Enzymatic metabolites of lycopene induce Nrf2‐mediated expression of phase II detoxifying/antioxidant enzymes in human bronchial epithelial cells

Lycopene can be cleaved by carotene 9′,10′‐oxygenase at its 9′,10′ double bond to form apo‐10′‐lycopenoids, including apo‐10′‐lycopenal, ‐lycopenol and ‐lycopenoic acid. The latter has been recently shown to inhibit lung carcinogenesis both in vivo and in vitro, however, the mechanism(s) underlying this protection is not well defined. In the present study, we report that treatment with apo‐10′‐lycopenoic acid, in a time‐ and dose‐dependent manner, results in the nuclear accumulation of transcription factor Nrf2 (nuclear factor E2‐related factor 2) protein in BEAS‐2B human bronchial epithelial cells. The activation of Nrf2 by apo‐10′‐lycopenoic acid is associated with the induction of phase II detoxifying/antioxidant enzymes including heme oxygenase‐1, NAD(P)H:quinone oxidoreductase 1, glutathione S‐transferases, and glutamate–cysteine ligases in BEAS‐2B cells. Furthermore, apo‐10′‐lycopenoic acid treatment increased total intracellular glutathione levels and suppressed both endogenous reactive oxygen species generation and H2O2‐induced oxidative damage in BEAS‐2B cells. In addition, both apo‐10′‐lycopenol and apo‐10′‐lycopenal induced heme oxygenase‐1 gene expression in BEAS‐2B cells. These data strongly suggest that the anti‐carcinogenic and antioxidant functions of lycopene may be mediated by apo‐10′‐lycopenoids via activating Nrf2 and inducing phase II detoxifying/antioxidant enzymes. © 2008 Wiley‐Liss, Inc.