Phases of Detoxification
Metabolic detoxification is comprised of Phase I, or biotransformation, Phase II, or conjugation, and Phase III, or elimination. The main role of detoxification is to convert fat-soluble (non-polar) toxins or toxicants into water-soluble (polar) metabolites so that they can be safely eliminated from the body through urine (via the kidneys), stool (via bile), or sweat (via skin).
Phase I of Detoxification
In Phase I detoxification, substances such as xenobiotics, dietary agents, or bacterial endotoxins are broken down by liver enzymes; the majority of which belong in the cytochrome P450 superfamily of mixed functional oxidases. Phase I requires the nutritional cofactors B2, B3, and iron (for NADH and oxygen), and involves oxidation, reduction, hydrolysis, hydration, and/or dehalogenation reactions exposing or adding a functional group such as a carboxyl, hydroxyl, or amino group to the molecule being detoxified.
Phase II of Detoxification
In Phase II, the resultant biotransformed molecule (metabolic intermediate) is conjugated via conjugase enzymes with a polar group and is attached to the active site that was exposed or added in Phase I in order to produce water-soluble substances that reduce the biological activity and toxicity of the parent molecule. Phase II involves reactions such as glucuronidation, sulfation, glutathione or amino acid conjugation, acetylation, and/or methylation—and enzymes glucuronosyl transferases, sulfotransferase, glutathione S-transferase, and methyltransferase—with cofactors glucuronic acid, sulfate, glutathione, or glycine. The water-soluble substances are then released to the kidney or back to the gastrointestinal track through enterohepatic circulation in order to be eliminated from the body.
Nutritional Influences
Macronutrients and micronutrients impact metabolism and elimination of substances and thus influence detoxification pathways. Individuals have varying detoxification capabilities and toxin accumulation due to a variety of factors, such as their environment, drug intake, genetic variants, health and nutrition status. Dietary nutrients, fiber, amino acids, and phytonutrients interact with and support modulatory genes of detoxification pathways in order to manage the mounting dietary and environmental toxin load faced by humans today. Both Phase I and Phase II systems must function properly, and in balance, in order for reactive metabolic intermediates, which may be more toxic than the original compound, to not exert substantial bodily harm. Antioxidants are vital in counteracting, or neutralizing, reactive electrophiles and reactive oxygen species produced in Phase I. Antioxidants include carotenoids, vitamins C and E; selenium; copper; zinc; manganese; CoQ10; thiols found in garlic, onions, and cruciferous vegetables; bioflavonoids; silymarin; and pycnogenol. Antioxidant enzymes include superoxide dismutase, catalase, glutathione peroxidase, and more. Each Phase requires certain nutrients in order for the reactions to take place—with Phase I reactions requiring B vitamins, branched-chain amino acids, glutathione, flavonoids, and phospholipids—while Phase II predominantly requires amino acids such as N-acetylcysteine, glycine, taurine, glutamine, cysteine, and/or methionine.
Induction and Inhibition of Detoxification Pathways
When Phase I or Phase II detoxification enzymes are induced, their rate of activity, or detoxification, increases. On the other hand, when detoxification enzymes are inhibited, their activity decreases. If there is competition for the same enzyme by two or more compounds, then Phase I or Phase II enzymes are inhibited. So if Drug A induces CYP3A4 for instance, then it is speeding up its enzymatic activity while decreasing the effects of Drug B. In contrast, if Drug A inhibits CYP2D6 for instance, then it is slowing down its enzymatic activity while increasing the effects of Drug B. If Phase I is induced, while Phase II is inhibited, then harmful intermediate metabolites in their more toxic form remain unconjugated and exert biochemical effects such as DNA, RNA, and protein damage; clinically manifesting as subsequent tissue injury. Laboratory markers could include deficiencies in folic acid and B12 with elevations in homocysteine due to impaired methylation. In the case of a patient taking prescriptions with supplements, the drugs would be converted to their more active and toxic metabolites causing potential interactions.
In this case, treatment with phytonutrients can upregulate genetic expression of Phase II enzymes, while increasing Nrf2 transcription factor which binds to antioxidant response elements. Pomegranates, cruciferous vegetables, and green tea would all be useful. Moreover, protein cofactors (whey protein) and the 5R program to help digestion can aid Phase II conjugation. If Phase I is inhibited with normal Phase II function, then toxins remain in their lipophilic form, circulating in the bloodstream and accumulating in fat tissue. If the patient is taking a drug that also inhibits one of the CYP450 systems, then metabolism of both the drug and other xenobiotics will be severely impaired, causing side effects or overdose. In this patient, while Phase I needs to be induced, it should be done by keeping in mind the appropriate balance between Phase I and Phase II; meaning, that too much Phase I without concomitant increases in
Phase II can lead to the aforementioned toxic metabolite issue if there aren’t enough cofactors to handle the increase in Phase I. In this case, bifunctional modulators, which exert balanced detoxification effects due to simultaneously modulating both Phase I and Phase II enzyme systems would be beneficial. Bifunctional modulators include watercress glucosinolates from cruciferous vegetables like broccoli; ellagic acid from pomegranates; or catechin from decaf green tea. Other treatments for detoxification include avoiding or reducing sources of toxin exposure; sauna therapy or exercise to facilitate sweating and removal of lipophilic substances through skin; hydrotherapy to increase lymphatic circulation; a low-calorie diet supplemented by a high-quality medical food that supports phase I and II pathways; and the 5R gut repair protocol to improve the gut-liver axis.
