Part Three: Key Nutrients and Pathways for Optimizing Detoxification

By Donnie Yance

Now we will begin digging into the amino acids, minerals, and pathways that support healthy detoxification.

Key Goals for Detoxification

1. Remove or reduce the source of toxic exposure. 
2. Regenerate networks through herbal, nutritional, dietary, and lifestyle medicine
3. Restore cellular energy primarily using adaptogens which are the root-system medicine for detoxification. 
4. Improve energy transfer by ensuring efficient utilization of oxygen, fats, proteins, and sugars for energy. The more efficient the system, the fewer toxins are produced. 
5. Reduce cellular inflammation. 
6. Activate key detoxification and antioxidant pathways, including: Cytochrome p450, Glutathione (GSH), Nrf-2, Methylation, Sulfation, and Glucuronidation. 
7. Eliminate stagnation of oxygen, blood, and lymph by engaging in gentle activities such as: deep breathing, walking in nature, swimming, or yoga. 
8. Reduce stress, stay calm, and manage anger, worry, and fear.

To support our body’s overall health, we need to boost vitality, detoxify, protect ourselves with natural compounds, and provide general and specific support. Natural compounds such as resveratrol, Ginkgo biloba extract, isothiocyanates (ITCs), glycine, N-acetylcysteine (NAC), and selenium offer cellular protection and detoxification support. 

Supporting glutathione, our body’s natural antioxidant, enhances our ability to detoxify harmful substances like glyphosate (a common plant killer). Glutathione (GSH) is a major intracellular antioxidant and redox regulator in cells. In addition to its essential role in redox homeostasis, it functions as a cofactor for a multitude of enzymes. 

The 15 Fundamental Roles of Glutathione 

1. As the body’s master antioxidant, it serves a central role in heavy metal, chemical, venom, and radiation detoxification, as well as boosting immune response powers in SARS-Cov-2 and common flu symptom reduction

2. DNA synthesis and repair

3. Gene regulation

4. Protein synthesis (involved in 1/3 of all proteins made in the body)

5. Modulating  proper immune response

6. Regulating apoptosis (the disintegration of dysfunctional or cancerous cells)

7. An increase in lymphocyte presence (T Cells, B Cells, and Innate Lymphoid Cells which includes Natural Killer Cells) while improving their effectiveness

8. Assists in the detoxification of the lungs, thus improving respiratory conditions, especially in cases of lung toxicity (mold, smoking, asbestos, coal mining, etc.)

9. Supports redox balance (electron transfer that increases or decreases oxygen in chemical reactions), thus reducing reactive oxygen species (ROS)

10. Helps maintain other antioxidants like Vitamin C and E in their active forms

11. Supports amino acid transport and enzyme activation 

12. Prostaglandin synthesis (controls vascular smooth muscle constriction or dilation, inflammation, and many other vital functions)

13. Assists in the detoxification of the small intestines, thus improving digestion

14. Assists in the protection of the nervous system, and thus the prevents or improves neurological disorders

15. Assists in the removal of toxins in fat before being incorporated into bile (your fat emulsifier)      

Rapid and long-term depletion of glutathione from Acetaminophen (Tylenol) intake can increase aging and susceptibility to disease.

Supporting Glutathione Antioxidant Levels

Glutathione is a major antioxidant, cell protectant, and detoxifying agent made by the body. Crucial for liver detoxification, It’s composed of three amino acids: glycine, glutamine, and cysteine. Glycine and N-acetyl cysteine (NAC) supplements stimulate glutathione production, improving detoxification of many substances including: glyphosate, heavy metals, fungicides, polycyclic aromatic hydrocarbons, lipid peroxides, and more.

In studies, NAC has shown antioxidant and cell-protective effects against glyphosate-induced oxidative stress. 

Along with supplemental glycine and NAC, I recommend supplementing with natural compounds that spare glutathione degradation, such as isothiocyanates (found in broccoli, cauliflower, kale, cabbage, brussels sprouts, watercress, horseradish and mustard), polyphenols (brightly colored fruits and vegetables), and organic forms of selenium (high in Brazil nuts and brewer’s yeast).

