Nrf2 Pathway: Increasing the body’s ability to get rid of toxins

This is part of an ongoing series on the genes involved in detoxification.

The Nrf2 (Nuclear factor erythroid 2–related factor) signaling pathway regulates the expression of antioxidants and phase II detoxification enzymes. I think of it as flipping the switch to call up the phase II enzymes to take out the trash produced in phase I detox.  It also clears out the free radicals produced in cells as part of their normal production of energy.

Nrf2 activates your body’s natural antioxidant defense system to reduce oxidative stress in the cell.  Specifically, the Nrf2 signaling pathway can increase the production of GSTs, NQO1, UGTs, and SULTs.  Chronic oxidative stress is implicated in causing may chronic diseases, so activating this pathway is thought to reduce disease risk.

Normally, Nrf2 is in the cytosol of the cell. When oxidative stress increases in the cell, it moves into the cell nucleus. There it is able to bind to certain areas of the DNA to cause the cell to produce the innate antioxidants needed to decrease the oxidative stress in the cell. [ref]


Genetic Variants:

Variants in the NFE2L2 (Nrf2 pathway) gene are fairly common, with some variants increasing Nrf2 pathway signaling and some diminishing it. Some of these are being studied in relation to cancer prognosis, lung volume in smokers, and Parkinson’s disease.

Genetic variants that increase Nrf2:

Check your 23andMe results for rs6726395 (v.4):

  • G/G:  greater lung volume in smokers [ref], decreased risk of AMD [ref]
  • A/G: somewhat greater lung volume in smokers
  • A/A: normal

 

Check your 23andMe results for rs13001694 (v5):

  • G/G: reduced risk of all-cause mortality, especially in smokers [study]
  • A/G: reduced risk of all-cause mortality, especially in smokers
  • A/A: normal

Check your genetic results for rs1806649 (23andMe v4):

  • C/C: normal
  • C/T: significantly reduced risk of death from COPD
  • T/T: significantly reduced risk of death from COPD (70% reduction) [ref]

A genetic variant that reduces Nrf2 expression:

Check your 23andMe results for rs6721961 (v.4):

  • G/G: normal
  • T/T: significantly diminished Nrf2 expression, increased risk of lung cancer [ref]

Lifehacks:

Normally, Nrf2 has a half-life of 7-15 minutes. When in the presence of an Nrf2 activator, that half-life increases to 30-100 minutes.[ref]

Regular exercise upregulates the Nrf2 pathway. [ref]

Sulforaphane, a natural substance found in broccoli sprouts, Brussels sprouts, cabbage, cauliflower, activates the Nrf2 pathway. [study][study]

Broccoli sprouts are supposed to be one of the best sources of sulforaphane that you can eat. There are also sulforaphane supplements available. Be sure to get one that includes the myrosinase enzyme such as this one from Jarrow.

Other activators of Nrf2 include:

More to read:

Video explaining Nrf2: https://www.youtube.com/watch?v=-pH9SOB_R1Q

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