The Science of Detoxification: Phase III & Detox Nutrients

Eat These 10 Foods to Support Detoxification

The Science of Detoxification: Phase III & Detox Nutrients

We live in a world where we are exposed to hundreds of toxins each day – in the form of pesticides, environmental chemicals, flame retardants, heavy metals, processed foods, stress and medications – to name a few.

Certain people are more vulnerable to toxins due to their unique genetic makeup and biochemistry. Pregnancy and nursing are especially important times to limit toxic exposures, and children are exceptionally vulnerable just their physiology alone.

While exposure to toxins in our modern world is inevitable, there’s a lot we can do to minimize those exposures and use food to our benefit. Certain nutrients and phytonutrients impact the body’s ability to process toxins and lower the total body burden.

My focus in this article is using whole foods and nutrition to support your body’s natural detoxification systems.

Find Out How I Can Help You, Too!

The basics of detoxification

Detoxification refers to your body’s ability to get rid of waste. If that is impaired, or if we are bombarded with too many toxins, we get sick.

The liver is central to metabolic detoxification. It works through a series of enzymes, via pathways referred to as Phase I and Phase II detoxification. This system is dependent on adequate nutrients, phytonutrients, antioxidants, and protein. The liver transforms chemicals, hormones and toxins into water-soluble metabolites that can then be excreted by the intestines, kidneys, and skin.

Healthy digestion is critical, since a healthy gut and regular bowel movements help excrete toxins. Leaky gut and constipation can make the problem worse.

The kidneys also play a role, which is why good hydration with clean, filtered water is important. Sweating is another way we detoxify, and some people even utilize infrared saunas.

Just be sure to support your body first with good nutrition and adequate hydration.

Limit exposures and maximize detox

Limiting toxic exposures is the first step. Buying organic foods free of pesticides and GMOs and limiting processed and packaged foods is important. You can read more in my article 10 Ways to Reduce Toxins in Your Life.

You can improve your body’s ability to detoxify using key foods that help balance the Phase I and II pathways in the liver, and provide good fiber. This may also help with weight loss, since resistant weight loss is often related to toxicity.

As a basic rule, aim for 8-10 servings a week of organic, colorful, non-starchy vegetables. Specifically, eat cruciferous vegetables and alliums, onions and garlic, daily.

The goal is not to eat kale everyday, but rather aim for variety. Try to eat a phytonutrient-dense diet with a diversity of foods and colors.

By eating these 10 foods regularly, you will help support your body’s ability to detoxify.

10 Foods to Support Detoxification

  1. Broccoli + Other Cruciferous Vegetables – The crucifer family includes arugula, bok choy, broccoli, Brussels sprouts, cabbage, cauliflower, collards, kale, kohlrabi, radish and turnips. They are rich in glucosinolates, which hydrolyze to indole-3-carbinol and isothiocyanate. These phytochemicals help metabolize and balance hormones, estrogens.

    Cruciferous vegetables are researched in cancer prevention, especially hormone-sensitive or estrogen related cancers. They are great for metabolic detoxification and liver support. As an added bonus, the green crucifers also contain chlorophyll, which boosts detox capacity even more.

    Try these recipes for Roasted Broccoli and Crispy Brussels Sprouts with Garlic Aioli, or start your morning with a berry and cabbage smoothie.

  2. Garlic + Other Alliums – Alliums, or Thiols, include chives, daikon, garlic, leeks, onions, scallions and shallots.

    The Allium family provides sulfur compounds, which are responsible for their strong smell and flavor, as well as their potential health benefits. They possess important anti-inflammatory and antioxidant properties thought to help prevent cardiovascular disease, and cancer of the stomach and colon.

    Specifically, alliums help catalyze phase II detoxification in the liver which helps promote the elimination of toxins, including potential carcinogens. Allyl sulfides increase the important antioxidant known as glutathione, and promote genes containing antioxidant response elements (ARE). Try this recipe for Lemon and Garlic Green Beans or roast a chicken over a bed of onions and garlic.

  3. Parsley + Other Leafy Greens – Leafy greens include beet greens, bok choy, chard, cilantro, collard greens, endive, escarole, kale, mustard greens, parsley and radicchio. Leafy greens get their color from chlorophyll.

    Chlorophyll and chlorophyllin are able to bind to certain carcinogens, including polycyclic aromatic hydrocarbons found in cigarette smoke, and heterocyclic amines from charred meats. This may decrease absorption in the gastrointestinal tract, decreasing the amount of carcinogen that reaches susceptible tissues.

    This is a great reason to have a big green salad with your grilled meat! Try this recipe for Fresh Herb Chimichurri with grilled steak and vegetables.

