Breaking Down Phase 2 Detoxification
The word detox usually brings to mind things like juice cleanses, diet pills, or extensive fasts. The reality is detoxing is much more complicated than that. Our bodies have numerous systems and processes aimed at detoxing chemicals and waste, but there are things we can do to support those systems to achieve optimal results. Which is why understanding phase 2 detox is so important—it’s the step that lots of people miss!
Detox Gone Wrong- The Order Matters
When I first started down the road of detoxification, I had a very simplistic mindset. This isn’t always bad- there is wisdom in simplicity, but I had patients experience the so-called “detox reactions” more than I would have liked. The issue? I was giving nutrients and herbs that supported detoxification, but giving them in the wrong order. The thing is, detoxification is not simple- it’s quite complex. Over the years, I’ve come to understand that detoxification should be systematic, it should be individualized, and it should be done with caution. When following THESE three principals, detoxification is a powerful tool for healing.
One of the areas where I see many people go wrong with detoxification protocols is the pushing of Phase 1 detox prior to Phase 2 detox. Phase 1 detoxification is the process of oxidation- which is the first step in breaking toxins down and transforming them into less harmful water-soluble molecules that can be eliminated from the body. The problem is that this process creates free radicals, also known as, reactive oxygen species. If kept in this stage for too long, these reactive oxygen intermediates can lead to inflammation and tissue damage. Therefore, we need to get these molecules out of this stage as quickly as possible – That is done by phase 2 processes! Moral of the story? Phase 2 detox support needs to come before phase 1 detox support.
Phase 2 Before Phase 1
Phase 2 detox is known as the conjugation pathway, whereby the liver attaches another molecule to the “intermediate toxin” to render is less harmful. There are 6 types of conjugation that takes place in this phase: sulfation, glucuronidation, glutathione conjugation, methylation, acetylation, and glycination. The following article outlines the pathways in detail, but there are still large gaps in our understanding of how many types of toxins are conjugated. You will notice that not every toxin is listed and some are listed in multiple sections; however, you will see that certain pathways require more support than others.
Supporting Phase 2 LIVER Detoxification
Sulfation:
Sulfation is dependent on inorganic sulfate availability and is important in the detoxification of the following substances.
Steroid hormones and Thyroid Hormones:
Estrogen
Progesterone
DHEA
Melatonin
Triiodothyronine (T3)
Tetraiodothyroinne (T4)
Xenobiotics
BPA (found in plastics, liner of food and drink cans, liner of water pipes, plastic cling wraps, lacquers, varnishes, inks, adhesives, flame retardants, dental sealants & composite materials, sunglasses, water coolers, sports equipment, etc.
Triclosan (antibacterial found in cleaning and personal care products; also used in kitchen ware, computer equipment, clothes, and children’s toys.)
Benoxophenone-3 (found in sunscreens, nail polish, makeup, hair & skin care)
Butylated Hydroxytoluene (BHT) (food additive/preservative in butter, meats, cereals, chewing gum, baked goods, snack foods, and dehydrated potatoes) and is also used in animal feed, cosmetics, pharmaceuticals, rubber, petroleum, and electrical transformers.
Xylenol (found in resins, laminates, construction material, and in electric motors (cars, home appliances, power tools, etc)
Catecholamines
Norepinephrine
Epinephrine
Dopamine
Impaired Sulfation
There are several reasons why someone may not have sufficient sulfate levels or have impaired ability to conjugate sulfate. These include a low protein diet, low intake of sulfate rich foods, high toxin exposure (which depletes sulfate), low magnesium levels, and issues with the sulfotransferase (SULTs) family of enzymes. Common conditions that are associated with poor sulfation include, autism, asthma, chemical sensitivities, chronic fatigue syndrome, degenerative joint disorders, intestinal disorders, lupus, neurodegenerative conditions, and migraines.
Ways to Support Sulfation
Consuming more sulphur containing amino acids (cysteine, methionine, and taurine). This can be done through dietary consumption of protein or more targeted support with NAC or glutathione.
Sulfur rich foods like cruciferous vegetables (broccoli, cauliflower, cabbage, brussels sprouts, kale etc), Allium vegetables (onions, garlics, leeks, shallots, chives), eggs, and meats.
Epson Salt (Magnesium Sulfate) Baths are a great way to increase sulfation in someone who doesn’t tolerate sulfate rich foods in the diet.
Going out into the sun, which stimulates production of choelsterol sulfate
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Glucuronidation:
Glucuronidation is one of the most important pathways for phase 2 detoxification, and as you will see- there is much overlap between glucuronidation and sulfation. Glucuronidation requires adequate levels of glucuronic acids and uses UDP-glucuronyltransferase (UGT). This pathway is especially important for metabolism of hormones, bilirubin, and medications.
Sex Hormones and Thyroid Hormones
Estrogens **
Androgens (Testosterone, DHEA)
Triiodothyronine (T3)
Tetraiodothyroinne (T4)
Bilirubin
Some Mycotoxins
Medications:
*It is estimated that up to 40-70% of all medications are metabolized by glucuronidation.
NSAID’s
Benzodiazepines (Lorazepam)
Tylenol (Paracetamol)
Codeine
Morphine
Impaired Glucuronidation:
Glucuronidation can be impaired int two main ways. First- the activity of the UGT enzymes can be impaired due to genetic predisposition or use of certain medications. One common condition where glucuronidation is impaired is Gilbert’s syndrome. Gilbert’s syndrome is an autosomal dominate disorder caused by a mutation in the UGT-1 gene-causing mild hyper-bilirubinemia. This is believed to be found in about 10% of the population and can be aggravated during times of extended fasting, stress, heavy physical activity, irregular sleep, and dehydration. Second- the metabolites that are conjugated via the glucuronidation pathway can be cleaved within the gut lumen and reabsorbed. This is seen with high beta-glucuronidase levels- an enzyme found within the gut microbiome. This enzyme cleaves glucuronide conjugates (such as estrogen), and allows these toxins and hormones to be reabsorbed. High beta-glucuronidase levels are a common culprit in estrogen dominance disorders.
Supporting Glucuronidation:
Supplements that induce UGT Enzymes: resveratrol, curcumin, d-limonene, quercetin
Supplements that inhibit beta-glucuronidase: calcium d-glucurate, probiotics/prebiotic, low meat diet.
Foods:
Citrus Fruits: limonene from the peels of oranges, lemons, limes, and grapefruit and believed to induce UGT activity.
Cruciferous vegetables
Dandelion, rooibos, honeybush, and rosemary tea
Astaxanthin found in algae, yeast, trout, krill, shrimp, and crayfish
Glutathione Conjugation
This pathway is by far the most important pathway for many of the environmental toxins and carcinogens we are exposed to on a daily basis. This process utilizes the enzyme glutathione s transferase (GST), and is dependent on glutathione, which is a tripeptide comprised of cysteine, glutamine, and glycine. Glutathione is the body’s chief antioxidant, and its actions within the detoxification pathways are multifaceted. This is why glutathione is one of the TOP supplements recommended for detoxification. Glutathione conjugation occurs in phase 2 detoxification for the following elements:
Pesticides & Herbicides
Heavy Metals
Mercury
Lead
Arsenic
Cadmium
Most Mycotoxins
Medications/Drugs
Tylenol (Acetaminophen)
Alcohol
Tetracycline
Impaired Glutathione conjugation
The main factor that impairs glutathione conjugation is glutathione deficiency. Many chronic illnesses are associated with glutathione deficiency, and this is believed to be due to increased utilization to combat oxidative stress and overall toxic burden.
Supporting Glutathione Conjugation
Supplements:
Glutathione or glutathione precursors: glutathione, NAC
Glutathione recyclers: Vitamin C, Vitamin E
Increasing GST Activity: Zea mays
Reducing free radicals to prevent glutathione depletion: omega 3 supplementation, alpha lipoic acid, selenium
Dietary considerations: cruciferous vegetables (rich in sulphur) and protein rich diet (for ample amounts of cysteine, glycine, and glutamine)
METHYLATION
Methylation is involved in many biochemical processes throughout the body, so it is no surprise that it is also involved in detoxification. Methyl conjugation occurs through a family of enzymes called methyl transferases. One of the most famous of these enzymes is cathecol-O-methyltransferase (COMT), which it’s known for it’s role in metabolizing estrogens and catecholamines. Most of the methyl groups used for conjugation of toxins come from s-adenosylmethionine (SAM). Methionine, choline, B12, and active folate are required for the synthesis of SAM.
Steroid Hormones
Specifically Estrogen
Catecholamines
Norepinephrine
Epinephrine
Dopamine
Histamine
Heavy Metals
Arsenic
phenols
Are both manufactured and natural substances. There are many different tpes of phenols found in the environment. Phenols can be found in coal tar, petroleum, plastics, vaccine preservatives, and BoTox
Aromatic Amines (polycystic aromoatic hydrocarbons)
carcinogens found in cigarette smoke, dyes, adhesives, perfume, pharmaceuticals, pesticides, explosives. diesel exhaust, combustion of wood chips, and grilled meats and fish.
