahemocoelic infections (PI), long before the appearance of antibacterial proteins in with the bacterium Serratia marcescens strongly reduced the insect hemolymph, we suggested that eicosanoids mediate nodulation response. Inhibition of eicosanoid biosynthesis also one or more hemocytic defense responses (6). reduced formation of cellular aggregates at 1 hr postinfection, This suggestion opens a crucial question: which
    [Show full text]
  • Serum Leukotriene Metabolism and Type I Hypersensitivity Reactions in Different Animal Species
    University of Montana ScholarWorks at University of Montana Graduate Student Theses, Dissertations, & Professional Papers Graduate School 1989 Serum leukotriene metabolism and Type I hypersensitivity reactions in different animal species Thulasi Sarojam Unnitan The University of Montana Follow this and additional works at: https://scholarworks.umt.edu/etd Let us know how access to this document benefits ou.y Recommended Citation Unnitan, Thulasi Sarojam, "Serum leukotriene metabolism and Type I hypersensitivity reactions in different animal species" (1989). Graduate Student Theses, Dissertations, & Professional Papers. 3533. https://scholarworks.umt.edu/etd/3533 This Thesis is brought to you for free and open access by the Graduate School at ScholarWorks at University of Montana. It has been accepted for inclusion in Graduate Student Theses, Dissertations, & Professional Papers by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. Maureen and Mike MANSFIELD TJBRARY Copying allowed as provided under provisions of the Fair Use Section of the U.S. COPYRIGHT LAW, 1976. Any copying for commercial purposes or financial gain may be undertaken only with the author's written consent. MontanaUniversity of SERUM LEUKOTRIENE METABOLISM AND TYPE I HYPERSENSITIVITY REACTIONS IN DIFFERENT ANIMAL SPECIES By Thulasi Sarojam Unnithan M.B.B.S., Trivandrum Medical College, India, 1981 Presented in partial fulfillment of the requirements for the degree of Master of Science University of Montana, 1989 8^'an, Graduate School ($hL& . & Date UMI Number: EP34626 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent on the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted.
    [Show full text]
  • Lipoxygenase Inhibition Activity of Coumarin Derivatives—QSAR and Molecular Docking Study
    pharmaceuticals Article Lipoxygenase Inhibition Activity of Coumarin Derivatives—QSAR and Molecular Docking Study Melita Lonˇcari´c 1 , Ivica Strelec 1 , Valentina Pavi´c 2 , Domagoj Šubari´c 3, Vesna Rastija 3 and Maja Molnar 1,* 1 Faculty of Food Faculty Osijek, Josip Juraj Strossmayer University, 31000 Osijek, Croatia; [email protected] (M.L.); [email protected] (I.S.) 2 Department of Biology, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; [email protected] 3 Department of Agroecology and Environmental Protection, Faculty of Agrobiotechnical Sciences Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; [email protected] (D.Š.); [email protected] (V.R.) * Correspondence: [email protected]; Tel.: +385-31-224-342 Received: 2 July 2020; Accepted: 15 July 2020; Published: 17 July 2020 Abstract: Lipoxygenases (LOXs) are a family of enzymes found in plants, mammals, and microorganisms. In animals and plants, the enzyme has the capability for the peroxidation of unsaturated fatty acids. Although LOXs participate in the plant defense system, the enzyme’s metabolites can have numerous negative effects on human health. Therefore, many types of research are searching for compounds that can inhibit LOXs. The best quantitative structure–activity relationship (QSAR) model was obtained using a Genetic Algorithm (GA). Molecular docking was performed with iGEMDOCK. The inhibition of lipoxygenase was in the range of 7.1 to 96.6%, and the inhibition of lipid peroxidation was 7.0–91.0%. Among the synthesized compounds, the strongest inhibitor of soybean LOX-3 (96.6%) was found to be 3-benzoyl- 7-(benzyloxy)-2H-chromen-2-one.