  4. Turmeric – Turmeric contains the phytochemical curcumin, which gives it a bright yellow color. Curcumin inhibits Phase I while stimulating Phase II detoxification in the liver, and increases glutathione.

    It is studied in the prevention and treatment of diseases including colorectal cancers and Alzheimer’s. Try adding fresh turmeric root to a smoothie or sprinkle ground turmeric on roasted cauliflower.

  5. Berries – Blackberries, blueberries, raspberries and strawberries get their deep, dark color from anthocyanins.

    These are antioxidants that help fight free radical damage, and are thought to be anti-inflammatory and vasoprotective. Berries are high in ellagic acid, which is a phenolic compound that may slow the growth of cancer cells and help the liver neutralize carcinogens. Try this easy recipe for Berry Compote.

    My personal favorite is a bowl of fresh berries with a drizzle of high quality balsamic vinegar.

  6. Lemon – Limonene, a monoterpenoid found in the peel of citrus fruit, is a potent antioxidant that promotes Phase I and Phase II liver detoxification. d-Limonene plays a potential role as an anti-cancer nutrient, especially for breast cancer prevention and treatment.

    Vitamin C, an antioxidant in lemons, also helps convert toxins into their water-soluble form so they can be eliminated. Try drinking a tall glass of filtered water with lemon first thing in the morning, or add a slice of lemon with the peel on to your Vitamix, Ninja or NutriBullet.

  7. Green Tea – The polyphenols in green tea are multiple flavanoids, the most significant component being epigallocatechin gallate (EGCG). They are strong antioxidants that help balance liver detoxification pathways. Green tea polyphenols may enhance the detoxification of carcinogens and have been associated with decreased risk of certain types of cancers in humans.

    Try your green tea with a slice of lemon, which potentiates it’s polyphenols.

  8. Beets – Beets contain a group of phytonutrients called betalains that support methylation and glutathione-dependent phase II detoxification. Beets provide the highest plant source of betaine, which is anti-inflammatory. The high amount of fiber in beets also improves digestion and elimination.

    Try this recipe for Mashed Sweet Potatoes and Golden Beets.

  9. Flax Seeds – Flax seeds are the richest dietary source of lignans. These fiber- compounds help detoxify harmful forms of estrogen. Lignan-rich foods are being studied for their role in prevention of hormone-associated cancers, osteoporosis, and cardiovascular disease. Flaxseeds also provide anti-inflammatory omega-3 fatty acids, and their high fiber content supports good digestion. Grind whole, fresh flax seeds and sprinkle on salads or in smoothies.
  10. Artichokes – Artichokes are rich in liver-protective agents, including cynarin, a compound that stimulates the liver and gallbladder. They also have a mild diuretic effect on the kidneys, ensuring proper removal of toxins once the liver breaks them down. The very high fiber content also helps with elimination. Try this recipe for Grilled Artichokes with Lemon Aioli.

Don’t forget protein!

While a plant heavy diet is important, high quality lean protein should not be neglected. Protein deficient diets impair detox pathways in the liver.

And one last word of caution… talk to your doctor or pharmacist if you’re on blood thinners, Coumadin, or multiple prescription medications.


Detoxing from Detox

The Science of Detoxification: Phase III & Detox Nutrients

Many of us are aware of the concept of a ‘meme,’ an idea that spreads from person to person within a culture as some sort of phenomenon. Memes are sticky, that song you can’t get your head no matter how hard you try.

‘Detoxification’ is one such meme; as a concept it has meaning to almost everyone, but the significance of that meaning may be quite different from person to person. On its most basic level, detoxification implies the removal of ‘toxins’ and again, this word can mean different things to different people.

For example, one might see toxins as things made via improper metabolism or internal microbial over-activity. These are usually considered ‘auto-toxins’ in the sense that they are generated the internal environment. Others might focus on the ever-increasing amounts of external toxins that are the result of chemical industrialization.

These are usually termed ‘environmental toxins’ or ‘xenobiotics,’ chemical compounds such as drugs, pesticides or carcinogens not normally found in living organisms. There is little doubt about their penetration into human physiology. For example, a toxic component of rocket fuel has been found in breast milk of women in 18 states.

The chemical, perchlorate, leaches into groundwater from various military facilities.

If you think this is all just a curse of modern living, you might be surprised to know that a lot of the genetic variation in our ability to effectively detoxify substances such as hydrocarbons is the result of our attempt to deal with the combustion byproducts of a very long history of crowding around smoky campfires.

Science or Commerce?

Detoxification has become big business. There is no shortage of products and nostrums that claim to ‘flush out toxins.

’ Most of the time these are simply harmless ways of wasting money, except when they delay proper analysis and treatment of a more serious medical condition.

