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NRF2: The Detox Hub & Core Antioxidant Defense

Written by Joe Cohen, BS | Reviewed by Nattha Wannissorn, PhD (Molecular Genetics) | Last updated:

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Nrf2 is a critical pathway to health, as it is the most important pathway to increase our natural and innate antioxidant defense.

What is NRF2?

Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a protein (transcription factor).

Nrf2 increases the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation.

Substances that stimulate the Nrf2 pathway are being studied for the treatment of diseases that are caused by oxidative stress.

Nrf2 is found in the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain [1].

Antioxidant Defense and Detoxification System Stimulated by Nrf2

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Nrf2 stimulates NQO1, which donates electrons and detoxifies a variety of chemicals and drugs. NQO1 is important for phase 2 detox.

I suspect that people sensitive to “everything” have less NQO1 or less of an electron supply.

Nrf2 produces two of the most important rate-limiting steps in glutathione (GSH) production. Glutamate-cysteine ligase, catalytic (Gclc) and glutamate-cysteine ligase, modifier (GCLM) bind together to form glutathione. These are produced by Nrf2.

The glutathione S-transferase (GST) allow glutathione to bind with drugs and toxins, which then allow the body to eliminate potentially harmful and toxic compounds. GSTs are produced by Nrf2 activation and represent an important route of detoxification.

Sulfiredoxin 1 (SRXN1) and Thioredoxin reductase 1 (TXNRD1) give over electrons to peroxiredoxins, proteins important in the detoxification of hydrogen peroxide and peroxynitrite.

Nrf2 stimulates Heme oxygenase-1.

Heme oxygenase-1 (HMOX1, HO-1) is an enzyme that catalyzes the breakdown of heme into the antioxidant biliverdin, the anti-inflammatory agent carbon monoxide, and iron.

HO-1 defends against sepsis, hypertension, atherosclerosis, acute lung injury, kidney injury, and pain.

The UDP-glucuronosyltransferase (UGT) family catalyze the conjugation of glucuronic acid to drugs, chemicals, and toxins, making them more water-soluble and readily excreted. Nrf2 has been shown to induce UGT1A1 and UGT1A6.

Bilirubin and Tylenol are examples of substances that are glucuronidated.

My clients are more likely to have higher bilirubin, and this can come from a decrease in glucuronidation enzyme activity.

Multidrug resistance-associated proteins (Mrps) are important membrane transporters that eject various compounds from various organs into bile or plasma, with subsequent excretion in the feces or urine, respectively.

Mrps have been shown to be increased by Nrf2 and alteration in their expression can dramatically alter the pharmacokinetics and toxicity of compounds.

People with CIRS or biotoxin related issues usually have a problem excreting toxins in an efficient way, and almost certainly the Nrf2 pathway will help excrete these toxins more easily.

Ideally, you’d want to combine Nrf2 activators with cholestyramine (disclaimer: not for personal use) if you have a biotoxin problem.

Reference.

The Negatives of Nrf2 Activation

Activation of NRF2 may promote the development of cancerous tumors. It can also contribute to the development of heart disease by raising cholesterol levels and cholesterol content in the liver.

Having low cholesterol might be an indicator of less Nrf2 function (although there are many other pathways that lower cholesterol).

Reference.

Top Ways to Increase Nrf2

Other Ways to Activate Nrf2

Inhibitors of Nrf2

SIRT1 decreases Nrf2-related gene production since acetylation allows Nrf2 to bind to DNA better and produce antioxidant genes [60]. This is a downside of SIRT1.

NAC inhibits Nrf2 [61], but it decreases oxidative stress directly.

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NRF2 SNPs on SelfDecode

The NRF2 gene has some SNPs that can tell you if you’re a high or low producer.

  1. RS10183914 (NRF2) TT
  2. RS16865105 (NRF2) AA
  3. RS1962142 (NRF2) GG
  4. RS2886161 (NRF2) TT
  5. RS35652124 (NRF2) TT
  6. RS6706649 (NRF2) CC
  7. RS6721961 (NRF2) GG
  8. RS6726395 (NRF2) AA
  9. RS7557529 (NRF2) CC

If you want to interpret your genes, you should use SelfDecode.

SelfDecode is the best gene analyzer around and helps you interpret your genetics.

SelfDecode is a sister company of SelfHacked. The proceeds from your purchase of this product are reinvested into our research and development, in order to serve you better. Thank you for your support.

About the Author

Joe Cohen, BS

Joe Cohen won the genetic lottery of bad genes. As a kid, he suffered from inflammation, brain fog, fatigue, digestive problems, anxiety, depression, and other issues that were poorly understood in both conventional and alternative medicine.Frustrated by the lack of good information and tools, Joe decided to embark on a journey of self-experimentation and self-learning to improve his health--something that has since become known as “biohacking”. With thousands of experiments and pubmed articles under his belt, Joe founded SelfHacked, the resource that was missing when he needed it. SelfHacked now gets millions of monthly readers.Joe is a thriving entrepreneur, author and speaker. He is the CEO of SelfHacked, SelfDecode and LabTestAnalyzer.His mission is to help people gain access to the most up-to-date, unbiased, and science-based ways to optimize their health.
Joe has been studying health sciences for 17 years and has read over 30,000 PubMed articles. He's given consultations to over 1000 people who have sought his health advice. After completing the pre-med requirements at university, he founded SelfHacked because he wanted to make a big impact in improving global health. He's written hundreds of science posts, multiple books on improving health, and speaks at various health conferences. He's keen on building a brain-trust of top scientists who will improve the level of accuracy of health content on the web. He's also founded SelfDecode and LabTestAnalyzer, popular genetic and lab software tools to improve health.

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