title: Hyperforin is a novel type of 5-lipoxygenase inhibitor with high efficacy in vivo.
abstract: 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.
authors: Institute of Pharmaceutical Chemistry, University of Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
authors: Christian
authors: C
authors: Feisst
authors: Carlo
authors: C
authors: Pergola
authors: Marija
authors: M
authors: Rakonjac
authors: Antonietta
authors: A
authors: Rossi
authors: Andreas
authors: A
authors: Koeberle
authors: Gabriele
authors: G
authors: Dodt
authors: Marika
authors: M
authors: Hoffmann
authors: Christina
authors: C
authors: Hoernig
authors: Lutz
authors: L
authors: Fischer
authors: Dieter
authors: D
authors: Steinhilber
authors: Lutz
authors: L
authors: Franke
authors: Gisbert
authors: G
authors: Schneider
authors: Olof
authors: O
authors: Rådmark
authors: Lidia
authors: L
authors: Sautebin
authors: Oliver
authors: O
authors: Werz
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000235:genetics; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002351:Carrageenan; D002478:Cells, Cultured; D004075:Diglycerides / Q000494:pharmacology; D006801:Humans; D020902:Hypericum / Q000737:chemistry; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism / Q000502:physiology; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013729:Terpenes / Q000494:pharmacology*; D014364:Tryptophan
chemical_list: D001643:Bridged Bicyclo Compounds; C118115:COTL1 protein, human; D004075:Diglycerides; D016859:Lipoxygenase Inhibitors; D008840:Microfilament Proteins; D010743:Phospholipids; D013729:Terpenes; D007975:Leukotriene B4; C038237:1-oleoyl-2-acetylglycerol; D014364:Tryptophan; D002351:Carrageenan; D010696:Phloroglucinol; D001094:Arachidonate 5-Lipoxygenase; C001654:hyperforin