    [Show full text]
  • The Role of 5-Lipoxygenase in Pathophysiology and Management of Neuropathic Pain
    REVIEW ARTICLE THE ROLE OF 5-LIPOXYGENASE IN PATHOPHYSIOLOGY AND MANAGEMENT OF NEUROPATHIC PAIN Pascanus Lamsihar PT∗, Faldi Yaputra∗∗, Jimmy FA Barus4 and I Putu Eka Widyadharma∗∗,1 ∗Department of Neurology, Provincial Mental Hospital, West Borneo, Indonesia., ∗∗Department of Neurology, Faculty of Medicine, Udayana University-Sanglah General Hospital, Bali, Indonesia., 4Department of Neurology, Faculty of Medicine, Atma Jaya Catholic University, Jakarta-Indonesia. ABSTRACT Neuropathic pain (NP) is a pain caused by lesions in the nervous system. Several causes of NP are traumatic, metabolic disorders, ischemia, toxins, infections, immune-related, and hereditary. The pathophysiology of NP is very complicated and unknown entirely. Therefore the treatment of NP is still unsatisfactory. Recent studies believed the critical role of primary inflammatory mediators in the pathophysiology of NP especially leukotrienes (LTs). The 5- lipoxygenase enzyme (5-LOX) is an enzyme that plays a role in the metabolism of arachidonic acid into LTs. Leukotrienes (LTs) are the essential inflammatory mediators in the pathophysiology of NP. Leukotriene B4 (LTB4) can cause chemotaxis on neutrophils, lowering nociceptors threshold and may contribute to NP. Several studies believed the administration of 5-LOX inhibitors or LTs receptor antagonists could be useful in the management of NP. The purpose of this review is to summarize the involvement of 5-LOX enzyme as an essential role in the pathophysiology and management of NP. KEYWORDS 5-lipoxygenase, leukotrienes,
    [Show full text]
  • DMD # 35121 1 Human Cytochrome P450, CYP2S1, Metabolizes
    DMD Fast Forward. Published on November 10, 2010 as DOI: 10.1124/dmd.110.035121 DMD FastThis Forward. article has not Published been copyedited on andNovember formatted. The 10, final 2010 version as maydoi:10.1124/dmd.110.035121 differ from this version. DMD # 35121 Human Cytochrome P450, CYP2S1, Metabolizes Cyclooxygenase – and Lipoxygenase – Derived Eicosanoids Peter Bui, Satoshi Imaizumi, Sudheer Reddy Beedanagari, Srinivasa T. Reddy, and Oliver Hankinson Department of Pathology and Laboratory Medicine (P.B., S.R.B., and O.H.), Molecular Toxicology Interdepartmental Program (P.B., S.R.B., and O.H.) , Jonsson Comprehensive Cancer Center (P.B., S.R.B., S.T.R., and O.H.), Department of Medicine (S.I., and S.T.R.), and Downloaded from Department of Molecular and Medical Pharmacology (S.T.R.), University of California at Los Angeles, Los Angeles, California 90095 dmd.aspetjournals.org at ASPET Journals on September 26, 2021 1 Copyright 2010 by the American Society for Pharmacology and Experimental Therapeutics. DMD Fast Forward. Published on November 10, 2010 as DOI: 10.1124/dmd.110.035121 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 35121 Running title: CYP2S1 metabolizes eicosanoids To whom correspondence should be addressed: Oliver Hankinson, Ph.D. Departmental of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles. 650 Charles E. Young Drive, Los Angeles, CA. 90095 Tel: 310-825-2936 Fax: 310-794-9272 Email: [email protected] Downloaded from Text: 36 pages Tables: 4 dmd.aspetjournals.org Figures: 10 References: 44 Abstract: 228 words at ASPET Journals on September 26, 2021 Introduction: 588 words Discussion: 1,146 words Abbreviations: CYP and P450, cytochrome P450; HPLC, high-performance liquid chromatography; LC-ESI-MS, liquid chromatography-electrospray ionization-mass spectrometry; MS/MS, tandem mass spectrometry; m/z, mass-to-charge ratio; M-H, molecular mass minus 1 2 DMD Fast Forward.
