title: Hyperforin, an Anti-Inflammatory Constituent from St. John's Wort, Inhibits Microsomal Prostaglandin E(2) Synthase-1 and Suppresses Prostaglandin E(2) Formation in vivo.
abstract: The acylphloroglucinol hyperforin (Hyp) from St. John's wort possesses anti-inflammatory and anti-carcinogenic properties which were ascribed among others to the inhibition of 5-lipoxygenase. Here, we investigated whether Hyp also interferes with prostanoid generation in biological systems, particularly with key enzymes participating in prostaglandin (PG)E(2) biosynthesis, i.e., cyclooxygenases (COX)-1/2 and microsomal PGE(2) synthase (mPGES)-1 which play key roles in inflammation and tumorigenesis. Similar to the mPGES-1 inhibitors MK-886 and MD-52, Hyp significantly suppressed PGE(2) formation in whole blood assays starting at 0.03-1 μM, whereas the concomitant generation of COX-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid, thromboxane B(2), and 6-keto PGF(1α) was not significantly suppressed up to 30 μM. In cell-free assays, Hyp efficiently blocked the conversion of PGH(2) to PGE(2) mediated by mPGES-1 (IC(50) = 1 μM), and isolated COX enzymes were not (COX-2) or hardly (COX-1) suppressed. Intraperitoneal (i.p.) administration of Hyp (4 mg kg(-1)) to rats impaired exudate volume and leukocyte numbers in carrageenan-induced pleurisy associated with reduced PGE(2) levels, and Hyp (given i.p.) inhibited carrageenan-induced mouse paw edema formation (ED(50) = 1 mg kg(-1)) being superior over indomethacin (ED(50) = 5 mg kg(-1)). We conclude that the suppression of PGE(2) biosynthesis in vitro and in vivo by acting on mPGES-1 critically contributes to the anti-inflammatory efficiency of Hyp.
authors.affiliation: Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tübingen Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.forename: Antonietta
authors.initials: A
authors.lastname: Rossi
authors.forename: Julia
authors.initials: J
authors.lastname: Bauer
authors.forename: Friederike
authors.initials: F
authors.lastname: Dehm
authors.forename: Luisella
authors.initials: L
authors.lastname: Verotta
authors.forename: Hinnak
authors.initials: H
authors.lastname: Northoff
authors.forename: Lidia
authors.initials: L
authors.lastname: Sautebin
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz