Phase I and II detox pathways

Detoxification is the process in which the body eliminates or neutralizes toxic substances. Toxins come from various sources including the air, diet, drugs, alcohol, smoking, as well as metabolic by-products. Thus, lifestyle factors play a significant role in the accumulation of toxins. The build-up of toxins results in cellular damage, and eventually chronic disease. The Centers for Disease Control and Prevention report that almost half of American adults have at least one chronic disease. Chronic diseases including heart disease, stroke, cancer, diabetes, and arthritis are among the most common, costly, and preventable of all health problems in the U.S.1

The body utilizes several routes of detoxification including the skin, lungs, kidneys, liver, and intestines. What’s important to keep in mind is that there are two pathways by which the body detoxifies harmful substances and it’s essential to support both of these pathways in order to detoxify effectively. Supporting only one of the detoxification pathways can actually do more harm than good.

Phase I and Phase II

The liver is the primary detoxification pathway responsible for processing all of the endogenous and exogenous chemicals within the body. Each minute, nearly one-third of the total body blood flow is pumped through the liver. The liver filters the blood and removes harmful substances such as drugs, bacteria, toxins and foreign proteins. There are two primary detoxification enzymatic pathways in the liver in which chemicals are eliminated or neutralized, known as phase I and phase II reactions. Ensuring that both phase I and phase II are optimally fueled with critical nutrients is vitally important to prevent potential destructive toxic build up and cellular damage. When educating patients in one’s clinical practice on this critical balance, one can compare this process to a relay race and the passing of a “toxic baton” from one runner to another. If either phase I or phase II is inefficient at passing the baton, the race is lost for optimal wellness. It is only through the maximum effort of each member of the team that ultimately yields the best results and ultimate victory.

Phase I reactions primarily process chemicals to undergo phase II reactions. Phase I converts toxins via oxidative, hydrolytic and reductive reactions. The most common reactions are oxidation, utilizing the microsomal cytochrome P450 monooxygenase family of enzymes. The cytochrome (CYP) family of enzymes plays an important role in the detoxification of drugs, as well as drug interactions. Some drugs, as well as natural substances such as grapefruit juice, can modulate the transcription of the CYP genes resulting in altered metabolism of drugs or other chemicals. The phase I metabolites are highly reactive and may cause damage if not properly removed from the body in phase II reactions.

Phase II reactions involve several pathways in which molecules undergo conjugation in the liver. The substances being metabolized are attached to endogenous molecules such as acetate, glucuronate, glycine or sulfate to form water-soluble metabolites. These water-soluble metabolites are then excreted from the body in the urine or in the bile.

Detoxification Imbalance

Ideally, the metabolites from phase I reactions are properly shuttled to the phase II pathways and excreted. However, any imbalance in between the two pathways can result in a build-up of phase I metabolites. Research indicates that there is a fivefold variability of phase I functioning even among healthy individuals.2 Many of these metabolites are free radicals and can cause significant cellular damage. Furthermore, many of the drugs, supplements, and even foods can alter the balance between these two pathways resulting in increased oxidative stress and free radical damage. For example, grapefruit juice inhibits the CYP 3A4 subfamily of enzymes. This subfamily of enzymes is responsible for catalyzing more than half of all microsomal drug oxidations. It is also believed that grapefruit juice affects the CYP 3A4 drug-metabolizing enzyme in the small intestines.3 Thus, the metabolism of drugs as well as other toxic substances can be affected without any particular disease process present. Another example of how individuals unknowingly modulate detoxification is caffeine. Caffeine activates CYP1A2 and related monooxygenases as well as UDP-glucuronyltransferase.4 Hormones are another particularly important consideration, both endogenous and exogenous. Many hormones including sex hormones are metabolized via glucuronidation and sulfation. Alterations in expression of these two gene families has been associated with increased breast density, altered estrogen and testosterone, and breast cancer risk.5-6

The pathway imbalance discussed above is literally the tip of the proverbial iceberg and thus a broad protective approach is often the simplest way to help buffer imbalances that occur with daily living. In clinical practice this means that simple dietary intake, and the use of several botanicals can alter phase I/phase II balance. Thus, use of a comprehensive detoxification product to ensure that daily existence in our modern toxic world is mitigated is foundational for full body wellness.

Gastrointestinal Tract and Detoxification

Phase I-IIGastrointestinal health and gut permeability also play a role in detoxification. Increased gut permeability allows for increased absorption of xenobiotics and toxins, which are processed and removed by the liver, thus increasing the demands on the liver detoxification system. Impaired gastrointestinal integrity can be improved via dietary support as well as pre- and probiotics.

Fiber is particularly important for supporting detoxification. Dietary fibers bind not only carcinogens, bile acids, and other potentially toxic agents, it also promotes a faster transit time and therefore less opportunity for toxin interaction with the intestinal lining and reabsorption.7 In addition, increased fiber intake helps positively balance the intestinal microflora, which minimizes endotoxin production from pathogenic bacteria.

The enzyme beta-glucuronidase may also be produced in the intestines by pathogenic bacteria. This enzyme breaks the bond that was created during glucuronidation in the liver, which is a primary pathway in which hormones are metabolized. When beta-glucuronidase breaks the bond, the hormone or toxic chemical that is released is available to be reabsorbed into the body instead of being excreted.

