Modification of eicosanoid profile in human blood treated by dual COX/LOX inhibitors.
The arachidonic acid metabolizing enzymes, the cyclooxygenases (COXs) and lipoxygenases (LOXs), have been implicated in the development of a variety of cancers and numerous new therapeutic inhibitors are currently under investigation. However, given the interdependence of the two pathways, the effect of inhibiting one pathway with relatively selective agents can only be appreciated in the in vivo situation. Clearly then, because of their potential beneficial or deleterious effects, it is important to understand the nature and levels of the resulting arachidonic acid metabolites when treating patients with relatively selective inhibitor drugs. In this study, using reference COX-2, 5-LOX and dual COX-2/5-LOX inhibitors, we devised a protocol which permitted the simultaneous quantification of eicosanoid metabolites formed during stimulation of human peripheral venous blood samples with the calcium ionophore, A23187, in the absence and presence of lipopolysaccharide (LPS). Not surprisingly, the end products of both COX and LOX pathways were affected depending on the inhibitor, or combination of inhibitors, used and the concentrations of drug tested. In conclusion, the method described permits the rapid screening of novel compounds for potentially positive and/or negative effects upon the products of arachidonic acid metabolism.
Pommery
J
J
Institut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, Lille, France.
Pommery
N
N
Hénichart
J-P
JP
D016718:Arachidonic Acid / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D000068579:Celecoxib; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015777:Eicosanoids / Q000097:blood*; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D016718:Arachidonic Acid; D000001:Calcimycin; D000068579:Celecoxib; C063449:zileuton; D006918:Hydroxyurea; D007213:Indomethacin