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.
Department of Allergology and Clinical Immunology, University of Bari, Bari 70124, Italy.
Rossella
R
Ramires
Maria F
MF
Caiaffa
Alfredo
A
Tursi
Jesper Z
JZ
Haeggström
Luigi
L
Macchia
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