The natural flavonoid quercetin is known to activate the transcription factor Nrf2, which regulates the expression of cytoprotective enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). In this study, a novel semisynthetic flavonoid 7-O-galloylquercetin (or quercetin-7-gallate, 3) was prepared by direct galloylation of quercetin, and its effect on the Nrf2 pathway was examined. A luciferase reporter assay showed that 7-O-galloylquercetin, like quercetin, significantly activated transcription via the antioxidant response element in a stably transfected human AREc32 reporter cell line. In addition, 7-O-galloylquercetin caused the accumulation of Nrf2 and induced the expression of HO-1 at both the mRNA and protein levels in murine macrophage RAW264.7 cells. The induction of HO-1 by 7-O-galloylquercetin was significantly suppressed by N-acetyl-l-cysteine and SB203580, indicating the involvement of reactive oxygen species and p38 mitogen-activated protein kinase activity, respectively. HPLC/MS analyses also showed that 7-O-galloylquercetin was not degalloylated to quercetin, but it was conjugated with glucuronic acid and/or methylated in RAW264.7 cells. Furthermore, 7-O-galloylquercetin was found to increase the protein levels of Nrf2 and HO-1, and also the activity of NQO1 in murine hepatoma Hepa1c1c7 cells. Taken together, we conclude that 7-O-galloylquercetin increases Nrf2 activity and induces Nrf2-dependent gene expression in RAW264.7 and Hepa1c1c7 cells.

Department of Medical Chemistry and Biochemistry Faculty of Medicine and Dentistry Palacký University Hněvotínská 3 Olomouc 77515 Czech Republic

Department of Medical Chemistry and Biochemistry Faculty of Medicine and Dentistry Palacký University Hněvotínská 3 Olomouc 77515 Czech Republic; Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Hněvotínská 3 Olomouc 77515 Czech Republic

Institute of Microbiology Laboratory of Biotransformation Czech Academy of Sciences Vídeňská 1083 Prague 14220 Czech Republic

Jacqui Wood Cancer Centre Division of Cancer Research School of Medicine University of Dundee Dundee DD1 9SY Scotland UK

Regional Centre of Advanced Technologies and Materials Department of Analytical Chemistry Faculty of Science Palacký University 17 listopadu 12 Olomouc 77146 Czech Republic

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