    [Show full text]
  • Ioi70902.Pdf
    ORIGINAL INVESTIGATION Montelukast, a Once-Daily Leukotriene Receptor Antagonist, in the Treatment of Chronic Asthma A Multicenter, Randomized, Double-blind Trial Theodore F. Reiss, MD; Paul Chervinsky, MD; Robert J. Dockhorn, MD; Sumiko Shingo, MS; Beth Seidenberg, MD; Thomas B. Edwards, MD; for the Montelukast Clinical Research Study Group Objectives: To determine the clinical effect of oral mon- Results: Montelukast improved airway obstruction telukast sodium, a leukotriene receptor antagonist, in asth- (forced expiratory volume in 1 second, morning and matic patients aged 15 years or more. evening peak expiratory flow rate) and patient-reported end points (daytime asthma symptoms, “as-needed” Design: Randomized, multicenter, double-blind, placebo- b-agonist use, nocturnal awakenings) (P,.001 com- controlled, parallel-group study. A 2-week, single- pared with placebo). Montelukast provided near- blind, placebo run-in period was followed by a 12- maximal effect in these end points within the first day week, double-blind treatment period (montelukast of treatment. Tolerance and rebound worsening of asthma sodium, 10 mg, or matching placebo, once daily at bed- did not occur. Montelukast improved outcome end points, time) and a 3-week, double-blind, washout period. including asthma exacerbations, asthma control days (P,.001 compared with placebo), and decreased periph- Setting/Patients: Fifty clinical centers randomly allo- eral blood eosinophil counts (P,.001 compared with pla- cated 681 patients with chronic, stable asthma to receive pla- cebo). The incidence of adverse events and discontinu- cebo or montelukast after demonstrating a forced expira- ations from therapy were similar in the montelukast and tory volume in 1 second 50% to 85% of the predicted value, placebo groups.
    [Show full text]
  • Strict Regio-Specificity of Human Epithelial 15-Lipoxygenase-2
    Strict Regio-specificity of Human Epithelial 15-Lipoxygenase-2 Delineates its Transcellular Synthesis Potential Abigail R. Green, Shannon Barbour, Thomas Horn, Jose Carlos, Jevgenij A. Raskatov, Theodore R. Holman* Department Chemistry and Biochemistry, University of California Santa Cruz, 1156 High Street, Santa Cruz CA 95064, USA *Corresponding author: Tel: 831-459-5884. Email: [email protected] FUNDING: This work was supported by the NIH NS081180 and GM56062. Abbreviations: LOX, lipoxygenase; h15-LOX-2, human epithelial 15-lipoxygenase-2; h15-LOX-1, human reticulocyte 15-lipoxygenase-1; sLO-1, soybean lipoxygenase-1; 5-LOX, leukocyte 5-lipoxygenase; 12-LOX, human platelet 12-lipoxygenase; GP, glutathione peroxidase; AA, arachidonic acid; HETE, hydoxy-eicosatetraenoic acid; HPETE, hydroperoxy-eicosatetraenoic acid; diHETEs, dihydroxy-eicosatetraenoic acids; 5-HETE, 5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid; 5-HPETE, 5-hydro peroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid; 12-HPETE, 12-hydroperoxy-5Z,8Z,10E, 14Z-eicosatetraenoic acid; 15-HPETE, 15-hydroperoxy-5Z,8Z,10Z,13E- eicosatetraenoic acid; 5,15-HETE, 5S,15S-dihydroxy-6E,8Z,10Z,13E-eicosatetraenoic acid; 5,15-diHPETE, 5,15-dihydroperoxy-6E,8Z,10Z,13E-eicosatetraenoic acid; 5,6- diHETE, 5S,6R-dihydroxy-7E,9E,11Z,14Z-eicosatetraenoic acid; LTA4, 5S-trans-5,6- oxido-7E,9E,11Z,14Z-eicosatetraenoic acid; LTB4, 5S,12R-dihydroxy-6Z,8E,10E,14Z- eicosatetraenoic acid; LipoxinA4 (LxA4), 5S,6R,15S-trihydroxy-7E,9E,11Z,13E- eicosatetraenoic acid; LipoxinB4 (LxB4), 5S,14R,15S-trihydroxy-6E,8Z,10E,12E- eicosatetraenoic acid. Abstract Lipoxins are an important class of lipid mediators that induce the resolution of inflammation, and arise from transcellular exchange of arachidonic acid (AA)- derived lipoxygenase products.
