Effect of natural and semisynthetic flavonoids on the expression of heme oxygenase-1

The natural flavonoid quercetin is known to activate the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) which regulates the expression of antioxidant and phase II xenobiotic metabolism enzymes such as heme oxygenase-1, superoxide dismutases and glutathione S -transferases. This study examined whether the expression of heme oxygenase-1 could also be activated either by natural derivatives of quercetin, isoquercitrin (quercetin-3- O -glucoside) and taxifolin (dihydroquercetin), or by new semisynthetic galloylated derivatives, 3- O -galloylquercetin and 7- O -galloyltaxifolin. In murine macrophage RAW264.7 cells, 7- O -galloyltaxifolin at the concentrations from 25µM significantly induced the expression of Hmox1 gene encoding heme oxygenase-1 and increased the protein levels of the enzyme as well. In contrast, the other tested compounds had negligible effects on the expression of heme oxygenase-1. The induction of Hmox1 gene expression by 7- O -galloyltaxifolin was accompanied by nuclear accumulation of Nrf2 and by downregulation of Keap1 (Kelch-like ECH-associated protein 1), a negative regulator of the Nrf2 activity. The increase in Hmox1 mRNA levels by 7- O -galloyltaxifolin was, at least partially, suppressed by SB203580 and PD98059, pharmacologic inhibitors of p38 mitogen-activated protein kinases (p38 MAPKs) and p44/42 MAPKs, respectively. We conclude that 7- O -galloyltaxifolin induces heme oxygenase-1 via activation of the MAPK/Nrf2 signaling pathway. This work was supported by grants GACR P301/11/0767 and LF_2012_10.