|Synonyms||Leukotriene modifier; Leukotriene receptor antagonist|
|Mechanism of action|| • Enzyme inhibition|
• Receptor antagonism
|Biological target|| • Enzymes: 5-LOX; FLAP|
• Receptors: CysLTRs
An antileukotriene, also known as leukotriene modifier and leukotriene receptor antagonist, is a medication which functions as a leukotriene-related enzyme inhibitor (arachidonate 5-lipoxygenase) or leukotriene receptor antagonist (cysteinyl leukotriene receptors) and consequently opposes the function of these inflammatory mediators; leukotrienes are produced by the immune system and serve to promote bronchoconstriction, inflammation, microvascular permeability, and mucus secretion in asthma and COPD. Leukotriene receptor antagonists are sometimes colloquially referred to as leukasts.
Leukotriene receptor antagonists, such as montelukast, zafirlukast, and pranlukast, and 5-lipoxygenase inhibitors, like zileuton and Hypericum perforatum, can be used to treat these diseases. They are less effective than corticosteroids for treating asthma, but more effective for treating certain mast cell disorders.
There are two main approaches to block the actions of leukotrienes.
Drugs that inhibit the 5-lipoxygenase enzyme will inhibit the synthetic pathway of leukotriene metabolism; drugs such as MK-886 that block the 5-lipoxygenase activating protein (FLAP) inhibit functioning of the 5-lipoxygenase enzyme and may help in treating atherosclerosis.
Some chemicals found in trace amounts in food, and some dietary supplements, also have been shown to inhibit 5-LOX, such as baicalein, caffeic acid, curcumin, hyperforin and St John's wort.
These modifiers have been shown to improve asthma symptoms, reduce asthma exacerbations and limit markers of inflammation such as eosinophil counts in the peripheral blood and bronchoalveolar lavage fluid. This demonstrates that they have anti-inflammatory properties.
Zileuton is a specific inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB4, LTC4, LTD4, and LTE4) formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients.
Hyperforin is found in alcoholic beverages. Hyperforin is a constituent of Hypericum perforatum (St John's Wort) Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum (St John's wort). The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) and published in 1975. Hyperforin is a prenylated phloroglucinol derivative. Total synthesis of hyperforin has not yet been accomplished, despite attempts by several research groups. Hyperforin has been shown to exhibit anti-inflammatory, anti-tumor, antibiotic and anti-depressant functions (PMID 17696442, 21751836, 12725578, 12018529 )
1. Arachidonate 5-lipoxygenase ...Specific function: Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes ...
2. Prostaglandin G/H synthase 1 ... General function: Involved in peroxidase activity
These researches are according to an investigation of the effect of H. perforatum on the NF-κB inflammation factor, conducted by Bork et al. (1999), in which hyperforin provided a potent inhibition of TNFα-induced activation of NF-κB . Another important activity for hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase . Moreover, this species attenuated the expression of iNOS in periodontal tissue, which may contribute to the attenuation of the formation of nitrotyrosine, an indication of nitrosative stress . In this context, a combination of several active constituents of Hypericum species is the carrier of their anti-inflammatory activity.
Anti-inflammatory mechanisms of hyperforin have been described as inhibition of cyclooxygenase-1 (but not COX-2) and 5-lipoxygenase at low concentrations of 0.3 μmol/L and 1.2 μmol/L, respectively , and of PGE2 production in vitro  and in vivo with superior efficiency (ED50 = 1 mg/kg) compared to indomethacin (5 mg/kg) . Hyperforin turned out to be a novel type of 5-lipoxygenase inhibitor with high effectivity in vivo  and suppressed oxidative bursts in polymorphonuclear cells at 1.8 μmol/L in vitro . Inhibition of IFN-γ production, strong downregulation of CXCR3 expression on activated T cells, and downregulation of matrix metalloproteinase 9 expression caused Cabrelle et al.  to test the effectivity of hyperforin in a rat model of experimental allergic encephalomyelitis (EAE). Hyperforin attenuated the symptoms significantly, and the authors discussed hyperforin as a putative therapeutic molecule for the treatment of autoimmune inflammatory diseases sustained by Th1 cells.