How three phases of detoxification work together to neutralize compounds so that they can be eliminated from the body and improve energy, help lose weight
By dr. Teresa Rispoli, PhD. ND, LAC
Detoxification is the process of eliminating unwanted compounds from the body—including endogenous metabolic byproducts and exogenous environmental toxicants.
Also called xenobiotics, environmental toxicants enter the body through the skin, the lungs, and the intestinal tract. Many of these compounds are lipid-soluble and thus readily accumulate in body tissues.
To prepare these lipophilic molecules for elimination in the bile or urine, they must be transformed via metabolic detoxification. The three phases of metabolic detoxification occur primarily in the liver but also to some extent in the small intestine, kidneys, lungs, brain, and throughout the body.
The concept of phase I and II detoxification was introduced by Richard Tecwyn Williams in 1947, and has since been well described. The purpose of these two phases is to neutralize compounds and make them soluble, so they can be eliminated in the bile or urine.
Phase III is a newer discovery, brought to light through investigations into drug transporter proteins. Phase III is an antiporter system, concentrated in cellular membranes of liver cells. Antiporter proteins actively pump phase II metabolites out of cells for elimination.
The activities of phase I, II, and III metabolic pathways are influenced by genetics, age, sex, hormones, environmental exposures, and diet. Targeted foods and supplements can influence these pathways in four important ways: they can provide necessary cofactors and substrates; they can induce (speed up) enzymatic activity; they can inhibit (slow down) enzymatic activity; and they can offer protection from harmful intermediate metabolites.
Let’s take a closer look at the physiology of the three phases of detoxification, and how specific nutrients can induce, inhibit, support, and protect each phase.
PHASE I
As the beginning of the process of making lipid-soluble toxins more water-soluble, phase I reactions include oxidation, reduction, hydrolysis, hydration, and dehalogenation.
Think of phase I as somewhat of a necessary evil. It’s “necessary” because it adds functional groups to toxic molecules so there will be binding sites for conjugation in phase II. And it’s “evil” because it creates intermediate metabolites that are often more toxic than the original molecules.
More than 90 percent of phase I reactions are catalyzed by the cytochrome P450 family of enzymes. Other phase I enzymes include the flavin monooxygenases (which metabolize nicotine), the alcohol dehydrogenases and aldehyde dehydrogenases (which metabolize alcohol), and the monoamine oxidases (which metabolize neurotransmitters).
Cofactors of phase I. Vitamins B2, B3, B5, B6, B12, folate, iron, magnesium, and branched chain-amino acids support phase I enzymatic activity. Adequate protein is also needed to support phase I. That is the reasoning behind many of the protein-based detoxification kits on the market that provide all the necessary nutrients for all 3 phases of liver detoxification.
Inducers of phase I. Caffeine, alcohol, and environmental toxins such as organophosphorus pesticides, paint fumes, and car exhaust, induce phase I activity. So do the isolated nutrients epigallocatechin gallate (EGCG) from green tea and indole-3-carbinols from cruciferous vegetables. It should be noted that induction of phase I is not always desirable at all times because phase I reactive-oxygen intermediates cause tissue damage if not neutralized by phase II.
Inhibitors of phase I. Compounds in grapefruit juice, soy, and garlic have been shown to inhibit the cytochrome P450 enzymes of phase I. Inhibition of cytochrome P450 might be desirable to allow phase II enough time to keep up. However, inhibition can have untoward consequences on drug metabolism and may potentially lead to unsafe levels of unmetabolized medications.
Protectors of phase I. Carotenoids (or vitamin A), ascorbic acid (vitamin C, tocopherols (vitamin E), copper, manganese, zinc, and coenzyme Q10 are antioxidant nutrients that can mitigate potential damage from phase I metabolites. Milk thistle (Silybum marianum) has also specifically demonstrated hepatoprotective properties by lowering oxidative stress.
PHASE II
Phase II detoxification conjugates the phase I metabolites into more water-soluble and neutral compounds to be ready for elimination in the bile or urine.
Many of the enzymes that catalyze phase II reactions are transferases: sulfotransferases catalyze sulfation, UDP-glucuronyl transferases catalyze glucuronidation, glutathione-S-transferases catalyze the transfer of glutathione, and methyltransferases catalyze methylation.
The master regulator of these enzymes is nuclear transcription factor E2-related factor (Nrf2). The free radical intermediates produced by phase I activate Nrf2, which in turn induces phase II enzyme systems via antioxidant response elements (AREs).
Conjugating substances for phase II include taurine, glycine, sulfate, glucuronic acid, ornithine, mercapturic acid, and glutamine. Phase II reactions depend on adequate levels of these nutrients as well as enzymatic cofactors. If necessary nutrients are in low supply, phase II reactions can’t keep pace with phase I. It’s said that these two metabolic phases “decouple,” allowing toxic intermediate compounds to accumulate.
