title: Inhibition of the myeloperoxidase chlorinating activity by non-steroidal anti-inflammatory drugs: flufenamic acid and its 5-chloro-derivative directly interact with a recombinant human myeloperoxidase to inhibit the synthesis of hypochlorous acid.
abstract: The present in vitro study was designed to assess the inhibition of the myeloperoxidase (MPO)/H(2)O(2)/Cl(-) system by several non steroidal anti-inflammatory drugs (NSAIDs) of the oxicam family and of nimesulide and to compare their effect with flufenamic acid in order to investigate their influence on the chlorinating activity of MPO as a protective mechanism during chronic inflammatory syndromes. The inhibition of the system was assessed by measurement of the taurine chlorination while the accumulation of compound II was used to investigate the mechanism of inhibition. The oxidation products of NSAIDs by the MPO/H(2)O(2)/Cl(-) system were identified and flufenamic acid and derivatives were also assessed in the inhibition of LDL oxidation in two models. Flufenamic acid (IC(50) = 1.1+/-0.3 microM) is the most efficient inhibitor of the MPO/H(2)O(2)/Cl(-) system and nimesulide (IC(50) = 2.1+/-0.3 microM) is more active than the other NSAIDs of the oxicam family (IC(50) = 8-12 microM). The accumulation of compound II revealed that flufenamic acid acts as an electron donor while the other NSAIDs are antagonists of chloride anions. The identification of the oxidation products confirms that flufenamic behaves like an electron donor and is directly oxidized in the 5-hydroxy-derivative but gives also the 5-chloro-derivative which similarly inhibits the MPO/H(2)O(2)/Cl(-) system. Flufenamic acid has the best inhibiting activity towards the MPO/H(2)O(2)/Cl(-) system. However, in models that assess the LDL oxidation, flufenamic acid and its derivatives were unable to properly inhibit MPO activity as the enzyme is adsorbed on macrostructures such as LDL molecules.
authors.affiliation: Laboratory of Pharmaceutical Chemistry, Institute of Pharmacy, Université Libre de Bruxelles, Campus Plaine 205-5, B-1050 Brussels, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Van Antwerpen
authors.forename: François
authors.initials: F
authors.lastname: Dufrasne
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lequeux
authors.forename: Karim Zouaoui
authors.initials: KZ
authors.lastname: Boudjeltia
authors.forename: Ilham
authors.initials: I
authors.lastname: Lessgyer
authors.forename: Sajida
authors.initials: S
authors.lastname: Babar
authors.forename: Patrick
authors.initials: P
authors.lastname: Moreau
authors.forename: Nicole
authors.initials: N
authors.lastname: Moguilevsky
authors.forename: Michel
authors.initials: M
authors.lastname: Vanhaeverbeek
authors.forename: Jean
authors.initials: J
authors.lastname: Ducobu
authors.forename: Jean
authors.initials: J
authors.lastname: Nève
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D002460:Cell Line; D002713:Chlorine / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005439:Flufenamic Acid / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008078:Cholesterol, LDL; D011994:Recombinant Proteins; D002713:Chlorine; D005439:Flufenamic Acid; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D009195:Peroxidase