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Molecular Pharmacology

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Research ArticleArticle

Inhibition of Cyclooxygenase-2 Expression by 4-Trifluoromethyl Derivatives of Salicylate, Triflusal, and Its Deacetylated Metabolite, 2-Hydroxy-4-trifluoromethylbenzoic Acid

Alberto Fernández de Arriba, Fernando Cavalcanti, Agustí Miralles, Yolanda Bayón, Andrés Alonso, Manuel Merlos, Julián García-Rafanell and Javier Forn
Molecular Pharmacology April 1999, 55 (4) 753-760;
Alberto Fernández de Arriba
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Fernando Cavalcanti
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Agustí Miralles
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Yolanda Bayón
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Andrés Alonso
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Manuel Merlos
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Julián García-Rafanell
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Javier Forn
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Abstract

The therapeutic potential of drugs that block the induction of cyclooxygenase-2 has been emphasized. When two 4-trifluoromethyl salicylate derivatives [2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal) and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB)] were compared with aspirin and sodium salicylate as cyclooxygenase-2 (COX-2) inhibitors, we observed that in bacterial lipopolysaccharide-activated human blood, triflusal, aspirin, and HTB, but not sodium salicylate, inhibited COX-2-mediated prostaglandin E2 (PGE2) production (IC50 = 0.16, 0.18, 0.39, and >10 mM, respectively). However, only triflusal and aspirin inhibited purified COX-2 enzyme. To test this apparent discrepancy, we realized that HTB and triflusal (but neither aspirin nor salicylate) produced a concentration-dependent inhibition of COX-2 protein expression in peripheral human mononuclear cells. This observation was further confirmed in a rat air pouch model in vivo, in which both aspirin and triflusal inhibited PGE2 production (ID50 = 18.9 and 11.4 mg/kg p.o., respectively) but only triflusal-treated animals showed a decrease in COX-2 expression. This different behavior may be, at least in part, due to the ability of HTB and triflusal to block the activation of the transcription factor nuclear factor-κB to a higher extent than aspirin and sodium salicylate. Thus, in addition to inhibiting the COX-2 activity at therapeutic concentrations, triflusal is able to block through its metabolite HTB the expression of new enzyme, and hence the resumption of PGE2synthesis. Triflusal and HTB may exert beneficial effects in processes in which de novo COX-2 expression is involved and, in a broader sense, in pathological situations in which genes under nuclear factor-κB control are up-regulated.

Footnotes

  • Send reprint requests to: Dr. Javier Forn, Department of Pharmacology, Uriach Research Center, Degá Bahı́, 59-67, 08026 Barcelona, Spain. E-mail rd{at}uriach.com

  • Abbreviations:
    COX-1
    cyclooxygenase-1
    COX-2
    cyclooxygenase-2
    ELISA
    enzyme-linked immunosorbent assay
    HTB
    2-hydroxy-4-trifluoromethylbenzoic acid
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
    HUVEC
    human umbilical vein endothelial cell
    LPS
    bacterial lipopolysaccharide
    NF-κB
    nuclear factor-κB
    NSAID
    nonsteroidal anti-inflammatory drug
    PBMC
    peripheral blood mononuclear cell
    PG
    prostaglandin
    • Received November 2, 1998.
    • Accepted January 19, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (4)
Molecular Pharmacology
Vol. 55, Issue 4
1 Apr 1999
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Research ArticleArticle

Inhibition of Cyclooxygenase-2 Expression by 4-Trifluoromethyl Derivatives of Salicylate, Triflusal, and Its Deacetylated Metabolite, 2-Hydroxy-4-trifluoromethylbenzoic Acid

Alberto Fernández de Arriba, Fernando Cavalcanti, Agustí Miralles, Yolanda Bayón, Andrés Alonso, Manuel Merlos, Julián García-Rafanell and Javier Forn
Molecular Pharmacology April 1, 1999, 55 (4) 753-760;

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Research ArticleArticle

Inhibition of Cyclooxygenase-2 Expression by 4-Trifluoromethyl Derivatives of Salicylate, Triflusal, and Its Deacetylated Metabolite, 2-Hydroxy-4-trifluoromethylbenzoic Acid

Alberto Fernández de Arriba, Fernando Cavalcanti, Agustí Miralles, Yolanda Bayón, Andrés Alonso, Manuel Merlos, Julián García-Rafanell and Javier Forn
Molecular Pharmacology April 1, 1999, 55 (4) 753-760;
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