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. 2014 Sep 19;6(9):3777–3801. doi: 10.3390/nu6093777

Table 1.

Overview of Nrf2 and changing cellular redox conditions.

Basal Conditions

  • Nrf2 is bound and degraded by Keap1

  • Nrf2 half-life is about 20 minutes

  • Constitutively active ARE-responsive genes

  • Free zinc is in ~nanoM range

Priming or Pre-Induction

  • No true oxidative stress present

  • Keap1:Nrf2 is actin-bound near plasma membrane; responds to endogenous electrophiles before cytoplasmic reductants have access

  • Level of activation may only reach the release of low affinity DLG “latch”, de novo Nrf2 evades Keap1 capture and is available for nuclear translocation

  • No zinc signals because complete Nrf2 release is limited

  • Subsequent upregulation of ARE-responsive genes

  • Inducible ARE-responsive genes are activated; GSH-related proteins, HO-1 and NQO1 in particular are most ARE-responsive

  • Transient exposure to dietary electrophilic phytochemicals boosts production of antioxidant and anti-carcinogenic enzymes without triggering an oxidative response with ensuing damage; concomitantly suppresses NFκB

  • Increases the fitness of the antioxidant/chemopreventive response when it truly presents itself, therefore increasing health resilience and reducing the risk of chronic disease development

  • Availability of adequate dietary sulfur, zinc and selenium are required to fully optimize the priming of Keap1/Nrf2/ARE pathway

Induction

  • True oxidative stress present: mild to moderate

  • Keap1 oxidized by wider variety of compounds, including some that may be irreversible

  • Zinc signals present because of complete release of Nrf2

  • Depending on level of oxidative stress, de novo Nrf2 evades Keap1 capture, Keap1-bound Nrf2 is released leading to further nuclear accumulation of Nrf2 and upregulation of ARE-responsive genes

  • Increased availability of Keap1 to bind IKKβ and suppress the NFκB activation while stress is moderate

Resolution or Next-Level Response

  • Either stress is resolved or Nrf2 can turn pro-oxidative and GSH stores are depleted

  • Higher oxidative state abrogates even Keap1 binding of IKKβ and NFκB suppression comes to an end

  • ARE-responsive genes are suppressed and NFκB targets are upregulated, inducing a pro-inflammatory response to higher order oxidative threat