Abstract 5666: Nrf2-mediated induction of phase 2 detoxifying enzymes by an active compound isolated from Chrysanthemum zawadskii

Abstract

Abstract Previous study demonstrated that methanolic extract of Chrysanthemum has the potential to induce detoxifying enzymes such as NAD(P)H:(quinone acceptor) oxidoreductase 1 (EC 1.6.99.2) (NQO1, QR). In this study we further fractionated methanolic extract of Chrysanthemum and investigated the detoxifying enzyme-inducing potential of each fraction. The fraction shown the highest NQO1-inducing activity was found to contain (+)-(3S,4S,5R,8S)-(E)-8-acetoxy-4-hydroxy-3-isovaleroyloxy-2-(hexa-2,4-diynyliden)-1,6-dioxaspiro[4,5]decane (CZ-5) which increased NQO1 enzyme activity in a dose-dependent manner. And the compound (CZ-5), like most phase 2 enzyme inducers, caused a increasing expression pattern of phase 2 detoxifying enzymes in a dose-dependent manner in mouse hepatoma Hepa1c1c7 and BPRc1 cells. Moreover, CZ-5 caused a dose-dependent enhancement of luciferase activity in HepG2-C8 cells generated by stably transfecting antioxidant response element-luciferase gene construct, suggesting that it induce antioxidant/detoxifying enzymes through antioxidant response element (ARE)-mediated transcriptional activation of the relevant genes. CZ-5 also stimulated nuclear accumulation of Nrf2 as evaluated by western blot analysis. In conclusion, our data showed that CZ-5 acted as a potent phase 2 detoxifying enzyme inducer by stimulating the nuclear accumulation of Nrf2 and had potential as chemopreventive agent Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5666.