The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin

An overview is provided of the cancer chemoprevention actions of phenolic a ntioxidants and 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline(ethoxyquin). These agents principally appear to exert their beneficial effects through i nduction of phase II drug-metabolizing enzymes such as glutathione S-transf erase (GST). The requirement for oxidative metabolism of the synthetic anti oxidants to carbonyl-containing compounds, including quinones, in order tha t they can induce gene expression is discussed. Previous work has shown tha t the basic leucine zipper transcription factor Nrf2 is involved in inducti on of GST by the phenolic antioxidant butylated hydroxyanisole (BHA). Evide nce is provided from a mouse possessing a targeted disruption of the Nrf2 g ene that, in murine liver, the transcription factor regulates basal express ion of several class Alpha and class Mu GST subunits, but not class Pi GST. In the Nrf2 knock-out mouse, hepatic induction of class Alpha and class Mu GST by BHA and the synthetic antioxidant ethoxyquin is similarly impaired, suggesting that these agents affect gene activation by a related mechanism . Significantly, residual induction of GST by antioxidants is apparent in t he Nrf2 mutant mouse, indicating the existence of an alternative mechanism of gene activation.