New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate

Abstract

Green tea is rich in polyphenol flavonoids including catechins. Epigallocatechin 3-gallate (EGCG) is the most abundant and potent green tea catechin. EGCG has been extensively studied for its beneficial health effects as a nutriceutical agent. Based upon its chemical structure, EGCG is often classified as an antioxidant. However, treatment of cells with EGCG results in production of hydrogen peroxide and hydroxyl radicals in the presence of Fe (III). Thus, EGCG functions as a pro-oxidant in some cellular contexts. Recent investigations have revealed many other direct actions of EGCG that are independent from anti-oxidative mechanisms. In this review, we discuss these novel molecular mechanisms of action for EGCG. In particular, EGCG directly interacts with proteins and phospholipids in the plasma membrane and regulates signal transduction pathways, transcription factors, DNA methylation, mitochondrial function, and autophagy to exert many of its beneficial biological actions.

Keywords: Anti-oxidant; EC, epicatechin; ECG, epicatechin gallate; EGC, epigallocatechin; EGCG; EGCG, epigallocatechin 3-gallate; Polyphenol; Pro-oxidant.

Graphical abstract

Fig. 1

EGCG-activated eNOS pathways that improve cardiovascular function and anti-cancer effect in the presence of PDE5 inhibitor. EGCG elevates cGMP levels through a specific receptor 67LR that stimulates the Akt/eNOS pathway. This pathway leads to vasodilation which contributes to improvement of cardiovascular function. In cancer cells, inhibition of PDE5 by treatment with Vardenafil leads to sustained elevations of cGMP levels. This elevated cGMP activates PKCδ/acidic sphingomyelinase (ASM) that contributes to apoptosis.

Fig. 2

The roles of 67LR as a specific receptor for EGCG. EGCG has multiple biological actions mediated through 67LR by enhancing (red) and inhibiting (blue) specific pathways.

Fig. 3

Metabolic and vascular functions of EGCG. A schematic diagram showing the mechanisms for the activation of AMPK by EGCG. AMPK is a key molecule that regulates enzymes involved with energy metabolism and endothelial functions.