More insidiously, they perpetuate the notion that the body is a helpless accumulator of all things malevolent, and desperately needs our help to do what it is incapable of doing itself.

Nothing could be farther from the truth. Detoxification is a well-understood biochemical process and there is no shortage of science behind it. Let’s take a look at how it works and what you can intelligently do to support it. I promise to keep things simple.

Most chemical detoxification occurs in the liver, the basic chemical powerhouse of the body. Toxins might come in via respiration, the digestive tract or some other means, but if they get into the blood, they’re going to the liver. There, they trigger a series of reactions that have been grouped into two ‘phases.’

In order to better understand the detoxification process, I will be discussing Phase I and Phase II separately, but actually, both of these occur simultaneously; an automated car wash, where one car might be getting air-dried while another has just gone under the soap; at any given point in time, various toxins will be in either phase of detoxification, although all will eventually go through both phases.

Phase I – Metabolism and Breakdown of Toxins

Phase I detoxification enzymes are intimately involved with drug metabolism and breakdown, which is why one has to be aware that foods, herbs and supplements can influence cytochrome activity and why, if you are using them and taking prescription medicines, you should be monitored by a physician who is skilled in their combination. If I feel a generalized boost to Phase I detoxification is in order, I’ll often recommend these natural products in various combinations:

Phase I detoxification is often not very gentle.

Conversion of these compounds involves sending a lot of free oxygen and hydrogen around and, in their high energy states, they can be very reactive and irritable.

The end products of Phase I detoxification can sometimes be even more problematic than the molecule they started with. The only ‘improvement’ is that, at the very least, they are now on the way out.

Phase II – Preparation of Metabolites for Excretion

After a toxin finishes Phase I, it passes on to the second stage of its processing, Phase II detoxification. Phase II involves picking up the toxin from where it was left off by Phase I and twiddling it so that it can be safely be excreted from the body. Because the products of Phase I can be very reactive, having our Phase II detoxification mechanism in sync is very important.

Think of it this: a toxin is similar to a baton used in a relay race. Phase I and Phase II are the runners running the race. Phase I takes its lap around the track, does its job on the toxin and then passes the baton to Phase II so that it can do its job on the toxin.

However, Phase II has to be able to very quickly determine whether Phase I has passed it a real baton or lit stick of dynamite.

If Phase II gets it wrong, the very effectiveness of Phase I instead becomes a problem; or as one of my patients, a choreographer, once explained modern dance to me: ‘40% of every dance is the ending.’

To be able to effectively handle the pass-off from Phase I, Phase II can call on a bevy of deactivation pathways that can pin all sorts of things on the baton to tone it down. The two most amenable to lifestyle modification are known as conjugation and glucuronidation.

I know I promised to keep it simple, so let me describe these as best as I can. marriage, conjugation involves wedding an antioxidant known as glutathione to the baton. Glutathione is made from the amino acid NAC (n-acetylcysteine) and is about as close to a ‘metabolic currency’ as you’ll find in biochemistry.

There are genetics involved, and some people make it better than others. However, having ample NAC is critical.

I might also add that an extra level of attention can be provided by supplementing NAC with the herb milk thistle (silymarin), as this herb has been shown to help increase the level of glutathione inside the cells, which is where you want it.

This doesn’t necessarily pertain to detoxification, but there is a strong and emerging evidence basis for using NAC for the treatment of psychiatric disorders.

NAC appears to reduce the negative symptoms of schizophrenia and also appears to be effective in reducing craving in substance use disorders, especially for the treatment of cocaine and cannabis use among young people, in addition to preventing relapse in already abstinent individuals.

NAC has also show some benefit in obsessive-compulsive and related disorders, as well as on mood disorders. (Biomed Res Int. 2018; 2018: 2469486.) All of this has been speculated to be the result of its ability to increase glutathione.

Glucuronidation is a very long word used to describe plunking a molecule known as glucaric acid (or its stable form, calcium glucarate) onto the Phase I baton.

During Phase II liver detoxification, certain hormones and various fat-soluble toxins will undergo glucuronidation and be excreted through the bile or urine. Calcium glucarate helps this elimination process occur without interruption.

Apples, grapefruits, bean sprouts, and cruciferous vegetables cabbage, broccoli and Brussels sprouts tend to be high in calcium glucarate.

So, which phase should you try to maximize? In most situations, you’ll want to assist both Phase I and Phase II at the same time. However, if you smoke, are drug sensitive or are caffeine sensitive, you might want to emphasize enhancing Phase I.

Phase II detoxification involves the synthesis and secretion of bile, a carrier in which many toxic substances eventually are passed into the intestines.

If you notice delayed reactions to foods, problems with digesting fats or a simple ‘sick feeling’ after eating certain heavy foods, you might want to work on optimizing Phase II.

