Green tea epigallocatechin-3-gallate inhibits microsomal prostaglandin E(2) synthase-1.
Prostaglandin (PG)E(2) is a critical lipid mediator connecting chronic inflammation to cancer. The anti-carcinogenic epigallocatechin-3-gallate (EGCG) from green tea (Camellia sinensis) suppresses cellular PGE(2) biosynthesis, but the underlying molecular mechanisms are unclear. Here, we investigated the interference of EGCG with enzymes involved in PGE(2) biosynthesis, namely cytosolic phospholipase (cPL)A(2), cyclooxygenase (COX)-1 and -2, and microsomal prostaglandin E(2) synthase-1 (mPGES-1). EGCG failed to significantly inhibit isolated COX-2 and cPLA(2) up to 30 microM and moderately blocked isolated COX-1 (IC(50)>30 microM). However, EGCG efficiently inhibited the transformation of PGH(2) to PGE(2) catalyzed by mPGES-1 (IC(50)=1.8 microM). In lipopolysaccharide-stimulated human whole blood, EGCG significantly inhibited PGE(2) generation, whereas the concomitant synthesis of other prostanoids (i.e., 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid and 6-keto PGF(1alpha)) was not suppressed. Conclusively, mPGES-1 is a molecular target of EGCG, and inhibition of mPGES-1 is seemingly the predominant mechanism underlying suppression of cellular PGE(2) biosynthesis by EGCG.
Koeberle
Andreas
A
Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tuebingen, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany.
Bauer
Julia
J
Verhoff
Moritz
M
Hoffmann
Marika
M
Northoff
Hinnak
H
Werz
Oliver
O
D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D028241:Camellia sinensis / Q000737:chemistry*; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008861:Microsomes / Q000201:enzymology*; D044262:Prostaglandin H2 / Q000378:metabolism; D000071876:Prostaglandin-E Synthases
D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D044262:Prostaglandin H2; D002392:Catechin; C045651:epigallocatechin gallate; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone