Hyperforin is a novel type of 5-lipoxygenase inhibitor with high efficacy in vivo.

We previously showed that, in vitro, hyperforin from St. John's wort (Hypericum perforatum) inhibits 5-lipoxygenase (5-LO), the key enzyme in leukotriene biosynthesis. Here, we demonstrate that hyperforin possesses a novel and unique molecular pharmacological profile as a 5-LO inhibitor with remarkable efficacy in vivo. Hyperforin (4 mg/kg, i.p.) significantly suppressed ...
leukotriene B(4) formation in pleural exudates of carrageenan-treated rats associated with potent anti-inflammatory effectiveness. Inhibition of 5-LO by hyperforin, but not by the iron-ligand type 5-LO inhibitor BWA4C or the nonredox-type inhibitor ZM230487, was abolished in the presence of phosphatidylcholine and strongly reduced by mutation (W13A-W75A-W102A) of the 5-LO C2-like domain. Moreover, hyperforin impaired the interaction of 5-LO with coactosin-like protein and abrogated 5-LO nuclear membrane translocation in ionomycin-stimulated neutrophils, processes that are typically mediated via the regulatory 5-LO C2-like domain. Together, hyperforin is a novel type of 5-LO inhibitor apparently acting by interference with the C2-like domain, with high effectiveness in vivo.
Mesh Terms:
Animals, Arachidonate 5-Lipoxygenase, Bicyclo Compounds, Binding Sites, Carrageenan, Cells, Cultured, Diglycerides, Humans, Hypericum, Leukotriene B4, Lipoxygenase Inhibitors, MAP Kinase Signaling System, Male, Microfilament Proteins, Neutrophils, Oxidation-Reduction, Phloroglucinol, Phospholipids, Pleurisy, Protein Structure, Tertiary, Protein Transport, Rats, Rats, Wistar, Terpenes, Tryptophan
Cell. Mol. Life Sci.
Date: Aug. 01, 2009
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