Activation of the NRF2 Signaling Pathway by Copper-Mediated Redox Cycling of Para- and Ortho-Hydroquinones

Xiu Jun Wang, John D. Hayes, Larry G. Higgins, C. Roland Wolf (Lead / Corresponding author), Albena T. Dinkova-Kostova

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    74 Citations (Scopus)

    Abstract

    Transcription factor NF-E2 p45-related factor 2 (Nrf2) mediates adaptation to oxidants and electrophiles through up-regulating genes that contain antioxidant response elements (AREs) in their promoters. Using the stably transfected human AREc32 reporter cell line, we found that copper and other transition metals enhanced induction of ARE-driven luciferase by 2-tert-butyl-1,4-hydroquinone (tBHQ) as a result of increased oxidation to 2-tert-butyl-1,4-benzoquinone (tBQ). Following exposure to tBHQ for 30 min, ARE-luciferase activity measured after 24 hr was dependent on the presence of Cu2+. In contrast, tBQ-induced activity was Cu2+-independent. The metal-catalyzed oxidation of tBHQ to tBQ occured rapidly and stoichiometrically. Compounds that share para- or ortho-hydroquinone structures, such as catechol estrogens, dopamine, and L-DOPA, also induced ARE-driven luciferase in a Cu2+-dependent manner. Thus, the oxidation of para- and orthohydroquinones to quinones represents the rate-limiting step in the activation of Nrf2.

    Original languageEnglish
    Pages (from-to)75-85
    Number of pages11
    JournalChemistry & Biology
    Volume17
    Issue number1
    DOIs
    Publication statusPublished - 29 Jan 2010

    Keywords

    • ANTIOXIDANT RESPONSE ELEMENT
    • PHASE-II INDUCERS
    • OXIDATIVE STRESS
    • DNA-DAMAGE
    • DEPENDENT ACTIVATION
    • KEAP1/NRF2 PATHWAY
    • CONSENSUS SEQUENCE
    • ADAPTIVE RESPONSE
    • A549 CELLS
    • IN-VITRO

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