Nrf2 and Detox Support
A Toxic World
The modern world exposes the human body to a daily multitude of metabolic toxins including heavy metals, pesticides, and herbicides. It has been estimated that there are between 25,000 and 84,000 chemicals currently in commerce in the United States, and biomonitoring has shown that hundreds of circulating synthetic chemicals make their way from the environment into the human body.1 Such a high chemical burden can put pressure on the body’s natural metabolic detoxification capacity, and toxicant exposure and bioaccumulation of xenobiotics may be a significant contributor to the increasing prevalence of chronic disease observed within the past several decades.2,3 Some conditions for which the improper clearance of toxins has been associated with include:
- Weight gain4
- Cardiovascular disease5
- Chemical sensitivity and intolerance
- Neurocognitive concerns (e.g. attention deficit/hyperactivity disorder6,7
- Immune dysfunctions, such as autoimmune disease8
- Reproductive and developmental concerns9,10
Reducing toxic exposure and enhancing the metabolism and excretion of toxicants appears to be crucial toward controlling oxidative stress and inflammation and in the prevention of disease. Thankfully, cells possess a broad range of sophisticated antioxidant mechanisms to help protect against environmental stressors such as exposure to toxins, and these pathways can be activated by phytochemicals found within foods. The ability for plants to prevent disease is possible in part through the activation of genetic transcriptional factors such as nuclear factor erythroid 2-related factor 2 (Nrf2), which has significant health-promoting properties and allows the body to better cope with harmful biochemical stressors.
Nrf2 & Detoxification
Within the last few decades, awareness around the importance of Nrf2 as a genetic transcriptional factor that regulates the body’s cellular resistance to oxidative stress has been increasing. By regulating oxidant levels, Nrf2 participates in the control of several important cell functions such as autophagy, inflammasome signaling, apoptosis, mitochondrial biogenesis, and stem cell regulation.11 Once activated, Nrf2 can:
- Control and induce the expression of antioxidant response element (ARE) dependent genes, which regulate antioxidant defenses and the pathophysiological outcomes of oxidant exposure
- Enhance the detoxification and elimination of numerous exogenous chemicals by mediating the induction of enzymes involved in phase one and two detoxification mechanisms including important phase two conjugation enzymes such as glutathione S-transferase (GST)12
As the production of most phase two detoxification enzymes is controlled by Nrf2, its activity and ability to protect cells against free radical damage and xenobiotics has been implicated in a range of characteristic chronic diseases typically associated with oxidative stress and exposure to harmful chemical exposures.13
| Understanding the Terms | |
| Autophagy | A cellular regulation process where unneeded or dysfunctional cell parts are broken down and recycled |
| Inflammasome | A bundle of proteins of the innate immune system linked to inflammation activation |
| Apoptosis | Self-activated programmed cell death |
| Mitochondrial biogenesis | The process by which mitochondria, energy-producing cell organelles, expand in number |
| Stem cell | Undifferentiated cells with diverse cell type potential |
Nrf2 Activators: The Brassicas
Consuming a higher intake of brassica vegetables has been associated with a decreased risk of chronic disease and the potential to reduce cancer risk through Nrf2 activation.1,2 Key phytochemicals in these plants are able to bind to Nrf2 and have been referred to as “Nrf2 activators.” They have been shown to protect against oxidative stress, exert cytoprotective and neuroprotective effects, and induce phase two detoxification enzymes when consumed through the diet.3-5 Though many phytochemicals have been identified as activators of Nrf2-signaling mechanisms, those which have been studied the most extensively include curcumin from turmeric (Curcuma longa), and sulforaphane from the Brassicaceae family of plants and – in particular – from broccoli.
Phytonutrient profiles unique to brassicas include compounds called glucosinolates, which are sulfur-containing molecules that exist almost exclusively in cruciferous plants and are responsible for the bitterness and pungency of many edibles such as mustard, cabbage, broccoli, Brussels sprouts, and radish. The breakdown products from chewing these foods imparts their distinctive taste and is responsible for converting glucosinolates such as glucoraphanin into isothiocyanates such as sulforaphane via myrosinase, an enzyme. Myrosinase is activated within the plant once it becomes damaged, and in this way the glucosinolates become hydrolyzed into potent Nrf2 activators through chewing, in part by the bacterial microbiota of the gastrointestinal tract. In vitro and in vivo studies suggest a chemopreventive activity of isothiocyanates through Nrf2 activation, and studies in humans support anti-inflammatory effects and the potential to regulate epigenetic pathways.6 Of the phytochemicals with Nrf2 inducer capacity, brassica-derived sulforaphane is thought to be the most potent naturally occurring biomolecule known at this time.7
Obtaining Sufficient Sulforaphane
As a generation under significant toxic burden, encouraging the mobilization and excretion of toxins while simultaneously enhancing antioxidant effects through upregulating Nrf2 pathways is a sensible way to prevent and mitigate the risk of chronic and inflammatory conditions. Consuming a brassica-rich diet over time appears to result in a range of clinically significant health benefits; however, achieving a therapeutic dose of sulforaphane solely through dietary intake has its challenges. Many individuals already struggle to consume their recommended daily number of vegetables, and in most cases when they do, preparation includes using heat. Raw brassicas are known to be a much better source of glucosinolates (and therefore sulforaphane) compared to those that are cooked as the cooking process inactivates myrosinase, producing an estimated three to four times less sulforaphane in the body.8,9 Moreover, glucoraphanin levels in plants can vary greatly dependent on their quality (i.e. growing and storage conditions) and genotype, making it difficult to achieve consistent levels through food.10 In these cases, high quality sulforaphane supplementation may be a useful consideration to help reduce the body’s toxic burden and leading to improved health outcomes for a wide range of clinical presentations.
