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Novel inhibitory effect on 5-lipoxygenase activity by the anti-asthma drug montelukast.

Abstract：

: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.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Ramires R,Caiaffa MF,Tursi A,Haeggström JZ,Macchia L

doi

10.1016/j.bbrc.2004.09.125

subject

Has Abstract

pub_date

2004-11-12 00:00:00

pages

815-21

issue

2

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(04)02172-2

journal_volume

324

pub_type

杂志文章

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