These are supplements I’m fond of using to aid in the overall detoxification process:

Finally, a word of encouragement. We are not biochemical bubbles who need to be protected from the big bad world out there. We’re designed to handle environmental challenges and even metabolize them.

In fact, the process of learning how to master these challenges is part of the process of engineering health itself.

 Eating right, exercising, sweating a little, expressing yourself, spending time in Nature, and limiting your exposure to toxic media and toxic people gives the innate wisdom of your body time to do what it does best: sort things out over time.


Integrative Approach to Liver Detoxification

The Science of Detoxification: Phase III & Detox Nutrients

By Jim Paoletti, B.S. Pharmacy, FAARFM, FIACP | Director of Education, Power2Practice

A discussion of detoxification could include everything from spiritual cleansing to scientific and physiological detoxification. Detox includes Integrative methods ranging from fasting, colon cleaning and ionic food detoxification to more conventional chelation and enzymatic nutritional support.

Metabolic Detoxification

This Integrative liver detoxification protocol refers to the metabolic pathways which process unwanted chemicals for elimination, otherwise known as “Metabolic Detoxification.

” The enzymatic reactions that neutralize and solubilize toxins so that the liver and kidneys can excrete them is the primary mechanism for elimination of foreign chemicals and unnecessary or excess endogenously produced substances.

Metabolic detoxification reactions help protect from environmental toxins, drugs, excess hormones, vitamins and inflammatory molecules.

The rationale for detoxification is simple: We ingest and are exposed to many toxins in today’s world. Toxins can act as carcinogens or mutagens and disrupt numerous metabolic pathways, leading to a multitude of detrimental effects.

In 2006, the CDC reported that the average American has 116 of 148 tested synthetic compounds in their body. Most food contains chemicals that need to be detoxified properly or they are deposited in various tissues. The increased toxic load leads to inflammation as most toxins are pro-inflammatory.

A chronic state of inflammation from accumulated toxins leads to disease.

Exogenous & Endogenous Toxin Exposure 

Lifestyle choices can increase toxic burden stressing the detox capacity of the liver. These include smoking, excessive alcohol and caffeine consumption, drugs (recreational, prescription and OTC), and dietary choices of fast foods, refined foods, artificial food additives preservatives and colors, antibiotics and growth hormone used in production of meats.

Additional environmental sources of exogenous toxins include (but are not limited to):

  • Air pollution (factories, vehicle emissions)
  • Smoke
  • Pesticides, herbicides, insecticides and fertilizers
  • Solvents (cleaning agents, gasoline, glue, paints, nail polish & remover, perfumes, etc.)
  • Plastics that have been subjected to heat
  • Artificial preservatives
  • Heavy metals
  • Non-purified water
  • Excessive alcohol or caffeine
  • Dyes
  • Chlorinated & brominated products (commercial bread products)
  • Radiation & EMFs (cell phone, Wi-Fi, cordless phones, radiology, air planes, electronic clocks). Keep phones, computers, electronic clocks, etc. at least 8 feet from bed.
  • Microwave ovens
  • Poor quality fats (canola, soy and corn oils, etc)

Endogenous toxins can add to the detoxification burden of the liver. Endogenous toxins include:

  • Bacterial, fungal and yeast overgrowth
  • Metabolic reaction byproducts CO2 and ammonia (in excess)
  • Hormones (excess)
    • Note: excess hormones can be caused by overproduction, and/or by poor elimination (which in turn leads to more toxic burden)
  • Undigested food in the GI tract
  • Stress
    • Turns off & on genes that regulate fat storage, immune function, and hundreds of enzymes that break down fats and detoxify drugs
    • Slows gut transit which increases recirculation of estrogens and exogenous toxins

Fat Soluble Toxins Can Deposit in the Lipid Membrane & Adipose Tissue

The effects of stored toxins can be continuous and permanent if allowed to remain in the body. Toxins may be an underlying causes for chronic illness because of their effects on the gastrointestinal, cardiovascular, neurological, immune and muscular systems. Optimizing function of the metabolic detoxification processes improves the efficiency of the liver, kidney and intestines.

Liver detoxification is part of the process for the functional approach to GI health. Chronic GI complaints are the most common reason why people seek medical care. Without good functioning of the GI tract, there won’t be proper absorption and assimilation of nutrients for running detox pathways.

The pillars of GI health include digestion, elimination, microflora balance and gut integrity.

  • Digestive enzymes can be very beneficial to help patients break down complex food molecules and nutrients to be absorbed, and therefore important to the detoxification pathway.
  • Elimination refers to getting rid of toxic metabolites from the body. When toxins are removed by enhancing liver detoxification pathways, often improvement is seen in all four pillars of GI health.