Cofactors of phase II. Vitamins B2, B3, B6, B12, and folate are necessary cofactors for phase II reactions. N-acetylcysteine and methionine are needed to replenish glutathione stores. Methyl donors, such as trimethylglycine (TMG), also support phase II. Sulfur-rich foods and supplements are necessary for phase II sulfation as well. Sulfate is excreted from the body on a daily basis, so sulfate reserves must be maintained by intake of garlic, onions, cruciferous vegetables, eggs, or dietary supplements.
Inducers of phase II. Sulfur-rich foods are not only important cofactors for phase II, but they also induce phase II by activating Nrf2. Sulfur-rich dietary supplements that have specifically been shown to activate Nrf2 are sulforaphane glucosinolate and indole-3-carbinol. Other Nrf2 activators include allicin (from garlic), berberine, curcumin, EGCG (from green tea), genistein (from soy), quercetin, resveratrol, silybin (from milk thistle), and tocotrienols.
Recently, an additional class of compounds—alkyl catechols—has gained attention as Nrf2 activators. Alkyl catechols are small electrochemicals that arise when compounds in common fruits and vegetables are transformed by Lactobacilli microorganisms. These compounds are present in fermented foods and beverages, suggesting a role for probiotic-rich foods in supporting phase II detoxification pathways.
PHASE III
Once phase II is complete, the metabolites are hydrophilic and need to be transported across a lipophilic membrane to exit the cell. Phase III is an ATP-dependent antiporter system that pumps phase II metabolites out of cells for elimination. Phase III antiporter proteins are concentrated in hepatocytes (where they pump compounds into bile) and in renal cells of the proximal tubules (where they pump compounds into urine).
Phase III transporter proteins are also concentrated in the intestinal epithelium, the endothelial cells of the blood-brain barrier, and the cells of the blood-testes barrier. The purpose of the transporter proteins in these locations is to prevent cellular entry of xenobiotics, which is a slightly different function than in the liver and kidneys.
At the blood-brain barrier and blood-testes barrier, phase III antiporters pump compounds back into the capillaries, whereas at the intestinal epithelium, they pump compounds back into the intestinal lumen. Because the phase III antiporters of the intestinal villi reduce the burden of unmetabolized toxins entering portal circulation, they can also be referred to as “pre-phase I” detoxification proteins.
Hundreds of different phase III transporter proteins have been identified, but p-glycoprotein is the most extensively studied. The gene encoding for p-glycoprotein is also called the multidrug-resistance gene because drug-resistant cancer cells use the antiporter proteins as protection against chemotherapeutic drugs.
Some isolated nutrients have demonstrated ability to induce or inhibit phase III activity, but there may be more clinically relevant ways to support this phase. Whereas phase III transporters are beneficial for transferring metabolized compounds out of cells and into the bile or urine, they can also be detrimental to cancer treatment, by providing a mechanism for cancer-cell drug resistance. It’s not generally recommended to strongly induce or inhibit phase III.
More relevant ways to support phase III are to encourage healthy bile flow, intestinal function and hydration. That’s because once phase II conjugates are excreted into bile by phase III transporters, these metabolites still need to be eliminated from the body via bile, stool and urine. Consider herbs, calcium-d-glucurate, probiotics, and l-glutamine to support final elimination.
Herbs like Artichoke leaf extract (Cynara scolymus), black radish (Raphanus sativus niger), dandelion root extract (Taraxacum), and yellow dock root extract (Rumex crispus) have traditionally been used to support healthy bile flow.
Calcium-d-glucarate. Compromised intestinal health can impede the final step of detoxification. Dysbiotic bacteria produce beta-glucuronidase and other enzymes that deconjugate phase II metabolites. And once they’re deconjugated, these metabolites can re-enter the portal vein and further burden the capacity of liver enzyme systems. Supplementation with calcium-d-glucarate has been shown to inhibit beta-glucuronidase activity. Probiotics to support a healthy balance of intestinal microflora can also be considered.
L-glutamine. Another reason why intestinal function relates to phase III metabolism is because of the high concentration of antiporters in the intestinal villi. These phase III transporters block entry of unmetabolized xenobiotics and drugs from the portal circulation. Compromised intestinal barrier function also sabotages antiporter efficiency. But dietary changes, probiotics and supplements like l-glutamine support healthy intestinal barrier function, along with the “pre-phase I” role of phase III antiporters in the intestinal wall.
OPTIMIZING 3-PHASE DETOXIFICATION
Metabolic detoxification takes place in the context of the whole body. Optimizing phase I, II, and III detoxification is the foundation to supporting this process. Optimizing function of the gallbladder, kidneys and intestines will ensure that metabolized toxins are efficiently eliminated from the body. All of these goals can be achieved with nutritional protocols and targeted nutritional supplements.
Phase I is best supported by adequate intake of protein and B vitamins; phase II is best supported by sulfur-rich nutrients and naturally occurring Nrf2 activators; and phase III is best supported by choleretic nutrients, protocols for healthy intestinal function and adequate hydration.
