What are the 3 stages of detoxification?

The Three Phases of Detoxification Phase I: Bioactivation. Phase II: Conjugation. Phase III: Transport.

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The Three Phases of Detoxification

The detoxification system is defined by three phase pathways:

Phase I: Bioactivation

Phase II: Conjugation

Phase III: 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

Detox 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 many chemical reactions (oxidation, reduction, hydrolysis, hydration, or dehalogenation) to add a reactive group (hydroxyl, carboxyl, or amino) to a toxin. Cruciferous vegetables such as Spanish black radish, 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 into reactive intermediate substances (activated toxins), producing free radicals in the process. The reactive intermediate substances are considered more toxic than the parent toxin compounds, so they need to be neutralized quickly. 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) and selenium

Copper, zinc, and manganese

Coenzyme Q10,

Thiols (found in garlic, onions, and cruciferous vegetables)

Silymarin

Bioflavonoids and polyphenols

Detox 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. Ideally, 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)

N-acetyltransferases (NAT) 6

Conjugation reactions not only require the water-soluble fraction that will be attached to the toxin—such as sulfate in the case of sulfation or glucuronic acid in the case of glucuronidation—but it also uses 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 Enzymes 6

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

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Methyltransferase Detoxification Enzymes and Methylation Capacity

A cell’s methylation capacity is defined as the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH). A ratio of less than four indicates an impaired methylation capacity, which could result from a decrease in SAM level (universal methyl donor) or an elevated SAH, a potent methyltransferase inhibitor. An increase in SAH level is detrimental to methylation pathway as it inhibits methyltransferases involved in methylation, and methyltransferases involved in Phase II enzyme and creatine synthesis, e.g. COMT and GAMT among others. Key nutrients for methylation support include:

Folate

Betaine

Choline

Methionine

Vitamins B12, B6, B2, and B3

Magnesium

Zinc

Molybdenum

Deficiency in any of these key nutrients would affect methylation capacity and hence ability to provide methyl groups to Phase II methyltransferases, affecting toxin removal, estrogen detox, and creatine synthesis. It is prudent for patients with impaired methylation capacity to first improve their SAM:SAH ratio before introducing any detoxification programs. Lowering homocysteine may not be enough to restore methylation capacity. Patients should ensure that homocysteine levels as well as the SAM:SAH ratio is within the reference range. Many patients have healthy homocysteine levels while also having impaired SAM:SAH ratios (impaired methylation capacity). Patients with SNPs in methylation pathway enzymes should not be discouraged from enrolling in detoxification regimens. Genes do not tell functional methylation capacity. Just because a patient has a SNP that might predispose them to a deficiency in methylation, it does not mean they actually have impaired methylation. In fact, they could have completely normal methylation.

Creatine and Methylation Capacity

Creatine in the form of creatine phosphate plays an important role in ATP regeneration. The human body excretes about two grams of creatine in the form of creatinine via urine daily. Humans replenish creatine stores via diet or de novo synthesis from glycine and arginine. Creatine is mainly found in red meat (muscle); it is scarce in other types of meat and is largely absent in plants. Vegans and vegetarians rely on de novo synthesis of creatine and place high demand for glycine, arginine, and SAM, a methyl donor for the GAMT enzyme, the key enzyme in creatine synthesis). It is estimated that 75 percent of SAH produced in the human body is from GAMT activity. Studies showed that vegans and vegetarians tend to have higher homocysteine levels than the general population and hence, elevated SAH. Glycine is the amino acid that is most frequently conjugated to toxins in humans. Glycine is also in high demand for creatine synthesis in vegetarians, vegans, and omnivores with low intake of red meat (creatine level is low in chicken and fish and is not enough to replenish creatine stores). During detoxification regimens, toxins stored in fat tissues are mobilized and activated by CYP450 enzymes to intermediate substances, leading to a demand for glycine by Phase II enzymes increases.

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With poor nutrition, the supply of creatine and glycine from the diet may be inadequate. This may quickly lead to depletion of glycine reserves. Glycine would be required for de novo creatine synthesis and toxin conjugation (the demand for both pathways increases during detoxification). For every toxin removed, a molecule of glycine is lost forever from the body. This situation is more problematic in patients with elevated SAH, as increases in GAMT activity requires replenishment of creatine reserves. Poor creatine in diet would further increase SAH levels, exacerbating methyltransferase inhibition and impairing toxin and estrogen detoxification. It is prudent for omnivores to cut down on red meat consumption but not to entirely eliminate red meat from their diet during detoxification. Vegans and vegetarians should be extra careful to consume a proper diet rich in glycine, arginine, cysteine, and key vitamins and minerals essential for methylation support especially vitamin B12.

Detox 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 ATP hydrolysis. Processed and water-soluble toxins are exported from the cell to the circulation for eventual elimination by the kidneys, or they are exported into bile and then excreted via the feces.

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