Sulforaphane and Nrf2 target

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• Nrf2 is the core transcription factor for human body to regulate the expression of antioxidant and metabolic detoxification genes [1]. It can regulate the expression of more than 500 cytoprotective genes, involving antioxidant response, metabolic detoxification, protein degradation, inflammation and immune response, etc. Therefore, Nrf2 is considered to be "the switch of cell protection" [2].

   

  
  

  Figure 1 Cellular pathways driven by Nrf2 target genes.

   

  As shown in Figure 1, Nrf2 heterodimerizes with sMAF proteins to initiate the transcription of antioxidant response element containing target genes. Verified Nrf2 target genes are involved in proteasome assembly, autophagy, prevention of apoptosis, maintaining redox balance, lipid and carbohydrate metabolism, heme metabolism, iron homeostasis, all three phases of drug/xenobiotic metabolism, transcriptional regulation of other transcription factors, and DNA repair. Representative target genes are included in parentheses below each transcriptional response. Abbreviation: GSH, glutathione [3].

  In 1992, Professor Paul Talalay of Johns Hopkins University extracted sulforaphane(SFN) from broccoli and proved its cancer prevention effect [4]. Studies have shown that SFN is the strongest Nrf2 inducer found in edible plants so far [5].

  SFN is widely present in cruciferous vegetables such as broccoli in the form of precursor glucoraphanin(GRA). The content of GRA in broccoli seeds is the highest. In 2016, glucoraphanin passed the GRAS (Generally Recognized As Safe) certification approved by the FDA.

  SFN has a significant ability to induce Nrf2, it is 105-fold greater than resveratrol, 18-fold greater than silymarin, and 13.5-fold greater than curcumin and quercetin [6].

  
  

  Figure 2 CD values of popular phytochemicals used as supplements and a commonly prescribed pharmaceutical. CD values refer to the concentration of a compound required to double the activity of the Phase II detoxification enzyme, quinone reductase[6].

   

  SFN can be efficiently utilized in the human body, the absolute bioavailability of SFN is 80% and it can be quickly absorbed because of its lipophilic characteristics low molecular weight [6].

   

  Figure 3 Comparative bioavailability of phytochemicals commonly used in supplements.Oral bioavailability of polyphenols is typically <10%, ranging between 2 and 20% , with many closer to 1%; cooking and processing significantly reduce polyphenol content. By comparison, a pharmacokinetic animal study showed that SFN was rapidly absorbed with its absolute bioavailability 80% [6].

  References

  [1] Moi P , Chan K , Asunis I , et al. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region[J]. Proceedings of the National Academy of Sciences, 1994.

  [2] Pall M L , Levine S , University W S , et al. Nrf2, a master regulator of detoxification and also antioxidant, antiinflammatory and other cytoprotective mechanisms, is raised by health promoting factors[J]. Acta Physiologica Sinica, 2015.

  [3] Dodson M , Vega M R D L , Cholanians A B , et al. Modulating NRF2 in Disease: Timing Is Everything[J]. Annual Review of Pharmacology, 2019, 59(1).

  [4] Zhang Y , Talalay P , Cho C G , et al. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure[J]. Proceedings of the National Academy of Sciences, 1992.

  [5] Kensler T W , Egner P A , Agyeman A S , et al. Keap1–Nrf2 Signaling: A Target for Cancer Prevention by Sulforaphane[J]. Topics in Current Chemistry, 2013, 329(8):163-177.

  [6] Houghton C A , Fassett R G , Coombes J S . Sulforaphane and Other Nutrigenomic Nrf2 Activators: Can the Clinician's Expectation Be Matched by the Reality?[J]. Oxidative Medicine and Cellular Longevity,2016,(2016-1-6), 2016, 2016:1-17.