DOCSLIB.ORG

Lipoxygenases and Their Involvement in Programmed Cell Death

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Lipoxygenases and Their Involvement in Programmed Cell Death Cell Death and Differentiation (2001) 8, 776 ± 784 ã 2001 Nature Publishing Group All rights reserved 1350-9047/01 $15.00 www.nature.com/cdd Review Lipoxygenases and their involvement in programmed cell death ,1 1 ,1 M Maccarrone* , G Melino and A Finazzi-AgroÁ* The lipoxygenase family 1 Department of Experimental Medicine and Biochemical Sciences, University of Lipoxygenases (linoleate:oxygen oxidoreductase, EC Rome Tor Vergata, I-00133 Rome, Italy 1.13.11.12; LOXs) are a family of monomeric non-heme, * Corresponding authors: Prof A Finazzi-AgroÁ or Dr M Maccarrone, Department non-sulfur iron dioxygenases, which catalyze the conversion of Experimental Medicine and Biochemical Sciences, University of Rome Tor of polyunsaturated fatty acids into conjugated hydroperox- Vergata, Via di Tor Vergata 135, I-00133 Rome, Italy. Tel: +39 06 72596468; ides. The unsaturated fatty acids, which are essential in Fax: +39 06 72596468; E-mail: [email protected] or [email protected] humans, are absent in most bacteria and thus LOXs are also absent in typical prokaryotes. LOXs are widely expressed in Received 7.3.01; revised 9.5.01; accepted 10.5.01 animal and plant cells, sometimes at high level, and their Edited by H Ichijo activity may initiate the synthesis of a signaling molecule or may induce structural or metabolic changes in the cell. Mammalian lipoxygenases have been implicated in the Abstract pathogenesis of several inflammatory conditions such as 1 Lipoxygenases are a family of enzymes which dioxygenate arthritis, psoriasis and bronchial asthma. They are also unsaturated fatty acids, thus initiating lipoperoxidation of thought to have a role in atherosclerosis, brain aging, HIV infection, kidney disease and terminal differentiation of membranes and the synthesis of signaling molecules. keratinocytes. In plants, lipoxygenases favor germination, Consequently, they induce structural and metabolic changes participate in the synthesis of traumatin and jasmonic acid and in the cell in a number of pathophysiological conditions. in the response to abiotic stress.2 Recently, a pro-apoptotic effect of lipoxygenase, and of the The phylogenetic tree shows that plant and animal LOXs hydroperoxides produced thereof, has been reported in are separate branches, each forming several subgroups.3 different cells and tissues, leading to cell death. Anti-apoptotic When arachidonic (eicosatetraenoic, C20:4; ETE) acid is effects of lipoxygenases have also been reported; however, the substrate, different LOX isozymes can add a thishasoften been basedon theuseof enzyme inhibitors. Here hydroperoxy group at carbons 5, 12 or 15, and therefore we review the characteristics of the lipoxygenase family and they are designated 5-, 12- or 15-lipoxygenases. Linoleic its involvement in the initiation of oxidative stress-induced (octadecadienoic, C18:2; OD) acid and linolenic (octade- apoptosis. Finally, we discuss the role of lipoxygenase catrienoic, C18:3; OT) acid are also substrates of LOXs. Soybean (Glycine max) lipoxygenase-1 (LOX-1) is a 15- activation in apoptosis of animal and plant cells, suggesting lipoxygenase widely used as a prototype for studying the a common signal transduction pathway in cell death homologous family of lipoxygenases from tissues of conserved through evolution of both kingdoms. Cell Death different species, both in structural4 and kinetic5 investiga- and Differentiation (2001) 8, 776 ± 784. tions. The primary sequence and three dimensional structure Keywords: arachidonate; calcium; membranes; mitochondrial of LOX-1 have been determined, showing that it is an uncoupling; peroxidation ellipsoid of 90 by 65 by 60 AÊ , with 839 amino acid residues and a molecular mass of 93840 Da.3 LOX-1 is made of two Abbreviations: CycA, cyclosporin A; ERK, extracellular regulated domains: a 146-residue b-barrel at the N-terminal (domain kinase; ETE, eicosatetraenoic (arachidonic) acid; ETYA, eicosate- I) and a 693-residue helical bundle at the C-terminal traynoic acid; FLAP, 5-lipoxygenase activating protein; GSH, (domain II). The iron-containing active site is in the center reduced glutathione; H(P), hydro(pero)xide; HR, hypersensitive of domain II, liganded to four conserved histidines and to response; IL-R, interleukin receptor; LO(O)H, lipid hydro(pero)xide; the carboxyl group of the C-terminal conserved isoleucine. LOX, lipoxygenase; LRP, lentil root protoplast; MAPK, mitogen- It can be reached through the two cavities (I and II), as activated protein kinase; NAC, N-acetylcysteine; NDGA, nordihy- shown in Figure 1. Cavity I presents an ideal path for the droguaiaretic acid; NF-kB, nuclear factor-kB; NSAID, nonsteroidal access of molecular oxygen to iron, whereas cavity II can anti-in¯ammatory drug; OD, octadecadienoic (linoleic) acid; OT, accommodate arachidonic acid or even slightly larger fatty octadecatrienoic (linolenic) acid; PCD, programmed cell death; acids. Mammalian lipoxygenases lack the N-terminal nPG, n-propyl gallate; ROS, reactive oxygen species; TGF, domain present in LOX-1 and related plant