Impaired Methylation Conjugation
Methylation can be impaired in several ways that are beyond the scope of this article. I do want to emphasize that while methylation genes can be part of the picture, they are by no means close to the full picture. Methylation genes tell us genetic predisposition, but do not tell us phenotypic expression, which can be modulated by nutrient levels, gut health, toxic load, and use of methylation inhibitors (such as birth control pills, PPIs, antibiotics, nitrous oxide, valproic acid, and cholestyramine). Additionally,other factors, such as sucrose, have been found to inhibit methylation enzymes. Within labwork, signs of low methylation include elevated whole blood histamine, elevated homocysteine, elevated MMA, low RBC folate, and low serum B12.
Supporting Methylation Conjugation
Supplements that donate or support creation of methyl groups: SAMe, methionine, methylB12, 5- MTHF (active folate), trimethylglycine, B6, B2, Magnesium, zinc, and choline.
Acetylation:
The process of acetylation attaches an acetyl co-A molecule to the toxin to render it less harmful. The enzyme that mediates this reaction is N-alpha-acetyltransferase (NAT). NAT 2 is the enzyme that is most responsible for liver detoxification. Acetylation is responsible for the metabolism of the following types of toxins:
Medication/Drugs:
Caffeine
Benzodiazepines
Isoniazid
Hydralazine
Sulphonamides
Histamine
Aromatic Amines
carcinogens found in cigarette smoke, dyes, adhesives, perfume, pharmaceuticals, pesticides, explosives. diesel exhaust, combustion of wood chips, and grilled meats and fish.
Impaired Acetylation:
Unlike other enzyme activity which can be greatly modified by environmental conditions, acetylation ability is primarily genetically determined. Reduced NAT2 activity is more common in Caucasians.
Supporting Acetylation:
In comparison to other pathways, little is known about stimulation of acetylation outside of its dependence on Vitamin B1, Vitamin B5, Vitamin C.
Glycination
There are several types of amino acid conjugation that occur in phase 2 detoxification. Glycination is the most common type of amino acid conjugation and is predominately utilized in salicylate and benzoate conjugation. Benzoate is widely used in food preservatives, while salicylates can be found naturally in our food supply and in synthetic forms within medications and personal care products. This pathway is dependent on sufficient amounts of the amino acid glycine.
Medication Salicylates:
Aspirin and 5-SA compounds similar to aspirin
Alka Seltzer
Various non-steroidal anti-inflammatory drugs
Food Salicylates:
Fruites: apricots, blackberries, blueberries, cantaloupe, cherries, cranberry, currants, dates, grapes, guava, loganberries, orange, pineapple, plums, prunes, raisons, raspberries, strawberries
Vegetables: capsicum, chili, mushroom, olives, pepper (sweet), radish, tomato, zuccinni
Seeds/Nuts: almonds, peanuts
Spices: anise, cayenne, celery, cinnamon, cumin, curry powder, dill, fenugreek, five spice, ginger, honey, mint, mustard, oregano, rosemary, sage, tumeric, thyme
Food Dyes: yellow dye (#5 and #6), red dye (
Salicylic Acid in Personal Care Products
Can be found in fragrances and perfumes, cosmetics, toothpaste, mouthwash, muscle pain creams, sunscreens, and skin care products
toluene
A popular industrial chemical that is converted into benzoate within the liver. It can be found in home within paint thinners, paint brush cleaners, nail polish, glues, inks, and stain removers.
Benzoate:
Sodium Benzoate is a widely used preservative in food, mediations, and personal care products. There is some concern that sodium benzoate can convert into the carcinogenic molecule benzene - this has been shown to happen on soda and other products that also contain vitamin C. Additional concerns also exist around increases risk for hyperactivity behavior.
Impaired Glycination:
Glycination is dependent on glyceine-N-acetyltransferase (GLYAT) enzymes and sufficient amount of glycine, thus SNPs in this gene or insufficient protein intake could impair glycine conjugation. Impaired glycine conjugation has been implicated in increased risk for non infectious hepatitis and liver cancer.
Supporting Glycination:
Decrease intake of salicylates and benzoates
Food high in glycine: collagen protein, turkey, pork, chicken, soybeans, seaweed, eggs, amaranth, beef, pumpkin seeds, almonds, duck, goose, mung beans, sunflower seeds, lentils, lamb, bison, lobster, fish.
Detoxification is far from simple. Our body’s innate system of recycling and taking out the trash is PROFOUND. For me, this is another incredible reminder that we have been crafted by an incredible God. Most of this occurs without any intervention, but with a world increasing in toxins by the second, our systems are becoming burdened. Supporting phase 2 detoxification can be a powerful tool, but before beginning any supplement regimen, I strongly recommend working with a physician who can help you understand your body’s specific needs!