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

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 mu M, whereas the concomitant generation of COX-derived 12(S)-hydroxy-5-cis-8, 10-trans-heptadecatrienoic acid, thromboxane B-2, and 6-keto PGF(1 alpha) was not significantly suppressed up to 30 mu M. In cell-free assays, Hyp efficiently blocked the conversion of PGH(2) to PGE(2) mediated by mPGES-1 (IC50 = 1 mu M), 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 (ED50 = 1 mg kg(-1)) being superior over indomethacin (ED50 = 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.