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

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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 B4 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.

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Acknowledgments

We thank Sven George and Bianca Jazzar for expert technical assistance. The study was supported by the Deutsche Forschungsgemeinschaft, the Beilstein-Institut zur Förderung der chemischen Wissenschaften, the Swedish Research Council, 03X-217, and the European Union (EICOSANOX, LSHM-CT-2004-005033. Disclaimer: The report reflects only the author’s views and the Community is not liable for any use that may be made of the information herein). C.P. received a Carl-Zeiss stipend.

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Authors and Affiliations

  1. Institute of Pharmaceutical Chemistry, University of Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt, Germany

    Christian Feißt, Marika Hoffmann, Christina Hoernig, Lutz Fischer & Dieter Steinhilber

  2. Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard-Karls-University Tuebingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany

    Carlo Pergola, Andreas Koeberle & Oliver Werz

  3. Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden

    Marija Rakonjac & Olof Rådmark

  4. IRCCS Centro Neurolesi “Bonino-Pulejo”, Messina, Italy

    Antonietta Rossi

  5. Interfakultäres Institut für Biochemie, Hoppe-Seyler-Straße 4, University of Tuebingen, 72076, Tübingen, Germany

    Gabriele Dodt

  6. Institute of Organic Chemistry and Chemical Biology, University of Frankfurt, Siesmayerstr. 70, 60323, Frankfurt, Germany

    Lutz Franke & Gisbert Schneider

  7. Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy

    Lidia Sautebin

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  1. Christian Feißt
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Correspondence to Oliver Werz.

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Feißt, C., Pergola, C., Rakonjac, M. et al. Hyperforin is a novel type of 5-lipoxygenase inhibitor with high efficacy in vivo. Cell. Mol. Life Sci. 66, 2759–2771 (2009). https://doi.org/10.1007/s00018-009-0078-3

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