Document Detail

Myrtucommulone, a natural acylphloroglucinol, inhibits microsomal prostaglandin E(2) synthase-1.
MedLine Citation:
PMID:  19298395     Owner:  NLM     Status:  MEDLINE    
BACKGROUND AND PURPOSE: 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.
EXPERIMENTAL APPROACH: 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.
KEY 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 AND IMPLICATIONS: 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.
A Koeberle; F Pollastro; H Northoff; O Werz
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  156     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2009 Mar 
Date Detail:
Created Date:  2009-04-15     Completed Date:  2009-07-20     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  952-61     Citation Subset:  IM    
Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tuebingen, Auf der Morgenstelle 8, Tuebingen, Germany.
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MeSH Terms
6-Ketoprostaglandin F1 alpha / biosynthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry,  pharmacology*
Cell Line, Tumor
Cyclooxygenase 1 / chemistry
Cyclooxygenase 2 / chemistry
Cyclooxygenase Inhibitors / chemistry
Dinoprostone / biosynthesis,  blood
Fatty Acids, Unsaturated / blood
Intramolecular Oxidoreductases / antagonists & inhibitors*
Microsomes / drug effects*,  enzymology
Phloroglucinol / analogs & derivatives*,  chemistry,  pharmacology
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Cyclooxygenase Inhibitors; 0/Fatty Acids, Unsaturated; 0/myrtucommulone A; 108-73-6/Phloroglucinol; 363-24-6/Dinoprostone; 50683-78-8/12-hydroxy-5,8,10-heptadecatrienoic acid; 58962-34-8/6-Ketoprostaglandin F1 alpha; EC 1; EC 2; EC 5.3.-/Intramolecular Oxidoreductases; EC synthase

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