- Pool, R., & Rusch, E. (2014). Identifying and reducing environmental health risks of chemicals in our society. Workshop Summary. In Identifying and reducing environmental health risks of chemicals in our society. Workshop Summary.. National Academies Press.
- Sears, M. E., Genuis, S. J. (2012). Environmental determinants of chronic disease and medical approaches: recognition, avoidance, supportive therapy, and detoxification. J Environ Public Health.
- Mostafalou, S., Abdollahi, M. (2013). Pesticides and human chronic diseases: evidences, mechanisms, and perspectives. Toxicol Appl Pharmacol, 268 (2), 157-77.
- Baillie-Hamilton P. F. (2002). Chemical toxins: a hypothesis to explain the global obesity epidemic. Journal of alternative and complementary medicine (New York, N.Y.), 8(2), 185–192
- Münzel, T., & Daiber, A. (2018). Environmental Stressors and Their Impact on Health and Disease with Focus on Oxidative Stress. Antioxidants & redox signaling, 28(9), 735–740
- Polanska, K., Jurewicz, J., Hanke, W. (2013). Review of current evidence on the impact of pesticides, polychlorinates biphenyls and selected metals on attention deficit / hyperactivity disorder in children. Int J Occup Med Environ Health, 26 (1), 16-38.
- Hauptman, M., & Woolf, A. D. (2017). Childhood Ingestions of Environmental Toxins: What Are the Risks?. Pediatric annals, 46(12), e466–e471.
- Jochmanova, I., Lazurova, Z., Rudnay, M., Bacova, I., Marekova, M., Lazurova, I. (2015). Environmental estrogen bisphenol A and autoimmunity. Lupus, 24 (4-5), 392-9.
- Mima, M., Greenwald, D., & Ohlander, S. (2018). Environmental Toxins and Male Fertility. Current urology reports, 19(7), 50.
- Chiu, Yet al. Association Between Pesticide Residue Intake From Consumption of Fruits and Vegetables and Pregnancy Outcomes Among Women Undergoing Infertility Treatment With Assisted Reproductive Technology. JAMA Intern Med. 2018;178(1):17–26.
- Bellezza I et al. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res. 2018;1865(5):721-733.
- Ma Q. (2013). Role of nrf2 in oxidative stress and toxicity. Annual review of pharmacology and toxicology, 53, 401–426. https://doi.org/10.1146/annurev-pharmtox-011112-140320
- Cuadrado A et al. Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach. Pharmacol Rev. 2018;70(2):348-383
- Ambrosone, C. et al. Cruciferous vegetable intake and cancer prevention: role of nutrigenetics. Cancer Prev Res (Phila). 2009 Apr;2(4):298-300.
- Sturm, C. et al.. Brassica-Derived Plant Bioactives as Modulators of Chemopreventive and Inflammatory Signaling Pathways. International Journal of Molecular Sciences. 2017;18(9):1890
- Lee, J., Jo, D. G., Park, D., Chung, H. Y., & Mattson, M. P. (2014). Adaptive cellular stress pathways as therapeutic targets of dietary phytochemicals: focus on the nervous system. Pharmacological reviews, 66(3), 815–868.
- Uddin, M. et al. Emerging promise of sulforaphane-mediated Nrf2 signaling cascade against neurological disorders. Sci Total Environ. 2020;707:135624.
- Schepici, G et al. Efficacy of sulforaphane in neurodegenerative diseases. Int J Mol Sci. 2020;21(22)
- Shapiro, T. et al. (1998). Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiology and Prevention Biomarkers, 7(12), 1091-1100.
- Wagner, A, et al. Health promoting effects of brassica-derived phytochemicals: from chemopreventive and anti-inflammatory activities to epigenetic regulation. Oxid Med Cell Longev. 2013;2013:964539.
- Houghton, C. Sulforaphane: its “coming of age” as a clinically relevant nutraceutical in the prevention and treatment of chronic disease. Oxid Med Cell Longev. 2019;2716870.
- Fahey, J. et al. (2015). Sulforaphane bioavailability from glucoraphanin-rich broccoli: Control by active endogenous myrosinase. PloS one, 10(11), e0140963.
- Conaway, C. et al. Disposition of glucosinolates and sulforaphane in humans after ingestion of steamed and fresh broccoli. Nutr Cancer. 2000;38(2):168-178.
- Farnham, M. et al. (2005). Glucoraphanin level in broccoli seed is largely determined by genotype. HortScience, 40(1), 50-53.