Top 5 Detox Foods to Incorporate into Your Diet
- Cruciferous Veggies
Broccoli, cabbage, kale, Brussels sprouts and other cruciferous veggies are bifunctional modulators of detoxification. These veggies contain glucosinolates, the precursors of isothiocyanates, as well as indole-3-carbinol, supporting both phase I (i.e. cytochrome P450s) and phase II (e.g. glutathione S-transferases) pathways of detoxification. Numerous studies have shown that consumption of cruciferous veggies is associated with reductions in the risk for various types of cancer (Liu, & Lv, 2013; Wu et al., 2013).
- Fiber
Fiber, especially insoluble fiber, has been shown to be an important phytochelator, helping the body detoxify from heavy metals. Rose, & Quarterman (1987) demonstrated the ability of dietary fibers to bind certain metals such as cadmium, in vitro.
- Whey Protein
Whey protein is a great source of amino acids, which are required for the production of both phase I CYP enzymes and for the substrates for phase II enzymes (Cline, 2015). Consuming whey protein in the form of a smoothie can be a simple and effective way to support these processes. Whey protein is also a source of gamma-glutamylcysteine, a precursor of glutathione, which acts as an intracellular antioxidant (Natural Medicines, 2018). Studies suggest that taking 20 grams of whey protein daily for 12 weeks may reduce liver dysfunction and hepatic macrovesicular steatosis (Natural Medicines, 2018).
- Berries
Berries are rich in flavonoids, which are potent antioxidants and detoxifying agents (Natural Medicine, 2018). Blueberries have been shown to increase levels of glutathione and support phase I detoxification (Natural Medicine, 2018). In one study, researchers showed that dietary berries and ellagic acid reduced the expression of phase I estradiol metabolizing enzymes, with black raspberries in particular demonstrating a tumor-reducing effect, thus signifying their potential role in breast cancer prevention (Aiyer, & Gupta, 2010).
- Green Tea
Green tea is a bifunctional modulator, supporting both phase I and phase II detoxification pathways (Cline, 2015). Green tea contains high concentrations of potent antioxidants called catechins and is thus used for a variety of medicinal purposes including improved mental alertness and cognition; hyperlipidemia; GI disorders; headache; depression; various cancers, and more (Natural Medicine Database, 2018).
References:
Aiyer, H & Gupta, R. (2010). Berries and Ellagic Acid Prevent Estrogen-Induced Mammary Tumorigenesis by Modulating Enzymes of Estrogen Metabolism. Cancer Prev Res (Phila). 3(6). Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896023/
Cline, J. C. (2015). Nutritional aspects of detoxification in clinical practice. Alternative Therapies In Health And Medicine, 21(3), 54-62. Retrieved from: https://uws.idm.oclc.org/login?url=http://search.ebscohost.com/login.aspx?direct=true&db=mdc&AN=26026145&site=eds-live&scope=site
Liu, X., & Lv, K. (2013). Cruciferous vegetables intake is inversely associated with risk of breast cancer: a meta-analysis. Breast (Edinburgh, Scotland), 22(3), 309-313. doi:10.1016/j.breast.2012.07.013
Retrieved from: https://uws.idm.oclc.org/login?url=http://search.ebscohost.com/login.aspx?direct=true&db=mdc&AN=22877795&site=ehost-live
Natural Medicines Database. (2018). Green Tea. Retrieved from: https://naturalmedicines-therapeuticresearch-com.uws.idm.oclc.org/databases/food,-herbs-supplements/professional.aspx?productid=960
Natural Medicines Database. (2018). Whey Protein. Retrieved from: https://naturalmedicines-therapeuticresearch-com.uws.idm.oclc.org/databases/food,-herbs-supplements/professional.aspx?productid=833
Rose, H. E., & Quarterman, J. (1987). Dietary fibers and heavy metal retention in the rat. Environmental Research, 42(1), 166-175. Retrieved from: https://www.sciencedirect.com/science/article/pii/S001393518780018X?via%3Dihub
Wu, Q. J., Yang, Y., Vogtmann, E., Wang, J., Han, L. H., Li, H. L., & Xiang, Y. B. (2013). Cruciferous vegetables intake and the risk of colorectal cancer: a meta-analysis of observational studies. Annals of Oncology, 24(4), 1079–1087. http://doi.org.uws.idm.oclc.org/10.1093/annonc/mds601
Retrieved from: https://www-ncbi-nlm-nih-gov.uws.idm.oclc.org/pmc/articles/PMC3603442/
