title: Celecoxib inhibits 5-lipoxygenase.
abstract: Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor used in the therapy of inflammatory and painful conditions. Various COX-2-independent pharmacological effects, such as a chemo-preventive and tumor-regressive activity have been suggested, but the respective non-COX-2 targets of celecoxib are still a matter of research. We now demonstrate that celecoxib inhibits 5-lipoxygenase (5-LO), a key enzyme in leukotriene (LT) biosynthesis. Celecoxib suppressed 5-LO product formation in ionophore A23187-activated human polymorphonuclear leukocytes (IC(50) approximately 8 microM). Similarly, celecoxib inhibited LTB(4) formation in human whole blood (IC(50) approximately 27.3 microM). Direct interference of 5-LO with celecoxib was visualized by inhibition of enzyme catalysis both in cell homogenates and with purified 5-LO (IC(50) approximately 23.4 and 24.9 microM, respectively). Related lipoxygenases (12-LO and 15-LO) were not affected by celecoxib. Other COX-2 inhibitors (etoricoxib and rofecoxib) or unselective NSAIDs (non-steroidal anti-inflammatory drugs, diclofenac) failed to inhibit 5-LO. In rats which received celecoxib (i.p.), the blood LTB(4) levels were dose-dependently reduced with an ED(50) value approximately 35.2 mg/kg. Together, celecoxib is a direct inhibitor of 5-LO in vitro and in vivo. These findings provide a potential molecular basis for some of the described COX-2-independent pharmacological effects of celecoxib.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, 60590 Frankfurt/Main, Germany. maier@pharmchem.uni-frankfurt.de
authors.forename: Thorsten J
authors.initials: TJ
authors.lastname: Maier
authors.forename: Lars
authors.initials: L
authors.lastname: Tausch
authors.forename: Michael
authors.initials: M
authors.lastname: Hoernig
authors.forename: Ovidiu
authors.initials: O
authors.lastname: Coste
authors.forename: Ronald
authors.initials: R
authors.lastname: Schmidt
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.forename: Julia
authors.initials: J
authors.lastname: Metzner
authors.forename: Sabine
authors.initials: S
authors.lastname: Groesch
authors.forename: Carlo
authors.initials: C
authors.lastname: Pergola
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
mesh_terms: D000328:Adult; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D000068579:Celecoxib; D002478:Cells, Cultured; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D007975:Leukotriene B4; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D001094:Arachidonate 5-Lipoxygenase; D000068579:Celecoxib