![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
B) Activation:
Role of Arachidonic Acid
Department of Anaesthesia and Critical Care Medicine, Acetylsalicylic acid (aspirin) is the drug most commonly
self-administered to reduce inflammation, swelling, and pain. The established mechanism of action of aspirin is inhibition of the enzyme
cyclo-oxygenase (COX). Once taken, aspirin is rapidly deacetylated to
form salicylic acid, which may account, at least in part, for the
therapeutic actions of aspirin. However, where tested, salicylic acid
has been found to be a relatively inactive inhibitor of COX activity
in vitro, despite being an effective inhibitor of
prostanoids formed at the site of inflammation in vivo.
Recently, the identification of a cytokine-inducible isoform of COX,
COX-2, has led to the suggestion that salicylate produces its
anti-inflammatory actions by inhibiting COX-2 induction through actions
on nuclear factor 
B (NF-B). We have used interleukin
1
-induced COX-2 in human A549 cells to investigate the mechanism of
action of salicylate on COX-2 activity. Sodium salicylate inhibited
prostaglandin E2 release when added together with
interleukin 1 for 24 hr with an IC50 value of 5 µg/ml,
an effect that was independent of NF-B activation or COX-2
transcription or translation. Sodium salicylate acutely (30 min) also
caused a concentration-dependent inhibition of COX-2 activity measured
in the presence of 0, 1, or 10 µM exogenous arachidonic
acid. In contrast, when exogenous arachidonic acid was increased to 30 µM, sodium salicylate was a very weak inhibitor of COX-2
activity with an IC50 of >100 µg/ml. Thus, sodium
salicylate is an effective inhibitor of COX-2 activity at
concentrations far below those required to inhibit NF-B (20 mg/ml)
activation and is easily displaced by arachidonic acid.
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
This article has been cited by other articles:
|
|
 |
|
  C. E. Minge, B. D. Bennett, R. J. Norman, and R. L. Robker Peroxisome Proliferator-Activated Receptor-{gamma} Agonist Rosiglitazone Reverses the Adverse Effects of Diet-Induced Obesity on Oocyte Quality Endocrinology, May 1, 2008; 149(5): 2646 - 2656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. B. Yan, J. K. Unthank, M. Castillo-Melendez, S. L. Miller, S. J. Langford, and D. W. Walker Novel method for in vivo hydroxyl radical measurement by microdialysis in fetal sheep brain in utero J Appl Physiol, June 1, 2005; 98(6): 2304 - 2310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Simmons, R. M. Botting, and T. Hla Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition Pharmacol. Rev., September 1, 2004; 56(3): 387 - 437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. B. DeMeritt, L. E. Milford, and A. D. Yurochko Activation of the NF-{kappa}B Pathway in Human Cytomegalovirus-Infected Cells Is Necessary for Efficient Transactivation of the Major Immediate-Early Promoter J. Virol., May 1, 2004; 78(9): 4498 - 4507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Aronoff, O. Boutaud, L. J. Marnett, and J. A. Oates Inhibition of Prostaglandin H2 Synthases by Salicylate Is Dependent on the Oxidative State of the Enzymes J. Pharmacol. Exp. Ther., February 1, 2003; 304(2): 589 - 595. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Pang, M. Nie, L. Corbett, and A. J. Knox Cyclooxygenase-2 Expression by Nonsteroidal Anti-inflammatory Drugs in Human Airway Smooth Muscle Cells: Role of Peroxisome Proliferator-Activated Receptors J. Immunol., January 15, 2003; 170(2): 1043 - 1051. