Mono-O-methylated flavanols and other flavonoids as inhibitors of endothelial NADPH oxidase.

The dietary flavan-3-ol (-)-epicatechin improves the bioactivity of nitric oxide in arterial vessels in vivo. Moreover, it effectively protects cultured vascular endothelial cells from signs of oxidative stress and elevates intracellular nitric oxide in vitro. We addressed the effects of (-)-epicatechin, its metabolic conversion products and structurally related compounds on NADPH oxidase activity in intact human umbilical vein endothelial cells (HUVEC) and in cell lysates. (-)-Epicatechin proved to be an O2*(-)-scavenger but did not inhibit NADPH oxidase activity, whereas the converse pattern was observed for the metabolites 3'- and 4'-O-methyl epicatechin. The dimer procyanidin B2 and (-)-epicatechin glucuronide were O2*(-)-scavengers and inhibited NADPH oxidase. Analysis of structure-activity relations with 45 compounds suggests an apocynin-like mode of NADPH oxidase inhibition. Notably, HUVEC converted (-)-epicatechin to NADPH oxidase-inhibitory methyl ethers. These data identify endothelial NADPH oxidase as candidate target of dietary flavonoids and particularly of their metabolites.