As you can see, GI health affects and is dependent on proper detoxification, and visa versa.

There is more than one organ that assists in the detoxification process, as the skin helps detoxify through sweating and the kidney through urination. However, the most important organ for detoxification is the liver.

The 2 Phases of Liver Pathway Detoxification

Both culminate in elimination of the products via liver metabolism.

Phase I detoxification is enzymatic transformation. Enzymes chemically transform lipid soluble compounds into water soluble compounds.

The majority of Phase I detoxification reactions are performed by the cytochrome P450 family of enzymes (CYPs). CYP enzymes are relatively non-specific and can act on numerous types of toxins.

Other enzymes that contribute to Phase I detoxification include:

  • Flavin monooxygenases (FMOs), which metabolize nicotine
  • Alcohol and aldehyde dehydrogenase, which metabolize alcohol
  • MOAs (monoamine oxidases) which metabolize neurotransmitters and some antidepressant drugs

The CYP1A2 enzyme is responsible for Phase I metabolism of approximately 50% of drugs. Patients taking multiple medications can overwhelm the CYP1A2 enzyme, leading to side effects and drug-to-drug interactions.

Phase II detoxification is enzymatic conjugation. Metabolic products from phase I detoxification are more water soluble. However, they are not yet made totally suitable for elimination.

These molecules may not be sufficiently water soluble for complete elimination and often are reactive molecules that if not eliminated can cause oxidative damage. Phase II enzymatic reactions make the molecules more water soluble and less reactive.

Phase II enzyme activity is considered anti-carcinogenic and anti-mutagenic. The Phase I metabolism of toxins triggers the oxidative stress response of activation of nuclear factor erythroid-derived 2 (Nrf2), the protein that controls the production of most Phase II enzymes.

Nrf2 also activates synthesis of the detoxification molecules superoxide dismutase (SOD) and glutathione, and activates the initial processes in heavy metal detoxification.

Phase II enzymes include:

  • Glutathione S-transferases (GSTs) that catalyze transfer of glutathione to Phase I metabolites including sex steroids, thyroid hormones, fat-soluble vitamins, bile acids, bilirubin, and prostaglandins. GSTs also have antioxidant properties and detoxify free radicals and oxidized lipids or DNA. Glutathione conjugates are excreted via the bile or delivered to the kidney for further processing and elimination.
  • Methyltransferase enzymes. Catechol 0-methyltransferase (COMT) eliminates catecholamine neurotransmitters.
  • Sulfotransferases (SULTs) that attach sulfate groups in Phase I and II reactions. SULTs metabolize drugs, sex steroids, thyroid, adrenal hormones, serotonin, ascorbate and Vitamin D). Note, un other Phase II enzymes, SULTs can convert some pro-carcinogens into more reactive intermediates which may act as chemical carcinogens and mutagens.
  • UDP-glucuronyltransferases (UGTs) which attach glucuronic acid to toxins in the process referred to as glucuronidation. Drugs, xenobiotics and many environmental toxins (including bisphenol A from plastics and benzopyrene from cooked meats) are metabolized by UGTs.
  • The amino acid conjugating enzymes attach amino acids to xenobiotics and food preservatives benzoic acid

The final step in detoxification is transport. Transporters actively pump water soluble Phase II metabolites cells of the liver, kidney and intestines. These transporters are proteins referred to as ABC transporters (for the ATP binding Cassette) because they require energy from ATP.

Caution: Phase I reactions potentially produce more reactive and toxic molecules, therefore inducing Phase I reactions when Phase II enzymes are not functioning at a rate to rapidly neutralize the Phase I products can increase health risks. Factors that increase Phase I reactions include nicotine and alcohol.

Signs and Symptoms of Toxin Buildup Include:

  • Headaches
  • Muscle aches and pains
  • Fatigue
  • Asthma
  • Allergies
  • Skin disorders, including acne and rosacea
  • Unexplained weight gain and inability to lose weight
  • High blood pressure
  • Fatty yellowish lumps around eyes
  • Abdominal bloating
  • Excessive abdominal fat
  • Pain or discomfort over the liver
  • Trouble digesting fatty foods
  • Acid reflux and heartburn
  • Dark spots on skin
  • Over-heating of the body and excessive perspiration
  • Chronic Infections
  • Mood swings
  • Poor mental function
  • Lowered stress tolerance
  • Decreased libido
  • Infertility

The Goals of a Liver Detox Are:

  • Minimize exposure to and consumption of all toxins.
  • Increase intake of nutrients required for detoxification by diet and/or supplementations.
  • Optimize bowel function and bile flow to help elimination.
  • Increase fruits and vegetables to increase alkalinity along with adequate purified water to increase urinary elimination.

How to Detox the Liver:

The detoxification process can be as simple as avoiding the toxins the body is exposed to for a certain period of time, usually 7 to 30 days. Add to that good, healthy eating.

Most often, the diet component is combined with nutritional support for Phase I and Phase II enzyme reactions, again for 7-30 days. Additional detox measures can be incorporated, such as daily sweating.

Break a good sweat daily and consume plenty of purified water during and after the exercise or sauna treatment.

Examples of other additional measure would be chelation therapy for heavy metal detoxification, or removal of mercury fillings by a qualified trained dentist.

The patient starts the process of detox by reducing the toxic load:

  • Avoid exposure to environmental toxins.
  • Reduce exposure from toxins in food and drink.
  • A liver detox diet emphasizes organic natural whole foods in order to avoid all pesticides, antibiotics, artificial additives, high fructose corn syrup, hormones, etc. It also should contain alkaline foods potassium-rich fruits and vegetables, while avoiding acid-inducing foods refined carbohydrates.
  • Increase purified water intake to the half of the patient’s weight in pounds in ounces (150 pounds equals 75 ounces of water).
  • Avoid common allergies to decrease risk of inflammation (gluten, daily, soy and egg).

Detox kits: Most nutritional companies have kits available for a 1 week to a 1 month detox program. The kits contained detailed information on the detox diet, and the supplements that support detoxification mechanisms. The kit may also contain a nutritional beverage mix.

Some of the nutritional supplements you may see used for detox support include milk thistle, artichoke leaf extract, pomegranate extract, green tea extract, turmeric, glucosinolates, sulphoraphane, n-acetylcysteine, MSM, alpha-lipoic acid, dandelion, selenium, methionine, and certain amino acids.

Phase 1 detoxification is supported by vitamins B2, B3, B6, B12, and C, folic acid, niacin, magnesium, copper, zinc, and flavonoids.

Lastly, I would caution against detox programs that include fasting, with or without a “cleanse.” These programs are a type of starvation, which slows down metabolism. A daily laxative for cleansing can cause dehydration, deplete electrolytes, and impair normal bowel function.

If a patient appears to be fairly toxic, or someone with high exposure to toxins (hairdresser, lawn service personnel, etc.)… my advice is to do a detox diet only for at least 7 days before adding nutritional support.

Toxins released from the fat cells into the bloodstream when metabolism is increased can cause temporary unpleasant symptoms including headache, chills, fatigue, dizziness, irritability, body odor, foul smelling stools, body aches and general flu- symptoms. These symptoms can persist several days in some individuals, so if in doubt, go more slowly with the detox.

Avoid toxins and follow a detox diet for 7-10 days before initiating nutritional supplementation to support liver metabolism.

Jim Paoletti, BS Pharmacy, FAARFM, FIACP, is the Director of Education at Power2Practice and a Clinical Consultant with over 30 years of experience creating and using bio-identical hormone therapies in both retail pharmacy and clinical practice.

Jim is a Diplomat in Functional Medicine in addition to being a former faculty member for the Fellowship of Functional Medicine.

At Power2Practice, he applies his wealth of knowledge and experience by hosting live webinars and creating useful content, such as blogs, podcasts and clinical support tools.


What is Phase III Detoxification?

The Science of Detoxification: Phase III & Detox Nutrients

From a biochemical standpoint detoxification can be described as the metabolic process by which a series of enzymatic reactions neutralise and solubilise exogenous and endogenous toxins for transport and excretion from the body. This is achieved through the well described system known as Phase I and Phase II detoxification pathways. 

Phase I is typically composed mainly of the cytochrome P450 supergene family of enzymes, begins the detoxification process by chemically transforming lipid soluble compounds into intermediate metabolites in preparation for Phase II detoxification.

In Phase II reactions the intermediate metabolites produced in Phase I are transformed into water-soluble compounds that can be excreted through urine or bile. This involves several types of nutrient dependant reactions, including glucuronidation, sulfation, glycination, glutathionation and amino acid conjugation.

Most literature on detoxification refers to these two phases, with greater emphasis traditionally placed on Phase I. The liver has long been recognised as the primary organ of detoxification but, there is now growing evidence that the gut also plays a central role in the detoxification process.

Given that the small intestine functions predominantly as an absorptive organ its significance in the metabolism of non-nutritive dietary constituents and xenobiotics seems to have been significantly underestimated.

This is in spite of the fact that the small intestine is the first site of xenobiotic exposure and that, over the course of a lifetime, is presented with the largest load of antigens and xenobiotics confronting the human body. 


Emerging evidence is now describing an additional detoxification process which is highly concentrated in the small intestine, known as antiporter activity. This is now often referred to as the Phase III detoxification system.

