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.
Feisst
Christian
C
Institute of Pharmaceutical Chemistry, University of Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Pergola
Carlo
C
Rakonjac
Marija
M
Rossi
Antonietta
A
Koeberle
Andreas
A
Dodt
Gabriele
G
Hoffmann
Marika
M
Hoernig
Christina
C
Fischer
Lutz
L
Steinhilber
Dieter
D
Franke
Lutz
L
Schneider
Gisbert
G
Rådmark
Olof
O
Sautebin
Lidia
L
Werz
Oliver
O
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
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