Myrtucommulone, a natural acylphloroglucinol, inhibits microsomal prostaglandin E(2) synthase-1.
OBJECTIVE
The selective inhibition of prostaglandin (PG)E(2) formation via interference with microsomal PGE(2) synthase (mPGES)-1 could have advantages in the treatment of PGE(2)-associated diseases, such as inflammation, fever and pain, compared with a general suppression of all PG biosynthesis, provided by inhibition of cyclooxygenase (COX)-1 and 2. Here, we addressed whether the naturally occurring acylphloroglucinol myrtucommulone (MC) from Myrtus communis L. (myrtle) affected mPGES-1.


METHODS
The effect of MC on PGE(2) formation was investigated in a cell-free assay by using microsomal preparations of interleukin-1beta-stimulated A549 cells as the source of mPGES-1, in intact A549 cells, and in lipopolysaccharide-stimulated human whole blood. Inhibition of COX-1 and COX-2 activity in cellular and cell-free assays was assessed by measuring 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid and 6-oxo PGF(1alpha) formation.


RESULTS
MC concentration-dependently inhibited cell-free mPGES-1-mediated conversion of PGH(2) to PGE(2) (IC(50) = 1 micromol x L(-1)). PGE(2) formation was also diminished in intact A549 cells as well as in human whole blood at low micromolar concentrations. Neither COX-2 activity in A549 cells nor isolated human recombinant COX-2 was significantly affected by MC up to 30 micromol x L(-1), and only moderate inhibition of cellular or cell-free COX-1 was evident (IC(50) > 15 micromol x L(-1)).


CONCLUSIONS
MC is the first natural product to inhibit mPGES-1 that efficiently suppresses PGE(2) formation without significant inhibition of the COX enzymes. This provides an interesting pharmacological profile suitable for interventions in inflammatory disorders, without the typical side effects of coxibs and non-steroidal anti-inflammatory drugs.
Koeberle
A
A
Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tuebingen, Auf der Morgenstelle 8, Tuebingen, Germany.
Pollastro
F
F
Northoff
H
H
Werz
O
O
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1 / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000737:chemistry; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry; D015232:Dinoprostone / Q000096:biosynthesis / Q000097:blood; D005231:Fatty Acids, Unsaturated / Q000097:blood; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000071876:Prostaglandin-E Synthases
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; C455139:myrtucommulone A; C008033:12-hydroxy-5,8,10-heptadecatrienoic acid; D015121:6-Ketoprostaglandin F1 alpha; D010696:Phloroglucinol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone