Koeberle Andreas, Bauer Julia, Verhoff Moritz, Hoffmann Marika, Northoff Hinnak, Werz Oliver
Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tuebingen, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany.
Biochem Biophys Res Commun. 2009 Oct 16;388(2):350-4. doi: 10.1016/j.bbrc.2009.08.005. Epub 2009 Aug 6.
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.
前列腺素（PG）E2是一种将慢性炎症与癌症联系起来的关键脂质介质。绿茶（茶树）中的抗癌表没食子儿茶素-3-没食子酸酯（EGCG）可抑制细胞内PGE2的生物合成，但其潜在的分子机制尚不清楚。在此，我们研究了EGCG对参与PGE2生物合成的酶的干扰作用，这些酶包括胞质磷脂酶（cPL）A2、环氧化酶（COX）-1和-2以及微粒体前列腺素E2合酶-1（mPGES-1）。在高达30μM的浓度下，EGCG未能显著抑制分离的COX-2和cPLA2，对分离的COX-1有中度阻断作用（IC50>30μM）。然而，EGCG能有效抑制mPGES-1催化的PGH2向PGE2的转化（IC50=1.8μM）。在脂多糖刺激的人全血中，EGCG显著抑制PGE2的生成，而其他前列腺素（即12(S)-羟基-5-顺式-8,10-反式-十七碳三烯酸和6-酮基PGF1α）的合成并未受到抑制。总之，mPGES-1是EGCG的分子靶点，抑制mPGES-1似乎是EGCG抑制细胞内PGE2生物合成的主要机制。