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Giuliano, J. A. Mitchell, and T. D. Warner Sodium Salicylate Inhibits Prostaglandin Formation without Affecting the Induction of Cyclooxygenase-2 by Bacterial Lipopolysaccharide in Vivo J. Pharmacol. Exp. Ther., December 1, 2001; 299(3): 894 - 900. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-G. DENG, K.-H. RUAN, M. DU, M. A. SAUNDERS, and K. K. WU Aspirin and salicylate bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its ATPase activity in human fibroblasts FASEB J, November 1, 2001; 15(13): 2463 - 2470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-L. Liao, Y.-L. Lin, B.-C. Wu, C.-H. Tsao, M.-C. Wang, C.-I Liu, Y.-L. Huang, J.-H. Chen, J.-P. Wang, and L.-K. Chen Salicylates Inhibit Flavivirus Replication Independently of Blocking Nuclear Factor Kappa B Activation J. Virol., September 1, 2001; 75(17): 7828 - 7839. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Jiang, I. Elson-Schwab, C. Courtemanche, and B. N. Ames gamma -Tocopherol and its major metabolite, in contrast to alpha -tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells PNAS, September 22, 2000; (2000) 200357097. [Abstract] [Full Text]
|
|
|
|
|
|
T. D. Warner, F. Giuliano, I. Vojnovic, A. Bukasa, J. A. Mitchell, and J. R. Vane Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: A full in vitro analysis PNAS, June 22, 1999; 96(13): 7563 - 7568. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-M. Xu, L. Sansores-Garcia, X.-M. Chen, N. Matijevic-Aleksic, M. Du, and K. K. Wu Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate PNAS, April 27, 1999; 96(9): 5292 - 5297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. SESTINI, R. M. REFINI, M. G. PIERONI, A. VAGHI, M. ROBUSCHI, and S. BIANCO Different Effects of Inhaled Aspirinlike Drugs on Allergen-Induced Early and Late Asthmatic Responses Am. J. Respir. Crit. Care Med., April 1, 1999; 159(4): 1228 - 1233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. F. de Arriba, F. Cavalcanti, A. Miralles, Y. Bayón, A. Alonso, M. Merlos, J. García-Rafanell, and J. Forn Inhibition of Cyclooxygenase-2 Expression by 4-Trifluoromethyl Derivatives of Salicylate, Triflusal, and Its Deacetylated Metabolite, 2-Hydroxy-4-trifluoromethylbenzoic Acid Mol. Pharmacol., April 1, 1999; 55(4): 753 - 760. [Abstract] [Full Text]
|
|
|
|
|
|
M. A. Saunders, M. G. Belvisi, G. Cirino, P. J. Barnes, T. D. Warner, and J. A. Mitchell Mechanisms of Prostaglandin E2 Release by Intact Cells Expressing Cyclooxygenase-2: Evidence for a `Two-Component' Model J. Pharmacol. Exp. Ther., March 1, 1999; 288(3): 1101 - 1106. [Abstract] [Full Text]
|
|
|
|
|
|
L. C. HAMILTON, J. A. MITCHELL, A. M. TOMLINSON, and T. D. WARNER Synergy between cyclo-oxygenase-2 induction and arachidonic acid supply in vivo: consequences for nonsteroidal antiinflammatory drug efficacy FASEB J, February 1, 1999; 13(2): 245 - 251. [Abstract] [Full Text]
|
|
|
|
 |
|
 K. Harms, I. Ramirez, and H. Peña-Cortés Inhibition of Wound-Induced Accumulation of Allene Oxide Synthase Transcripts in Flax Leaves by Aspirin and Salicylic Acid Plant Physiology, November 1, 1998; 118(3): 1057 - 1065. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. A. Saunders, L. Sansores-Garcia, D. W. Gilroy, and K. K. Wu Selective Suppression of CCAAT/Enhancer-binding Protein beta Binding and Cyclooxygenase-2 Promoter Activity by Sodium Salicylate in Quiescent Human Fibroblasts J. Biol. Chem., May 25, 2001; 276(22): 18897 - 18904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Jiang, I. Elson-Schwab, C. Courtemanche, and B. N. Ames gamma -Tocopherol and its major metabolite, in contrast to alpha -tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells PNAS, October 10, 2000; 97(21): 11494 - 11499. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
