A Novel Semisynthetic Flavonoid 7-O-Galloyltaxifolin Upregulates Heme Oxygenase-1 in RAW264.7 Cells via MAPK/Nrf2 Pathway

作者：Vrba Jiri^*; Gazak Radek; Kuzma Marek; Papouskova Barbora; Vacek Jan; Weiszenstein Martin; Kren Vladimir; Ulrichova Jitka

来源：Journal of Medicinal Chemistry, 2013, 56(3): 856-866.

DOI：10.1021/jm3013344

Quercetin and gallic acid are natural activators of the transcription factor Nrf2, which regulates the expression of many cytoprotective enzymes including heme oxygenase-1 (HO-1). We developed procedures for the synthesis of monogalloyl esters of quercetin and taxifolin (dihydroquercetin), namely, 3-O-galloylquercetin and 7-O-galloyltaxifolin, and examined their effect on the Nrf2 pathway in RAW264.7 cells. Unlike quercetin and free gallic acid, 3-O-galloylquercetin and natural quercetin derivatives isoquercitrin (quercetin-3-O-beta-D-glucoside) and taxifolin had no effect on the expression of HO-1. In contrast, 7-O-galloyltaxifolin increased both mRNA and protein levels of HO-1 at concentrations of 25 mu M and above. The induction of HO-1 by 7-O-galloyltaxifolin was primarily associated with the production of reactive oxygen species and phosphorylation of mitogen-activated protein kinases (MAPKs), including p38 MAPKs and ERKs, followed by nuclear accumulation of Nrf2 and downregulation of Keap1, a negative regulator of Nrf2. We conclude that 7-O-galloyltaxifolin upregulates HO-1 via activation of the MAPK/Nrf2 signaling pathway.

• 出版日期2013-2-14