- 4035 Epidemiological studies have found an inverse association between the consumption of tomato products and the risk of certain types of cancers. Induction of phase II detoxification enzymes seems to be an important mechanism by which phytonutrients prevent cancer. Expression of phase II enzymes, such as NAD(P)H:quinone oxidoreductase (NQO1) and γ-glutamylcysteine synthetase (GCS), is regulated by the antioxidant response element (ARE), which is found in the promoters of genes encoding these proteins. The nuclear transcription factor Nrf2 binds to the ARE and positively regulates the expression of phase II enzymes. We tested whether carotenoids exert their cancer-preventive effect by stimulation of ARE and induction of NQO1 and GCS. In transiently transfected MCF-7 mammary cancer cells and HepG2 hepatoma cells, lycopene transactivated the expression of a reporter gene (luciferase) fused with ARE sequences. The transactivation was dose-dependent and unexpectedly specific for lycopene, since astaxanthin, β-carotene and phytoene had no effect. This specificity suggests that activation of ARE-mediated transcription by carotenoids is not related solely to their antioxidant properties. Measurement of carotenoid-induced changes in the intracellular levels of reactive oxygen species using a fluorescent probe (dichlorofluorescein diacetate) further supported this conclusion. In accordance with the transactivation data, lycopene treatment caused an increase in NQO1 and GCS protein levels in both MCF-7 and HepG2 cells. A lower potency was found for β-carotene, whereas astaxanthin and phytoene had no effect whatsoever. The induction of GCS protein was accompanied by an increase in the cellular levels of glutathione, a potent substrate for carcinogen detoxification. Nrf2 was found predominantly in the cytoplasm in non-treated (control) cells, but appeared predominantly in the nucleus after treatment with both tert-butylhydroquinone (the known ARE activator) and lycopene. Other carotenoids also induced Nrf2 translocation but with a lower potency. Our results suggest that activation of the ARE-driven induction of phase II enzymes by lycopene represents a novel molecular mechanism for the cancer-preventive action of a diet rich in tomato products.