Induction of human NAD(P)H:quinone oxidoreductase (NQO1) gene expression by the flavonol quercetin

Flavonoids are plant polyphenolic compounds ubiquitous in fruits, vegetables and herbs. The flavonol quercetin is one of the most abundant dietary flavonoids. It has diverse biological properties in cultured cells, including cytoprotection, and exhibits antitumorigenic effects in animal models. The mechanism(s) for the protective properties of flavonoids are currently unknown but may involve modulation of phase II detoxifying enzymes. We have investigated the effect of quercetin on expression and enzymatic activity of one of the major phase II detoxification systems, NAD(P)H:quinone oxidoreductase (NQO1) in the MCF-7 human breast carcinoma cell line. We show that treatment of MCF-7 cells for 24 h with 15 microM quercetin results in a twofold increase in NQO1 protein levels and enzyme activity, and a three- to fourfold increase in NQO1 mRNA expression. We found that when these cells were transiently transfected with a luciferase (Luc) reporter plasmid containing two copies of the antioxidant response element (ARE) of the human NQO1 gene linked to a minimal viral promoter, quercetin caused an approximately twofold increase in Luc activity. Quercetin failed to increase Luc activity in cells transfected with a reporter vector containing a mutated ARE. The increase in NQO1 transcription in response to quercetin suggests that dietary plant polyphenols can stimulate transcription of phase II detoxifying systems, potentially through an ARE-dependent mechanism. Induction of the human NQO1 gene by dietary polyphenolics could afford protection against carcinogenic chemicals in molecular pathways utilizing the ARE.