    [Show full text]
  • Montelukast, a Leukotriene Receptor Antagonist, for the Treatment of Persistent Asthma in Children Aged 2 to 5 Years
    Montelukast, a Leukotriene Receptor Antagonist, for the Treatment of Persistent Asthma in Children Aged 2 to 5 Years Barbara Knorr, MD*; Luis M. Franchi, MD‡; Hans Bisgaard, MD§; Jan Hendrik Vermeulen, MDʈ; Peter LeSouef, MD¶; Nancy Santanello, MD, MS*; Theresa M. Michele, MD*; Theodore F. Reiss, MD*; Ha H. Nguyen, PhD*; and Donna L. Bratton, MD# ABSTRACT. Background. The greatest prevalence of baseline period. Patients had a history of physician-di- asthma is in preschool children; however, the clinical agnosed asthma requiring use of ␤-agonist and a pre- utility of asthma therapy for this age group is limited by defined level of daytime asthma symptoms. Caregivers a narrow therapeutic index, long-term tolerability, and answered questions twice daily on a validated, asthma- frequency and/or difficulty of administration. Inhaled specific diary card and, at specified times during the corticosteroids and inhaled cromolyn are the most com- study, completed a validated asthma-specific quality-of- monly prescribed controller therapies for young children life questionnaire. Physicians and caregivers completed a with persistent asthma, although very young patients global evaluation of asthma control at the end of the may have difficulty using inhalers, and dose delivery can study. be variable. Moreover, reduced compliance with inhaled Efficacy end points included: daytime and overnight therapy relative to orally administered therapy has been asthma symptoms, daily use of ␤-agonist, days without reported. One potential advantage of montelukast is the asthma, frequency of asthma attacks, number of patients ease of administering a once-daily chewable tablet; ad- discontinued because of asthma, need for rescue medica- ditionally, no tachyphylaxis or change in the safety pro- tion, physician and caregiver global evaluations of file has been evidenced after up to 140 and 80 weeks of change, asthma-specific caregiver quality of life, and pe- montelukast therapy in adults and pediatric patients ripheral blood eosinophil counts.
    [Show full text]
  • Leukotriene Modifiers (Accolate®, Singulair®, Zileuton®)
    Leukotriene Modifiers (Accolate®, Singulair®, Zileuton®) What are They? Leukotriene modifiers reduce swelling and inflammation in the airways to prevent asthma symptoms. You may not notice a change in your asthma symptoms for one to two week, after starting to use them. • These medicines will not stop a sudden asthma attack. Albuterol should be used for sudden asthma attacks. • Only regular daily use of the leukotriene modifiers will prevent asthma symptoms. • It is important that you do not stop or decrease the dose of these medications without contacting your doctor. How should they be used? • Zafirlukast (Accolate®) is a tablet that is taken by mouth twice a day on an empty stomach (1 hour before you eat or 2 hours after you eat). It is very important to take this medicine on an empty stomach. o Zafirlukast must be taken every day even if you don’t have asthma symptoms. If you forget to take your dose on time, do not take twice as much the next time. Take the regularly scheduled dose as soon as you remember, then get back to your regular schedule. o Side effects . Zafirlukast (Accolate®) causes very few side effects. Some people may have headaches, nausea, or diarrhea. Although these side effects are quite uncommon, it is important for you to let your doctor know if you are experiencing any of these while taking zafirlukast. • Montelukast (Singulair®) o A tablet that is taken once a day at nighttime. o You can take Montelukast with or without food. o Montelukast must be taken every day even if you don’t have asthma symptoms.
    [Show full text]