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. This is a fundamental pathway that is important in how well your body functions.
I think of it as flipping the switch to call up the phase II enzymes to take out the trash produced in the first phase of detoxification. It is also important in clearing out the free radicals produced in cells as part of their normal production of energy.
Your body’s antioxidant defense:
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. These are the body’s natural antioxidant defense system, important in every cell, all the time — but especially important when your body is under stress from an increased toxic burden.
Chronic oxidative stress is implicated in causing may chronic diseases, so activating this pathway is thought to reduce disease risk. The Nrf2 pathway is thought to be important for protecting against autoimmune diseases, metabolic-based diseases, and neurodegenerative problems. [ref]
How does Nrf2 work?
Normally, Nrf2 is located in the cytosol of the cell. It is hanging out, waiting to be needed. When oxidative stress increases in the cell, Nrf2 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) 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. A genetically increased Nrf2 pathway is associated with a decreased mortality risk in smokers, likely due to the body’s upregulated antioxidant defense protecting against the cellular damage from cigarettes. [ref]
Genetic variants that increase Nrf2:
Check your 23andMe results for rs6726395 (v.4):
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: typical
Check your genetic results for rs1806649 (23andMe v4):
- C/C: typical
- 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: typical
- G/T: typical
- T/T: significantly diminished Nrf2 expression, increased risk of lung cancer [ref]
Lifehacks:
Normally, Nrf2 has a half-life of 
Regular exercise upregulates the Nrf2 pathway.[ref] This is a free and easy lifehack – and one more reason to get outside and get active today.
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.
EGCG, a component of green tea, has been shown in animal studies to upregulate the Nrf2 pathway. [ref] If you want to try EGCG, it is available as a supplement — or you could switch to drinking more green tea!
Curcumin, which is found in the spice turmeric, upregulates the Nrf2 pathway and may also protect against brain injury. [ref] You can get curcumin as a supplement or through adding (a lot) of turmeric to your food.
Black garlic extract has been shown in animal studies to upregulate the Nrf2 pathway. You can get black garlic extract as a supplement, or you may be able to find it at your local grocery store and use it in cooking.
