Polyphenols activate Nrf2 in astrocytes via H ₂O ₂, semiquinones, and quinones

Polyphenols, which occur both in edible plants and in foodstuff, have been reported to exert a wide range of health effects; however, the mechanism of action of these molecules is not fully understood. One important cellular pathway affected by polyphenols is the activation of the transcription factor Nrf2 via the electrophile response element, which mediates generation of phase 2 detoxifying enzymes. Our study found that Nrf2 nuclear translocation and the activity of NAD(P)H quinone oxidoreductase (NQO1) were increased significantly after treatment of astrocytes with tert-butylhydroquinone (tBHQ), resveratrol, or curcumin, at 20-50 μM. Incubation of tBHQ, resveratrol, and curcumin in the growth medium in the absence of astrocytes caused the accumulation of H ₂O ₂. Treatment of cells with either glutathione or metmyoglobin was found to decrease Nrf2 translocation and NQO1 activity induced by polyphenols by up to 40 and 60%, respectively. Addition of both glutathione and metmyoglobin to growth medium decreased Nrf2 translocation and NQO1 activity by up to 100 and 80%, respectively. In conclusion, because metmyoglobin, in the presence of polyphenols and glutathione, is known to interact with H ₂O ₂, semiquinones, and quinones, the up-regulation of the antioxidant defense of the cells through activation of the Nrf2 transcription factor, paradoxically, occurs via the generation of H ₂O ₂ and polyphenol-oxidized species generated from the exogenous microenvironment of the cells.