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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.

Koeberle A, Rossi A, Bauer J, Dehm F, Verotta L, Northoff H, Sautebin L, Werz O - Front Pharmacol (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tübingen Tübingen, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

Effects of hyperforin on the activity of isolated COX-1 and -2. Purified ovine COX-1 [(A) 50 units] or human recombinant COX-2 [(B) 20 units] were added to a COX reaction mix containing 5 mM glutathione. The COX enzymes were pre-incubated with the test compounds for 5 min, and then, the reaction was started with 5 μM (COX-1) or 2 μM (COX-2) AA. After 5 min at 37°C, the formation of 12-HHT was determined by RP-HPLC as described. The 100% values in individual experiments are in the range of 110–140 ng ml−1 and 90–120 ng ml−1 12-HHT for COX-1 and COX-2 assays, respectively. Indomethacin (Indo, 10 μM) and celecoxib (Cele, 5 μM) were used as controls. Data are given as mean ± SE, n = 3, *p < 0.05, ***p < 0.001 vs. vehicle (0.1% DMSO) control, ANOVA + Tukey HSD post hoc tests.
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Figure 3: Effects of hyperforin on the activity of isolated COX-1 and -2. Purified ovine COX-1 [(A) 50 units] or human recombinant COX-2 [(B) 20 units] were added to a COX reaction mix containing 5 mM glutathione. The COX enzymes were pre-incubated with the test compounds for 5 min, and then, the reaction was started with 5 μM (COX-1) or 2 μM (COX-2) AA. After 5 min at 37°C, the formation of 12-HHT was determined by RP-HPLC as described. The 100% values in individual experiments are in the range of 110–140 ng ml−1 and 90–120 ng ml−1 12-HHT for COX-1 and COX-2 assays, respectively. Indomethacin (Indo, 10 μM) and celecoxib (Cele, 5 μM) were used as controls. Data are given as mean ± SE, n = 3, *p < 0.05, ***p < 0.001 vs. vehicle (0.1% DMSO) control, ANOVA + Tukey HSD post hoc tests.

Mentions: We determined the direct interference of Hyp with the catalytic activity of isolated COX enzymes. Purified ovine COX-1 and human recombinant COX-2 were pre-incubated with Hyp for 5 min prior to addition of AA (5 μM for COX-1, 2 μM for COX-2). Formation of 12-HHT, the major COX-1/2-derived product under these experimental conditions (Capdevila et al., 1995), was analyzed by RP-HPLC. Hyp concentration-dependently reduced 12-HHT formation by COX-1 with an IC50 = 12 μM (Figure 3A), whereas COX-2 was not significantly inhibited up to 30 μM (Figure 3B). The reference compounds indomethacin (10 μM) and celecoxib (5 μM) potently inhibited 12-HHT formation, as expected.


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.

Koeberle A, Rossi A, Bauer J, Dehm F, Verotta L, Northoff H, Sautebin L, Werz O - Front Pharmacol (2011)

Effects of hyperforin on the activity of isolated COX-1 and -2. Purified ovine COX-1 [(A) 50 units] or human recombinant COX-2 [(B) 20 units] were added to a COX reaction mix containing 5 mM glutathione. The COX enzymes were pre-incubated with the test compounds for 5 min, and then, the reaction was started with 5 μM (COX-1) or 2 μM (COX-2) AA. After 5 min at 37°C, the formation of 12-HHT was determined by RP-HPLC as described. The 100% values in individual experiments are in the range of 110–140 ng ml−1 and 90–120 ng ml−1 12-HHT for COX-1 and COX-2 assays, respectively. Indomethacin (Indo, 10 μM) and celecoxib (Cele, 5 μM) were used as controls. Data are given as mean ± SE, n = 3, *p < 0.05, ***p < 0.001 vs. vehicle (0.1% DMSO) control, ANOVA + Tukey HSD post hoc tests.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108608&req=5

Figure 3: Effects of hyperforin on the activity of isolated COX-1 and -2. Purified ovine COX-1 [(A) 50 units] or human recombinant COX-2 [(B) 20 units] were added to a COX reaction mix containing 5 mM glutathione. The COX enzymes were pre-incubated with the test compounds for 5 min, and then, the reaction was started with 5 μM (COX-1) or 2 μM (COX-2) AA. After 5 min at 37°C, the formation of 12-HHT was determined by RP-HPLC as described. The 100% values in individual experiments are in the range of 110–140 ng ml−1 and 90–120 ng ml−1 12-HHT for COX-1 and COX-2 assays, respectively. Indomethacin (Indo, 10 μM) and celecoxib (Cele, 5 μM) were used as controls. Data are given as mean ± SE, n = 3, *p < 0.05, ***p < 0.001 vs. vehicle (0.1% DMSO) control, ANOVA + Tukey HSD post hoc tests.
Mentions: We determined the direct interference of Hyp with the catalytic activity of isolated COX enzymes. Purified ovine COX-1 and human recombinant COX-2 were pre-incubated with Hyp for 5 min prior to addition of AA (5 μM for COX-1, 2 μM for COX-2). Formation of 12-HHT, the major COX-1/2-derived product under these experimental conditions (Capdevila et al., 1995), was analyzed by RP-HPLC. Hyp concentration-dependently reduced 12-HHT formation by COX-1 with an IC50 = 12 μM (Figure 3A), whereas COX-2 was not significantly inhibited up to 30 μM (Figure 3B). The reference compounds indomethacin (10 μM) and celecoxib (5 μM) potently inhibited 12-HHT formation, as expected.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tübingen Tübingen, Germany.

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.

No MeSH data available.


Related in: MedlinePlus