[1] More than 350 unique antiporter proteins have been identified with the best known and most studied transporter known as P-glycoprotein. These efflux transporters, Phase I and Phase II enzymes, work on specific substrates. Efflux transporters can also be induced, increasing the transporters activity.

They can also be inhibited causing substrate levels to become higher.

P-glycoprotein is extensively distributed and expressed in the intestinal epithelium where it pumps xenobiotics back into the intestinal lumen.

It is also found in liver cells where it pumps toxins into bile ducts, in the cells of the proximal tubule of the kidney where it pumps them into urine-conducting ducts, and in the capillary endothelial cells composing the blood–brain barrier and blood-testis barrier, where it pumps them back into the capillaries.[2]

Antiporter activity is an important factor in the first-pass metabolism of xenobiotics, thereby decreasing the intracellular concentration of xenobiotics and reducing total toxin load in the liver.

[3] This energy-dependent trans-membrane protein has also been associated with the Phase I enzyme CYP3A which appears to play a role in the co-regulation of this system in the intestines to further promote detoxification.[4]

In the small intestine, antiporter activity is found at the tips of the villi [5] and by pumping non-metabolised xenobiotics cells and back into the intestinal lumen may reduce the total load on Phase I and allow for greater xenobiotic detoxification efficiency before metabolised toxins are transported into the circulation. 


While the antiporter system is described primarily through its role in first-pass metabolism, occurring pre-Phase I and Phase II, the same efflux pump is also responsible for the transport of hydrophilic metabolites hepatocytes after Phase II conjugation, and is therefore referred to as Phase III of detoxification. Thus, the antiporter system serves a dual function with the Phase III terminology used to describe both functions of transportation of conjugated metabolites after Phase II and the elimination of toxins pre-biotransformation.


Conjugated xenobiotics and toxins are pumped into the bile and intestinal lumen by the antiporter system so they can be excreted.

At this stage, effective elimination of these compounds is dependant on a number of factors, with diet and microflora playing a pivotal role.

Deconjugation of these metabolites by hydrolytic enzymes such as beta-glucuronidase, sulfatase and beta-lyase results in subsequent enterohepatic recirculation, shunting the toxin back to the liver where it will, once again, go through the biotransformation process. 

Resident bacteria in the GI tract are largely responsible for the production of these enzymes, with beta-glucuronidase recognised as particularly significant, being present throughout the GI tract, due to the fact that glucuronides are the largest class of xenobiotic conjugates excreted in the bile.

[6] This process is attributed to enzyme activity produced significantly by Clostridium perfringens as well as Escherichia coli and Klebsiella sp.,[7] suggesting that dysbiosis may contribute to increased metabolite deconjugation and enterohepatic recirculation.

Elevated beta-glucuronidase activity is associated with an increased risk for various cancers, particularly hormone-dependent cancers such as breast, prostate, and colon cancers.[8]

The implications of this further support the notion that diet and probiotic supplementation may assist with normal detoxification processes.

In addition, calcium d-glucurate, a nutrient found in grapefruit, apples, oranges, broccoli, and brussels sprouts is known to be a beta-glucuronidase inhibitor via its metabolite D-glucaro-1,4-lactone.

Oral supplementation of calcium-D-glucarate has also been shown to inhibit beta-glucuronidase activity [9] resulting in the proper elimination of conjugated toxins.

According to Dr Chris Shade, an environmental and analytical chemist who specialises in the human detoxification system, the most significant cause of Phase III dysfunction is inflammation, especially in the gut.

When Phase III is blocked a negative feedback loop results in the down regulation of Phase II enzymes.

Intermediate metabolites produced in Phase I are then at risk of building up resulting in increased oxidative damage which further impairs detoxification capacity.[10]

The clinical goal here should include supporting the GI tract by reducing inflammation, binding toxins in the gut and promoting efficient elimination. Therapeutic considerations may include high-bioavailability curcumin, chlorella and water soluble fibre.

Consider also supplementing with nutrients required for normal Phase II function and antioxidant support which specifically includes glutathione and R-alpha-lipoic acid. These nutrients have poor bioavailability and would therefore have limited therapeutic value unless provided in a more advanced delivery system.

Liposomal technology allows these nutrients to be delivered in nano-sized vesicles for enhanced absorption through the mucosa of the mouth. 

The human detoxification system is a delicate and complex process involving three distinct phases. However, it is only very recently that we have elucidated the function and significance of Phase III.

We now understand that any successful therapeutic management of detoxification requires us to restore, manage and augment this phase, which can then have profound implications for health and resilience.


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The information provided on FX Medicine is for educational and informational purposes only. The information provided on this site is not, nor is it intended to be, a substitute for professional advice or care. Please seek the advice of a qualified health care professional in the event something you have read here raises questions or concerns regarding your health. 