N-Acetyl-L-Cysteine (NAC) 

N-Acetyl-l-cysteine (NAC) acts as the most important precursor of the antioxidant glutathione (GSH), one of the principal cell mechanisms for reactive oxygen species (ROS) detoxification.  NAC acts as a sulfur donor in Phase II detoxification and is a powerful compound found to be particularly effective at removing heavy metals from the body. NAC also supports cellular detoxification systems and healthy cellular function.

As an antidote to acetaminophen poisoning, NAC restores the pool of glutathione in the liver that was depleted in the drug detoxification process. More recently, improved knowledge of the mechanisms by which NAC acts has expanded its clinical applications. In particular, the discovery that NAC can modulate the homeostasis of glutamate has prompted studies of NAC in neuropsychiatric diseases characterized by impaired glutamate homeostasis. 

NAC was discovered to help breakdown mucus in the early 1960s, and since then, it has been extensively used in lung disorders. NAC also has antifibrotic effects on lung fibroblasts.

Studies show that NAC is effective at reducing acute attacks of chronic bronchitis. A meta-analysis from 2000 looked at 8 different studies and concluded that NAC prevented acute exacerbations of chronic bronchitis.   

There are a number of large and well-designed trials reporting the efficacy and safety of NAC for the treatment of chronic obstructive pulmonary disease^,,  (COPD) and idiopathic pulmonary fibrosis (IPF). ^,

Positive effects of N-acetylcysteine in vivo and in vitro tests.

Bisphenol-A (BPA) exposure increases ROS levels and decreases GSH content. NAC has been shown to reduce these harmful effects of BPA.

In rat studies, NAC has been shown to protect cells from the toxic plant-killer glyphosate

Glycine 

As I mentioned earlier, the similarity between glyphosate and glycine allows glyphosate to replace glycine in proteins if it’s not present in sufficient amounts. This leads to numerous health problems. I recommend supplementing with glycine for two reasons: if provided, the body will prefer glycine over glyphosate, and aging peptides and proteins containing glyphosate will be flushed from the body.

Glycine has many protective effects, including:

• Anti-inflammatory, immunomodulatory, and cytoprotective
• Protection against liver and kidney injury caused by toxicants and drugs
• Suppression of inflammatory cell activation and free radical formation
• Stabilization of the plasma membrane potential
• Protection against arthritis and stress-induced ulcers.

Interestingly, research suggests that glycine supplementation can significantly extend the lifespan of C. elegans, a simple invertebrate often used to study cellular and molecular processes. 

Glycine can counteract specific age-related transcriptional changes. Glycine and NAC, in older adults, improve glutathione deficiency, reduce oxidative stress, enhance mitochondrial function, lower inflammation, and improve physical function. Glycine and NAC supplementation improves and reverses multiple age-associated abnormalities in aging humans.

Glycine and N-Acetylcysteine (Gly-NAC) supplementation enhances brain health in aging mice; by improving brain: glutathione deficiency, oxidative stress, glucose uptake, mitochondrial dysfunction, genomic damage, inflammation, and neurotrophic factors.

Glycine can be found in chelated compounds like Creatine MagnaPower, magnesium glycinate, and magnesium glycyl glutamine. I prefer it in powder form, mixed with other compounds for relaxation and detoxification.

Glutamine: A Key Compound For Toxin Removal

A new study reveals how our bodies keep blood cells healthy through a remarkable cleaning process. Here’s what scientists discovered:

• Red blood cells need to produce heme (a key component that carries oxygen)
• This process creates a toxic waste product called ammonium (ammonia with one extra positively charged proton)
• To remove this toxin, blood cells use an enzyme called glutamine synthetase
• This enzyme transforms the toxic waste (ammonium and glutamate) into the amino acid glutamine.

Ammonia is toxic because it disrupts critical metabolic, neurological, and physiological processes in the body. Its accumulation, typically due to liver or kidney dysfunction, highlights the importance of these organs in detoxification. Treating underlying conditions and supporting detoxification pathways are essential to managing ammonia toxicity.

Glutamine synthetase catalyzes the transformation of ammonia with glutamate into glutamine. Glutamine serves, with alanine, as a major nontoxic interorgan ammonia carrier.¹  Glutamine can carry ammonia from the brain and muscle to the liver and kidneys where it is neutralized and then excreted. 

Glutathione synthesis in the red blood cell. Synthesis of reduced glutathione (GSH) is represented in the top half of the figure and regeneration of reduced glutathione from oxidized glutathione (GSSG) in bottom half of figure. 

Glutamine, α-ketoglutarate, and alanine, with smaller contribution from aspartate, are the main precursors for the intracellular synthesis of glutamate. Glutamine is also used in the synthesis of NAD⁺. 

Cysteine, glycine, and glutamate are required for the synthesis of glutathione and this reaction is catalyzed by glutamate cysteine ligase (GCL), which is the rate-limiting enzyme in this pathway. 

GSH reduces hydrogen peroxide by the action of glutathione peroxidases, and in turn is oxidized to GSSG. Glutathione reductase catalyzes the reverse reaction with the use of NADPH. Reduced NADPH is regenerated from NADP⁺ by the enzyme glucose-6-phosphate dehydrogenase (G6PD).

Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; NADS: nicotine adenine diamide synthetase; GCL: glutamate cysteine ligase; GSH: reduced glutathione; GSSG: oxidized glutathione; GPO: glutathione peroxidase; GR: glutathione reductase; G6PD: glucose-6-phosphate dehydrogenase.

Cysteine and glycine are the other amino acids that are required for glutathione production, and can also enter human RBCs via specific amino acid transport systems.

Selenium

The element Selenium (Se), has an essential nutritive and biological role as a trace mineral known primarily for its vital antioxidant function as a part of the enzyme, glutathione peroxidase. However, Se also has a much more global biological impact beyond its antioxidant function.

The versatile roles of selenium include:

• Antioxidant protection by glutathione peroxidase

• Selenium-dependent thyroid-hormone conversion

• Immune-system modulation

• Decreasing inflammation from reactive oxygen species (ROS) 

• Removing misfolded proteins

• Decreasing DNA damage

• Promoting telomere length (antiaging)

• Slowing HIV progression. 

Se has both structural and enzymatic roles. It influences a number of endocrine processes, most notably, those involved in thyroid hormone synthesis and metabolism. Se is needed for the proper functioning of the immune system, viral suppression, and delay of the aging process. 

Its deficiency has been linked to a number of disorders such as heart disease, diabetes, liver disease, miscarriage, and poor sperm motility. Se supplementation has recently moved from the realm of correcting nutritional deficiencies to one of pharmacological intervention, especially in the domain of cancer chemoprevention.

Exposure to mobile-phone-induced electromagnetic radiation (EMR) may affect biological systems by increasing free radicals, apoptosis, and mitochondrial dysfunction. Selenium may reduce this EMR damage through a reduction of oxidative stress and restoring mitochondrial membrane potential.

Se treatment increases mitochondrial biogenesis and respiratory capacity. Se dependent deiodinases regulate thyroid hormone activation which impacts muscle-cell regeneration, metabolism, and reactive oxygen species production. 

In a meta-analysis, a significant connection was seen between lower selenium levels and breast cancer.  Se supplementation with organic forms (not sodium selenite) can be beneficial in breast cancer patients with low Se. Se deficiency is very common in our soils and bodies.

Recent research suggests that selenium has anti-aging properties and may even protect against age-associated diseases such as tumors, cardiovascular disease, and neuropsychiatric disorders.

Boosting the NRF2 Antioxidant Pathway

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of cell defense, a guardian of health-span, and gatekeeper of longevity. Nrf2 is expressed in all tissues, but the key detoxification organs (kidneys and liver) have the highest levels. 

Nrf2 may be further induced by cellular stressors (hormesis) including internal reactive-oxygen species or external chemicals. The Nrf2 pathway mediates cell protection by activating the transcription of more than 200 genes that are crucial in the metabolism of many drugs and toxins. It also protects against oxidative stress, inflammation, instability of proteins, and the buildup of damaged proteins. 

Nrf2 interacts with other important cell regulators such as tumor suppressor protein 53 (p53) and nuclear factor-kappa beta (NF-κB) and, through their combined interactions, protects against many age-related diseases including cancer and neurodegeneration.^,

Nrf2 is essential to antioxidant-response-element-mediated host defense. NRF2 acts as a cytoplasmic “switch” to activate several cytoprotective genes, arguably heralding a new paradigm in nutrition science.

The mechanism of action of nuclear factor erythroid-derived 2-related factor 2 (NRF2) in basal and oxidative stress conditions.

Isothiocyanates Are Potent Enhancers of NRF2

Isothiocyanates are natural compounds found mainly in vegetables like broccoli, cauliflower, kale, cabbage, and watercress. These compounds give the vegetables their distinctive spicy and bitter flavors. All isothiocyanates work in the body through the same mechanism, interacting with NRF2 through a specific chemical reaction.

Research shows that isothiocyanates offer numerous health benefits. They may help prevent diabetes and cancer, reduce pain, protect heart health, treat neurological conditions, and regulate thyroid function. Given these significant health effects, scientists are studying how different forms of isothiocyanates may work better than others as antioxidants or cancer-fighting compounds. I will go into more detail on this in Detox part 4.

Regulation of the Nrf2-mediated pathways by natural phytochemicals provides multiple modes of resistance to EDCs and other chemical-induced carcinogens.

Echinacoside (ECH), a natural glycoside, was discovered and isolated from the garden plant Echinacea angustifolia, about sixty years ago.  

ECH possesses multiple health benefits on humans, including anti-tumor effects. ECH activates the Nrf2 signaling pathway and ameliorates oxidized-LDL-cholesterol-induced dysfunction of coronary artery endothelial cells.

Cancer cells can frequently hijack the protective capability of NRF2 to sustain themselves and meet their metabolic requirements for proliferation. Further, abnormal activation of NRF2 in cancer cells confers resistance to commonly used chemotherapy drugs and radiation. 

During the last decade, many research groups have attempted to block NRF2 activity in tumors to counteract the survival and proliferative advantage of cancer cells and reverse resistance to treatment. 

The active compound in Magnolia, Honokiol, effectively inhibits NRF2-induced renal tumor growth through increased oxidative stress.

Baicalin, a major active ingredient in Chinese Skullcap (Scutellaria baicalensis), has

antioxidant, anti-inflammatory, and anti-cancer properties. 

Baicalin can significantly reduce the protein levels of NRF2, increasing selective cancer-cell death in a cancer cell line IPEC-J2.

In healthy cells, baicalin slows cognitive impairment and protects against neuroinflammation by enhancing NRF2.

Baicalein increases stress resistance and life span in the roundworm C. elegans by activating the NRF2 pathway and dose-dependently prolongs its life span.

White willow (Salix alba) bark extract increases antioxidant enzymes, preventing and reducing oxidative stress through activation of Nrf2 independent of salicin.

Phytochemicals scavenge reactive oxygen species (ROS) and free radicals reducing oxidative stress in the brain. They also upregulate NRF2

The identification of NRF2 gave the first real clue that compounds from the diet like sulforaphane (SFN) had the potential to influence many protective genes.

When Nrf2 is activated, it triggers the production of specific genes that have a special element called Antioxidant Response Element (ARE) in their DNA.

Conclusion

Optimizing detoxification pathways is crucial for maintaining overall health and resilience against environmental and internal toxins. By leveraging amino acids like glycine, cysteine, and glutamine; minerals like selenium; and natural compounds such as resveratrol, and isothiocyanates, we can support key processes like glutathione production and Nrf2 activation. 

These actions can help reduce oxidative stress, boost cellular energy, and calm inflammation, ultimately enhancing the body’s ability to detoxify effectively.

This holistic approach not only promotes detoxification but also supports longevity, brain health, and protection against age-related conditions. By prioritizing these foundational elements, we empower our bodies to function at their best in an increasingly toxic environment.

In part 4, we will cover several herbs and lifestyle habits to target these essential detoxification processes. 

About the Author:

Donald R. Yance is the founder of the Mederi Center. A Clinical Master Herbalist and Certified Nutritionist, Donnie is renowned for his extraordinary knowledge and deep understanding of the healing properties of plants and nutrition, as well as of epigenetics, laboratory medicine, oncologic pathology, and molecular oncology. He is a professional member of the American Herbalists Guild, National Association of Nutrition Professionals, Academy of Integrative Health and Medicine, and the Society for Integrative Oncology.

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