Challenging the Wisdom of Nrf2 as a Target for Drug Development

     A little regulatory protein called NF-E2 related nuclear transcription factor, commonly abbreviated Nrf2, interacts with DNA upstream of many cellular defense genes, in conjunction with other proteins, to control toxins that contribute to oxidative stress. Since oxidative stress, a condition characterized by overabundance of free radicals, is associated with aging, inflammation, exposure to environmental toxins, and almost every disease known to humanity, the ability to manage oxidative stress would clearly be coveted by anyone concerned about their health.  Viewed from this perspective, it is not surprising that drug companies are testing and developing pharmaceutical products that act as "Nrf2 activators."  Is this wise?
     The illustration below shows us that an activator molecule can stimulate release of Nrf2 proteins, which then enter the cell nucleus and interact with DNA to promote production of diverse cellular defense proteins. This pathway outlines a powerful survival mechanism that is almost identical in humans and other mammals. The newly synthesized proteins will combat a variety of free radicals and toxins, and will utilize cell nutrients and cofactors to create any materials necessary for carrying out this critical task.

Nrf2 activation of cellular defense genes offers a powerful, but complex, mechanism for reducing oxidative stress that fosters disease. This drawing shows us that Nrf2 remains bound to a multi-protein complex in the cell.  Upon activation (which results when free radicals collide with and activator), Nrf2 breaks free, enters the cell nucleus, and hooks up with a protein called Maf.  The Nrf2-Maf complex binds to a sequence, or site within your DNA, which is found in many locations of the genome upstream of about 1400 unique cellular defense genes.  When bound to this antioxidant response element, or activation site, the defense genes are transcribed.  This leads to the production of thousands of enzymes which destroy free radicals and other toxins and waste products in the cell.  

     The illustration is simplified, but still demonstrates a complex, multi-step process that offers numerous possibilities for malfunction. Because Nrf2 interacts with, and stimulates production of, many different kinds of enzymes, there is potential for Nrf2 activation to have infinite direct and indirect and effects on your cells. Assuming Nrf2 is successfully activated, turns on production of  more than 1000 defense and repair genes, and cleans up all the excess free radicals and toxins in the cell, what happens next?  What becomes of the 1400 different kinds of protein that now have no job to do?  Will they be degraded and eliminated, along with all the nutrients they contain?  Will they sit around causing cellular mischief like sterotypical high school dropouts? Will they be broken down like scrap auto parts and recycled? Each of these scenarios creates potential for unintended secondary or tertiary effects that may harm cells.  Sounds like a setup for harmful side effects.
    Such complex pathways and unpredictable outcomes are one reason to be leary of pharmaceutical solutions to problems as fundamental as oxidative stress and removal of toxins. It is relatively easy to for a pharmaceutical developer to demonstrate that a drug activates Nrf2 and reduces oxidative stress. It is relatively easy to run basic toxicity analyses that look at a handful of indicators to evaluate long term safety.  But looking at all the potential side effects which may be caused, not by the drug itself, but by those 1400 gene products and related proteins that were activated in response to the drug is more difficult.  Side effects might not be evident for years, may vary among users, and might not be evident until the next generation.
    The good news is that there are proven natural solutions to oxidative stress, which are less prone to unwanted side effects. In fact, herbal dietary supplements that activate Nrf2 are already being marketed. While quality varies with manufacturers, a comparison of herbal and pharmaceutical Nrf2 activators by Lim et. al. indicated that the herbal formula outperformed the pharmaceutical Nrf2 activator  (Nrf2 activators: a novel strategy to promote oligodendrocytesurvival in multiple sclerosis? J. Lim, S. van der Pol, J. Drexhage, E. de Vries, J. van Horssen. Multiple Sclerosis Journal 2011; 17: S277–S505).  While more research is needed, the results are not surprising.  An herbal product provides biochemical complexity that can mitigate the potential for side effects which are inevitable when a drug targets a regulatory pathway as diverse as Nrf2.

Why is an herbal Nrf2 activator better than a pharmaceutical? Two reasons are included here: 

1) Herbal supplements are biochemically complex.  This means that in addition to the activator, the herbs are adding thousands of other enzymes, antioxidants, minerals, lipids, fatty acids, signal molecules, nucleic acids, vitamins, and more, all of which co-evolved with the Nrf2 activator, and are thereby proven safe at the cellular level (at least in the host species). These components offer the biocomplexity necessary to buffer side effects and maintain cellular homeostasis.

2) The risk of unwanted side effects is low.  Medicinal herbs with long histories of human dietary and/or medicinal usage have already provided evidence of safety.  While problems associated with legal use of medicinal herbs are rare, the informed user can easily examine ingredients to assess safety.  If in doubt, one can contact any number of licensed health professionals, peer reviewed research reports, or reputable dealers and distributors to learn about safe dosages and potential drug interactions.

What to look for in a manufactured herbal Nrf2 activator?
     Anyone experiencing negative effects of aging, combatting a chronic disease, taking medications with potential side effects, or undergoing excessive physical, emotional, or environmental stress should explore the benefits of Nrf2 activation and reduced oxidative stress.  Since Nrf2 activation requires a laboratory facility to demonstrate, and herbal interactions can modify the Nrf2 properties of any individual herb, a manufactured product from a reputable company provides the greatest confidence that your herbal formula is activating Nrf2. Because oxidative stress is a ubiquitous condition that increases with age, it is likely that you will be taking your Nrf2 activator for a long time.  For this reason, doing your research in advance will help you feel confident that you have made a safe and healthy choice.  Three things to look for are:

1. A formula prepared by a reputable, transparent company.  The best companies will provide details about their quality control standards, implement standards for where and how the herbs are grown, and insist on herbs that are free of chemical contaminants.  Factors like the expertise of the product developers, testimonials from customers you know, and public trading reports or press releases can add layers of confidence about who you are doing business with.
2. Ingredients.  Are the ingredients in the formula safe for you?  Do you have any allergies to ingredients? Are there any potential interactions with the ingredients in the formula and medications or other products you are taking?  You can discuss this with your physician or healthcare provider.
3. Product validation.  Has there been any research on the product formula?  Note that research on individual herbs in the product is less informative than research that has been carried out using the complete formula.  Are there peer reviewed studies indicating potential to reduce oxidative stress?

What will a Nrf2 activator do for me?    
     Peer reviewed studies of phase II detox indicate that when Nrf2 is activated, genes will be transcribed that increase the abundance of enzymes which eliminate free radicals and toxins from cells.  This is expected to reduce oxidative stress-an important driver of aging and disease.  Herbal Nrf2 activators may have additional benefits associated with the herbs from which they are formed.  Since Nrf2 activation is sensitive, and can be disrupted by other herbal components, it is important to use a formula that has been subjected to laboratory studies that demonstrate effective Nrf2 activation and subsequent reduction of oxidative stress.