Novel inhibitory effect on 5-lipoxygenase activity by the anti-asthma drug montelukast.
5-Lipoxygenase is the key enzyme in the biosynthesis of leukotrienes, powerful lipid mediators involved in inflammation, cell-cell communication, and other important physiological and pathological conditions. Particularly, cysteinyl-leukotrienes have been recognized as playing a significant role in the pathophysiology of asthma and potent and effective Cys-LT1 receptor antagonists have been developed for the treatment of this illness. Here we report that montelukast, a structural Cys-LT1 receptor antagonist, also exerts a substantial and apparently direct inhibitory effect on 5-lipoxygenase activity in vitro, at concentrations in the lower micromolar range, which are of potential therapeutic relevance. Thus, when human mast cells HMC-1 were stimulated with the Ca ionophore A23187 in the presence of montelukast (up to 100 microM) a substantial decline in 5-lipoxygenase biosynthesis was observed. Similar results were obtained in the rat mast cell-like RBL-1 cell model (IC50 congruent with 2.5 microM) and in human polymorphonuclear leukocytes. Moreover, montelukast directly inhibited human recombinant 5-lipoxygenase. Kinetic experiments revealed that the inhibition was of the non-competitive type, suggesting that montelukast binds a yet undefined allosteric site on 5-lipoxygenase. 5-Lipoxygenase inhibition by montelukast appears to be highly selective since the drug had no effects on other enzymes of the leukotriene cascade, viz. LTC4 synthase and LTA hydrolase.
Ramires
Rossella
R
Department of Allergology and Clinical Immunology, University of Bari, Bari 70124, Italy.
Caiaffa
Maria F
MF
Tursi
Alfredo
A
Haeggström
Jesper Z
JZ
Macchia
Luigi
L
D000085:Acetates / Q000494:pharmacology*; D000495:Allosteric Site; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002384:Catalysis; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003521:Cyclopropanes; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007975:Leukotriene B4 / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008407:Mast Cells / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism; D011485:Protein Binding; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D013440:Sulfides
D000085:Acetates; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; D011994:Recombinant Proteins; D013440:Sulfides; D007975:Leukotriene B4; D017997:Leukotriene C4; D000001:Calcimycin; D003907:Dexamethasone; C093875:montelukast; D002118:Calcium