Dietary fiber fermented by the human gut flora results in the formation of short-chain fatty acids (SCFAs). Research suggests that the SCFAs may activate detoxifying and antioxidative enzymes including sufur-transferases and glutathione transferases.8 Some researchers propose that the induction of glutathione S-transferases by SCFAs may contribute to the detoxification of dietary carcinogens.9

Supporting All Aspects of Detoxification

In order to optimize detoxification, nutrients, precursors and enzymatic cofactors must be constantly replenished and both phase I and phase II must be supported. Below are some processes involved in detoxification and the nutrients needed to support those processes.


Glucuronidation is a critical detoxification process where glucuronic acid is coupled (conjugated) with numerous drugs, hormones, bilirubin, pollutants and bile acids. The enzyme UDP-glucuronosyltransferase catalyzes this reaction while the enzyme beta-glucuronidase minimizes it. Research has shown that calcium-D-glucarate and glucaric acid found in various fruits and vegetables including oranges, apples, grapefruit and cruciferous vegetables inhibit beta-glucuronidase, thereby supporting detoxification. Silymarin, a constituent of milk thistle, also inhibits the enzyme beta-glucuronidase.10 Elevated beta-glucuronidase activity is associated with an increased risk for various cancers, particularly hormone-dependent cancers such as breast, prostate and colon cancers.11


Glutathione is an antioxidant compound synthesized from the precursor amino acids glutamate, cysteine and glycine. It is mainly involved in detoxification mechanisms of xenobiotics (foreign chemicals) and carcinogens through conjugation reactions via the enzyme glutathione transferase. Heavy metals such as mercury are removed from the body by conjugation with glutathione.12 Numerous substances have been shown to support glutathione levels in addition to the amino acid precursors including N-acetyl cysteine (NAC),13 S-adenosyl-methionine (SAMe),14 milk thistle15 and vitamin C.16 Increased free radical metabolite production during phase I reactions can result in depleted glutathione levels and glutathione conjugation in phase II detoxification.


Acetylation is a process in which toxins are conjugated by N-acetyltransferase with acetyl coenzyme A. This pathway is responsible for metabolizing numerous drugs and carcinogens. Variations in acetylation (“slow acetylators”) are associated with drug interactions such as reactions to sulfa drugs.17 Research suggests that vitamin B1, vitamin B5 (pantothenic acid) and vitamin C (ascorbic acid) support acetylation.18

Amino-Acid Conjugation

Numerous amino acids such as arginine, glutamine, glycine, ornithine and taurine, are conjugated with toxins for neutralization. Most commonly, glycine is involved in phase II detoxification.


Methylation is the addition of a methyl group to any substrate. SAMe is the primary methyl donor and requires adequate levels of methionine, choline, vitamin B12 and folic acid for synthesis. Methylation is important for the metabolism of several pharmaceuticals as well as neurotransmitters.19

Sulfation and Sulfoxidation

The addition of a sulfur-containing compound by sulfur transferases is used to eliminate hormones, neurotransmitters and numerous medications including acetaminophen. The amino acids methionine and cysteine are important sources of inorganic sulfate. Sulfation is also an important detoxification pathway of bile acids resulting in increased bile acid solubility, decreased intestinal absorption, and enhanced fecal and urinary excretion. Additionally, bile acid-sulfates are also less toxic than their un-sulfated counterparts.20 The enzyme sulfite oxidase transforms sulfites to sulfate to promote detoxification by sulfoxidation. Molybdenum is a cofactor for sulfite oxidase and thus required for optimal detoxification. Sulfites are used as a preservative and are found in many processed foods, wine and some medications.

Comprehensive Approach

Detox 365 provides comprehensive nutritional and botanical support to maintain proper functioning of the various detoxification pathways. By incorporating the nutrients mentioned above, it is able to address both phase I and phase II detoxification pathways. Additionally, Detox 365 supports gastrointestinal health. Gastrointestinal support for detoxification is provided by rice bran, psyllium husk powder, larch arabinogalactan, chia seed powder, digestive enzymes and several probiotic strains. Vitamins and minerals, antioxidants to remove free radicals, and amino acids required in phase II reactions such as L-glutamine, L-lysine HCL, glycine, L-carnitine and taurine, also support detoxification. Furthermore, specific ingredients such as NAC, milk thistle, citrus bioflavonoids and calcium D-glucarate have been shown to aid in various aspects of detoxification.21-22 Cruciferous vegetables provide sulfur metabolites, contain selenium, protect against reactive oxygen species, and induce phase II enzymes.23 Also, energy and adaptogenic support is provided by Maca root and immune function and toxin binding is assisted with modified citrus pectin. Thus, nutrients for all aspects of detoxification are provided.24-25


Imbalance in the primary detoxification pathways can result in an increase of even more toxic intermediates. Supporting only one detoxification pathway is counterproductive and consequently, supplementing with nutrients that support both phase I and II pathways are essential. Supporting all aspects of detoxification reduces free radical damage and promotes optimal detoxification.

by Nieske Zabriskie, ND



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25. Eliaz I, Hotchkiss AT, et al. The effect of modified citrus pectin on urinary excretion of toxic elements. Phytotherapy Research. 2006 Oct;20(10):859-864.

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