Abstract
Xenobiotic metabolizing enzymes, such as glutathione S-transferases (GSTs) and NAD(P)H:quinone oxidoreductase 1 (NQO1), play an important role in the detoxification of chemical carcinogens and suppression of oxidative stress. The induction of these detoxifying enzymes is regulated by a cis-acting sequence, referred to as the antioxidant response element (ARE). The most effective transcription factor that binds to ARE is the NF-E2 related factor 2 (Nrf2), a member of the NF-E2 family of basic leucine zipper transcription factors. Many lines of evidence indicate that Nrf2 activation enables adaptation to oxidants and electrophiles. In the present study, various herbal medicines were screened for inducers of Nrf2-regulated enzymes. This assay showed that Notopterygium incisum extract potently increased GST and NOQ1 at both mRNA and protein levels. According to bioactivity-guided cell-based assays, falcarindiol was isolated from the extract and identified as a novel Nrf2 activator. Several experimental models were used to understand effects of falcarindiol on normal cells. Pretreatment with falcarindiol activated Nrf2 in vitro and in vivo and conferred protection against menadione-induced cytotoxicity through enhancement of the menadione detoxification process and carbon tetrachloride-induced liver toxicity through suppression of lipid peroxidation. Dextran sulfate sodium (DSS) has been known to induce intestinal inflammation and nitrosative stress. DSS-induced colitis was suppressed in accordance with Nrf2 activation by falcarindiol. These results demonstrated that falcarindiol has a key role for Nrf2 in controlling the ability to withstand oxidative and electrophilic stress.