Detox 101

The Science of Detoxification: Phase III & Detox Nutrients

The word “detoxification” can trigger a lot of negative responses from people. When we think “detox,” we think discomfort or something we are afraid to do. Everyone has a friend who has some kind of detox story, and fears range from, “Will I be starving?” to “Will I be in the bathroom all day?” Detox has become a dirty word because we don’t really understand what it is.

Truth be told, our bodies are designed to naturally detox; we do it every single day without even thinking about it.

A built-in garbage disposal, detoxification is the cleaning system that enables us to discard foreign, unwanted, non-nutritive or chemical substances, referred to sometimes as “xenobiotics” or foreign particles.

And, lately, we have an onslaught of xenobiotics entering our food supply, poisoning our lakes and rivers, finding their way into cookware and clothing, and even manufactured from our own overburdened metabolic processes (i.e., insulin and uric acid are natural metabolites).

With toxin buildup associated with a number of chronic health issues including cardiovascular disease, diabetes, autoimmune disease, neurological diseases, reproductive disease and infertility, ADD/ADHD/Autism and, also, depression and anxiety, we not only need to understand our natural detoxification ability, we need to maximize it.

The detox process happens, basically, in two phases called phase I and phase II, with the combined purpose of converting the fat-soluble toxins into water-soluble compounds that can then be excreted by the body.

In phase I, a set of enzymes called cytochrome P450 enzymes (CYPs) are responsible for the oxidative metabolism of the toxins. These enzymes, of which 57 have been identified, transform the toxins into a water-soluble form that can then be metabolized by the phase II enzymes, and ultimately excreted.

CYPs, located in the liver and the intestines, are non-specific and recognize countless toxins. They are responsible for the majority of phase I drug metabolism reactions, which is why they are so well-researched.

Several other enzymes, including flavin monooxygenases (FMOs), alcohol and aldehyde dehydrogenases, and monoamine oxidases (MAOs), also contribute to phase I detoxification when faced with nicotine, alcohol and antidepressant drugs, respectively.

In phase II reactions, the toxins are conjugated to the water-soluble substances, which increases their solubility and enhances secretion.

Some of the phase II enzymes include UDP-glucuronlytransferases (UGTs), which catalyze some clinical drugs and environmental toxins, glutathione-S-transferases (GSTs), and sulfotransferases (SULTs). Each catalyzes a different type of conjugation reaction.

In summary, phase I converts the toxin into a water-soluble compound and phase II helps conjugate the compound, preparing it for excretion.

Ideally, phase I and phase II enzymatic processes are functioning optimally, and we are successful in eliminating these unwanted substances. Sometimes, however, our bodies are not equipped to detoxify the toxins. A nutrient deficiency can make detoxification difficult because vitamins and minerals act as co-factors in the enzymatic pathways of phase I and phase II.

In one study, the detoxification of a common toxin, Bisphenol A, was found to be dependent on retinoids (natural derivatives and synthetic analogs of vitamin A). The enzymatic activity necessary to eliminate BPA required retinoid stores in the liver, and the extent of the damage from BPA toxicity was affected by retinoid administration and liver stores of vitamin A.

In addition to nutrient deficiencies, some people have genetic polymorphisms that make detoxification more challenging or simply a deluge of toxins in the system, rendering it impossible for their bodies to manage.

Take, for example, the popular pain reliever, Tylenol®, or its active ingredient, acetaminophen (paracetamol). The most common cause of liver toxicity in the U.S. is caused by acetaminophen toxicity due to what has been identified as a phase I/phase II imbalance.

Ideally, most of this drug is detoxified by phase II UGT and SULT enzymes. A small portion of it, however, is first transformed into a toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI) by phase I CYP enzymes, and is then conjugated with glutathione using GST during phase II.

In cases of toxicity, what can happen is that the system gets overwhelmed and the UGT and SULT enzyme activity gets impaired. This forces the drug to undergo the mechanism whereby it first gets converted into NAPQI and then uses glutathione for conjugation.

Eventually the glutathione stores get depleted, and the rising levels of NAPQI in the liver cause widespread damage.

To counteract the rising level of NAPQI, glutathione or N-acetyl-cysteine, a precursor to glutathione, is often administered after an acetaminophen overdose. So much success was found in the administration of NAC to reverse the hepatotoxicity from acetaminophen that NAC is now being used to reverse non-acetaminophen liver failure.

Our bodies have natural intelligence, and can handle the occasional xenobiotic entering the body. However, when much of what we eat, drink and breathe is laced with non-nutritive substances, our bodies need additional nutritional support to bolster our natural detoxification pathways, phase I and phase II.

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