lipoxygenases, transforming growth factor; TI, toxic intermediates; TNF, tumor thus showing smaller molecular mass (75 ± 80 kDa com- necrosis factor pared to 94 ± 104 kDa in plants). The N-terminal domain in LOX-1 makes only a loose contact with the C-terminal domain; this may be dispensable for plant lipoxygenases, Lipoxygenases and apoptosis M Maccarrone et al 777 Figure 1 Schematic diagram of the three-dimensional structure of soybean (Glycine max) lipoxygenase-1, showing the small N-terminal domain I and the large C- terminal domain II. The iron-containing active site is located in domain II, and can be reached by molecular oxygen through cavity I and by arachidonic acid through cavity II. The b-sandwiches are represented in yellow, the a-helices in blue, the random coils in gray and the iron in red. The three-dimensional structure was modeled through the MOLSCRIPT program, using the lipoxygenase-1 sequence (PDB accession number: 2SBL) because all the amino acid side chains responsible for plays a central role in cellular leukotriene synthesis. The catalysis are located in the C-terminal domain. However, interaction of human 5-LOX with cellular proteins has been limited proteolysis experiments indicated that the two recently investigated through the two-hybrid approach,6 domains are instead tightly associated, and that domain ± showing that this enzyme binds to proteins as different as a domain interactions play a role in the reversible unfolding of coactosin-like protein (an element of the cytoskeleton), a LOX-1, through ionic interactions. LOX-1 is usually in the transforming growth factor (TGF) type b receptor-I- inactive Fe2+ form and oxidation to the active Fe3+ enzyme associated protein 1 (involved in TGF signaling), and a is required for catalysis. Substrate dioxygenation by LOX-1 hypothetical helicase (a DNA metabolizing enzyme). can be explained by two different mechanisms, indicated as Complex protein-protein interactions have been demon- `free-radical' and `organoiron' respectively, both compatible strated in nuclear membrane translocation, activation and with the iron coordination in the active site (Figure 2A). substrate binding by 5-LOX in intact cells.3 In fact, cell They explain in different ways the C-H bond cleavage of activation by different stimuli results in translocation of 5- the substrate, which is the rate-limiting step of the overall LOX to the nuclear membrane, where it associates with a dioxygenation reaction.3 Thefreeradicalmechanism `5-LOX activating protein' (FLAP), an 18 kDa integral assumes an involvement of Fe in the (stereospecific) membrane protein which acts as an arachidonic acid hydrogen abstraction from the methylene group in the transfer protein and is essential for full leukotriene pentadiene system of the substrate, yielding a free radical biosynthesis. FLAP shows homology with leukotriene C4 intermediate. The hydrogen removal implies the reduction synthase and other microsomal glutathione transferases, of Fe3+ to Fe2+ (Figure 2B). The organoiron hypothesis but no enzymatic activity itself. Initially, FLAP was believed involves concerted deprotonation, catalyzed by a basic to be localized at the outer cell membrane, but later it group (B) in the active site and electrophilic attack of Fe on became clear that it is associated with the nuclear the substrate, without any formal change in the iron envelope. Thus, arachidonic acid released from the oxidation state (Figure 2C). nuclear membrane of leukocytes, and presented to 5-LOX In mammals, most work has been done on 5- by FLAP, may be the substrate for leukotriene synthesis.3 lipoxygenase (arachidonate:oxygen 5-oxidoreductase, EC Recently, growing evidence has accumulated suggesting 1.13.11.34; 5-LOX), which is found primarily in polymorpho- that FLAP can have effects independent of 5-LOX.7 Also nuclear leukocytes, macrophages and mast cells, where it regulatory, nonenzymatic activities of 5-LOX have been Cell Death and Differentiation Lipoxygenases and apoptosis M Maccarrone et al 778 reported, made possible by an Src homology 3 (SH3) binding motif, which enables the interaction with growth factor receptor-bound protein 2 (Grb2) and cytoskeletal proteins.6 In this line, a possible interaction of 5-LOX with the nuclear factor-kB(NF-kB) complex seems to indicate that 5-LOX protein might also indirectly influence gene transcription.6 The ability of 5-LOX to enter the nucleus supports its regulatory role on the transcription process, though possible nonenzymatic functions of 5-LOX protein wait to be investigated. Lipoxygenase involvement in apoptotic pathways LOX products have been shown to induce PCD in human T cells,8 neutrophils,9 PC12h cells10 and Jurkat cells.11 There- fore, it is not surprising that activation of lipoxygenases has been associated to programmed death of different cells and tissues, induced by different, unrelated stimuli (Table 1 and references therein). Several studies have shown the pro- apoptoticactivityof5-LOX,15,23 of leukocyte type 12- LOX,21,26 and of 15-LOX,24,28 and have indicated molecular targets for lipoxygenase interaction able to contribute to the induction of apoptosis (Table 2 and references therein).
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]