Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase |
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Authors: | Albert Dana Zündorf Ilse Dingermann Theo Müller Walter E Steinhilber Dieter Werz Oliver |
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Affiliation: | Institute of Pharmaceutical Chemistry, University of Frankfurt, D-60439 Frankfurt, Germany. |
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Abstract: | The acylphloroglucinol derivative hyperforin is the major lipophilic constituent in the herb Hypericum perforatum (St. John's wort). The aim of the present study was to investigate if hyperforin as well as extracts of H. perforatum can suppresses the activities of 5-lipoxygenase (5-LO) and cyclooxygenases (COX), key enzymes in the formation of proinflammatory eicosanoids from arachidonic acid (AA). In freshly isolated human polymorphonuclear leukocytes stimulated with Ca(2+) ionophore A23187, hyperforin inhibited 5-LO product formation with IC(50) values of about 1-2 microM, in the absence or presence of exogenous AA (20 microM), respectively, being almost equipotent to the well-documented 5-LO inhibitor zileuton (IC(50) = 0.5-1 microM). Experiments with purified human 5-LO demonstrate that hyperforin is a direct 5-LO inhibitor (IC(50) approximately 90 nM), acting in an uncompetitive fashion. In thrombin- or ionophore-stimulated human platelets, hyperforin suppressed COX-1 product (12(S)-hydroxyheptadecatrienoic acid) formation with an IC(50) of 0.3 and 3 microM, respectively, being about 3- to 18-fold more potent than aspirin. At similar concentrations, hyperforin suppressed COX-1 activity in platelets in presence of exogenous AA (20 microM) as well as in cell-free systems. Hyperforin could not interfere with COX-2 product formation and did not significantly inhibit 12- or 15-LO in platelets or leukocytes, respectively. We conclude that hyperforin acts as a dual inhibitor of 5-LO and COX-1 in intact cells as well as on the catalytic activity of the crude enzymes, suggesting therapeutic potential in inflammatory and allergic diseases connected to eicosanoids. |
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Keywords: | AA, arachidonic acid COX, cyclooxygenase 12-HETE, 12(S)-hydroxy-5,8-cis-10-trans-14-cis-eicosatetraenoic acid 15-HETE, 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid 12-HHT, 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid LO, lipoxygenase LPS, lipopolysaccharide LT, leukotriene NSAIDs, nonsteroidal antiinflammatory drugs PBS, phosphate-buffered saline, pH 7.4 PG, prostaglandin PGC buffer, PBS containing 1 mg/mL glucose and 1 mM CaCl2 PMNLs, polymorphonuclear leukocytes TGFβ, transforming growth factor beta. |
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