title: Carnosol and carnosic acids from Salvia officinalis inhibit microsomal prostaglandin E2 synthase-1.
abstract: Prostaglandin E(2) (PGE(2)), the most relevant eicosanoid promoting inflammation and tumorigenesis, is formed by cyclooxygenases (COXs) and PGE(2) synthases from free arachidonic acid. Preparations of the leaves of Salvia officinalis are commonly used in folk medicine as an effective antiseptic and anti-inflammatory remedy and possess anticancer activity. Here, we demonstrate that a standard ethyl acetate extract of S. officinalis efficiently suppresses the formation of PGE(2) in a cell-free assay by direct interference with microsomal PGE(2) synthase (mPGES)-1. Bioactivity-guided fractionation of the extract yielded closely related fractions that potently suppressed mPGES-1 with IC(50) values between 1.9 and 3.5 μg/ml. Component analysis of these fractions revealed the diterpenes carnosol and carnosic acid as potential bioactive principles inhibiting mPGES-1 activity with IC(50) values of 5.0 μM. Using a human whole-blood assay as a robust cell-based model, carnosic acid, but not carnosol, blocked PGE(2) generation upon stimulation with lipopolysaccharide (IC(50) = 9.3 μM). Carnosic acid neither inhibited the concomitant biosynthesis of other prostanoids [6-keto PGF(1α), 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid, and thromboxane B(2)] in human whole blood nor affected the activities of COX-1/2 in a cell-free assay. Together, S. officinalis extracts and its ingredients carnosol and carnosic acid inhibit PGE(2) formation by selectively targeting mPGES-1. We conclude that the inhibitory effect of carnosic acid on PGE(2) formation, observed in the physiologically relevant whole-blood model, may critically contribute to the anti-inflammatory and anticarcinogenic properties of S. officinalis.
authors.affiliation: Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tuebingen, Tuebingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bauer
authors.forename: Susanne
authors.initials: S
authors.lastname: Kuehnl
authors.forename: Judith M
authors.initials: JM
authors.lastname: Rollinger
authors.forename: Olga
authors.initials: O
authors.lastname: Scherer
authors.forename: Hinnak
authors.initials: H
authors.lastname: Northoff
authors.forename: Hermann
authors.initials: H
authors.lastname: Stuppner
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects* / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D018515:Plant Leaves / Q000737:chemistry; D000071876:Prostaglandin-E Synthases; D011453:Prostaglandins / Q000378:metabolism; D027543:Salvia officinalis / Q000737:chemistry*
chemical_list: D045784:Abietanes; D010936:Plant Extracts; D011453:Prostaglandins; C068623:carnosol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; C018381:salvin