Nutrition Education and Racial Disparities in Health


Detox Blog Series Part 2 | The Three Phases of Detoxification

Key Topics: Digestive Health
March 29, 2018 • 2 min read

The human body has a well-defined detoxification system that is highly dependent on proper nutrient support for optimal functioning.

The 3 Phases of Detoxification

The human body has a well-defined detoxification system to eliminate toxins. This system is defined by three phase pathways: bioactivation, conjugation, and transport. The detoxification system is highly dependent on proper nutrient support for optimal functioning. Nutritional support for the biotransformation system is extremely important for any detoxification program.1

Phase I | Bioactivation

Phase I reactions are catalyzed by a number of different enzymes, primarily from the cytochrome P450 (CYP450) superfamily of enzymes. CYP450 enzymes conduct one of many chemical reactions (oxidation, reduction, hydrolysis, hydration, or dehalogenation) to add a reactive group (hydroxyl, carboxyl, or an amino group) to the toxin. Cruciferous vegetables such as broccoli (frozen or raw), cauliflower, fresh daikon radish sprouts, cabbage, and Brussels sprouts activate CYP450 enzymes.

The result of this reaction is the generation of a reactive site on the transformed toxin. This reactive site is very much like that of reactive oxygen species (ROS), and can readily bind to other molecules, such as DNA and proteins. Phase I activity converts toxin molecules to reactive intermediate substances (activated toxins), and produces free radicals in the process. The reactive intermediate substances are considered more toxic than the parent toxin compounds, and need to be neutralized quickly and in a timely fashion.

Protective nutrients with antioxidant properties that may help to mitigate oxidative stress, produced by phase I enzyme activity, include carotenes (Vitamin A), ascorbic acid (Vitamin C), tocopherols (Vitamin E), selenium, copper, zinc, manganese, coenzyme Q10, thiols (found in garlic, onions, and cruciferous vegetables), bioflavonoids, silymarin, and polyphenols.

Phase II | Conjugation

Phase I activation results in the generation of reactive intermediates which are often even more reactive — and potentially more toxic — than the parent molecule. These reactive compounds should be converted to a non-toxic, water-soluble molecule at the site of production, as soon as possible. Conjugation of the reactive intermediates to water-soluble molecules is accomplished by Phase II conjugation enzymes, which consist of many enzyme superfamilies including sulfotransferases (SULT), UDP-glucuronosyltransferases (UGT), glutathione S-transferases (GST), and N-acetyltransferases (NAT) (see table I).1

Conjugation reactions not only require the water-soluble moiety that will be attached to the toxin—such as sulfate in the case of sulfation, or glucuronic acid in the case of glucuronidation—but also use a large amount of energy in the form of adenosine triphosphate (ATP). In addition to energy repletion, Phase II reactions require an abundance of co-factors. Multiple nutrients and phytonutrients may help support Phase II reactions.

Table I. Phase II: Conjugation enzymes1

Enzyme(s) Reaction Name Mechanism Conjugated Compound(s)
UDP-Glucuronosyltransferases (UGTs)  Glucuronidation Glucuronidation consists of transfer of the glucuronic acid component of uridine diphosphate glucuronic acid to a substrate (e.g. drugs, toxins, pollutants, estrogens, and glucocorticoids) Glucuronic acid
Sulfotransferases (SULTs)  Sulfation (a.k.a. sulfonation or sulfurylation) Sulfation consists of transfer of sulfuryl group to a substrate Sulfuryl group
Glutathione S-transferases (GSTs) Transfers a glutathione molecule to a substrate  Glutathione
Amino acid transferases Transfers amino acids of various types to a substrate Amino acids used in phase II conjugation: arginine, cysteine, glutamine, glycine (most conjugated), ornithine, taurine
N-Acetyl transferases Transfers an acetyl group to a substrate Acetyl group
Methyltransferases (MTs) Methylation Transfers a methyl group from a methyl donor such as s-adenosylmethionine (SAMe) to a substrate Methyl group

Phase III | Transport

Also known as the elimination phase, Phase III includes transmembrane-spanning proteins that transport substrate out of the cell. Most Phase III proteins are energy-dependent and utilize energy from hydrolysis of ATP. Processed and water soluble toxins are exported from the cell to the circulation for eventual elimination by the kidneys, or they are exported into the bile and then excreted via the feces.

Human urine pH can range from 4.6 (acidic) to 8.0 (alkaline), and urinary pH may affect the elimination of toxins.2 For example, urine alkalinization increases the urine elimination of methylchlorophenoxyproprionic acid and 2,4-dichlorophenoxyacetic acid (herbicides).3 In the event of acute poisoning or overdose of toxins, alkalinization of urine to pH ≥ 7.5 is a method for the enhanced elimination of toxins under acute medical settings.3 Clinical studies have shown that alkaline minerals (commonly found in fruit and vegetables) and plant-based dietary supplements increase urinary pH.4-5 Thus, progressive alkalinization of urine via dietary agents may assist metabolic detoxification by enhancing urinary excretion of weak acids. In addition, adequate intake of water is essential to maintaining healthy kidney function and promoting urinary excretion of toxins.

Read part 3 of the Detox Blog Series.

Learn more.

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  1. Hodges, R. E., Minich, D. M. (2015). Modulation of metabolic detoxification pathways using foods and food-derived components: a scientific review with clinical application. J Nutr Metab, 760689.
  2. Urine pH test. Retrieved from,
  3. Proudfoot, A. T., Krenzelok, E. P., Vale, J. A. (2004). Position paper on urine alkalinization. Journal of toxicology. Clinical toxicology, 42 (1), 1-26.
  4. Berardi, J. M., Logan, A. C., Rao, A. V. (2008). Plant based dietary supplement increases urinary pH. J Int Soc Sports Nutr, 5, 20.
  5. Konig, D., Muser, K., Dickhuth, H. H., Berg, A., Deibert, P. (2009). Effect of a supplement rich in alkaline minerals on acid-base balance in humans. Nutrition journal, 8, 23.

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