Phase III Detoxification and Excretion Pathways-White-Paper-final.pdf

® WHAT EXACTLY IS PHASE III OF DETOXIFICATION? While many functional medicine practitioners are familiar with phases I and II of detoxification, which involve functionalization and conjugation of toxins through various biochemical processes1, many practitioners are unfamiliar with, or overlook the c...

® WHAT EXACTLY IS PHASE III OF DETOXIFICATION? While many functional medicine practitioners are familiar with phases I and II of detoxification, which involve functionalization and conjugation of toxins through various biochemical processes1, many practitioners are unfamiliar with, or overlook the critical phase III detoxification pathway. Phase III of detoxification is the final stage of physiological detoxification within the body involving the movement of toxins out of liver, kidney, and intestinal cells into the stool and urine for excretion. The movement or filtration of toxins is a critical aspect of phase III detoxification. A requirement for phase III includes optimal bile production and fluidity, supporting the transport and elimination of toxins through membrane-bound cellular proteins, including the multidrug resistance protein (MRP), organic anion transport proteins (OATP), and P-glycoprotein. The kidneys and intestines also play pivotal roles in phase III detoxification. These organs benefit from drainage support and binding agents to ensure elimination of toxins. Detoxification strategies that fail to support phase III can result in toxin recirculation, uncomfortable detox reactions, and collateral damage to patients’ health. Phase III Support: Bile, Bitters, Binders, and Phosphatidylcholine Proper bile flow is the foundation of Phase III detoxification and support the transport and elimination of toxins. Read on to learn more about bile and supplementation to support phase III detoxification. Bile Bile is a fluid produced in the liver and secreted by the gallbladder. It is made up of several components, including bile acids, salts, phospholipids, cholesterol, and water. Bile supports the digestion of dietary fats, regulates the composition of the gut microbiome, and is a component of phase III detoxification. Fascinating research indicates that the cellular transporters that move bile acids and salts in and out of the intestine also transport toxins.2,3 Therefore, sluggish bile flow, known as cholestasis, slows toxin efflux and impedes successful detoxification. Various factors drive cholestasis, including gallstones, biliary disease, chronic liver disease, certain medications, excess estrogen, and endotoxin, or lipopolysaccharide (LPS).4,5 In addition to directly impacting phase III of detoxification, poor bile flow drives gastrointestinal dysbiosis and conditions such as small intestinal bacterial overgrowth (SIBO), which further increase the body’s toxic burden.6 Bitters Bitter herbs, also known simply as “bitters,” have been an intrinsic part of life throughout human history. Traditional Chinese Medicine has a long, rich history of using bitter herbs for conditions ranging from diabetes to arthritis.7 Swedish bitters, a combination of aloe, rhubarb, saffron, myrrh, gentian, zedoary, and agarikon, have been consumed in Europe as an herbal tonic since the 15th century.8 Today, we can use bitter herbs such as dandelion, solidago, myrrh, milk thistle, and gentian, to support bile flow and phase III detoxification at a cellular level. For example, guggulsterone, a bitter compound found in myrrh resin, stimulates the human bile salt export pump (BSEP), located in cell membranes. BSEP stimulation is a major phase III detoxification mechanism.9,10 Silymarin, a constituent of milk thistle seeds, enhances bile salt production and biliary excretion.11 Silbinin and silychristin, additional constituents of milk thistle seeds, stabilize the membrane-bound bile acid export pump (BSEP) and multidrug resistance protein 2 (MRP2) transporters, facilitating the excretion of bile acids and toxins.12,13 Binders Binding agents or ‘binders’ are a key component of Phase III detoxification. Binders support toxin elimination by adsorbing toxins. Different from absorption, adsorption is the chemical process of attracting, binding, and accumulating particles on a surface. At an atomic level, adsorption involves the sharing of electrons between the surface of the “adsorbent,” such as activated charcoal, QUICKSILVERSCIENTIFIC.COM *These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease. Information provided by this website or this company is not a substitute for individual medical advice. ® 1 and the “adsorbate,” the substance being adsorbed. Therefore, ingesting binders allows toxins to be chemically “captured” in the gut and eliminated, rather than recirculated. Toxins that are transported from the liver to the intestine can be reabsorbed into systemic circulation through a process called enterohepatic circulation. Recirculating toxins wreak havoc on numerous body systems. For example, mycotoxins can cause cellular damage when recirculated between the intestine, bloodstream, and liver. Endotoxin, also known as lipopolysaccharide (LPS), is a bacterial toxin released by gram-negative bacteria. If not eliminated properly, it can travel through the enterohepatic circulation, triggering widespread inflammation and symptoms such as cognitive dysfunction, headaches, joint pain, and malaise.14,15 Conversely, when a binder is present in the intestine, it can capture toxins, such as mycotoxins and LPS, and prevent their reabsorption via the enterohepatic circulation. The natural world offers a variety of binding agents, including activated charcoal, bentonite clay, and chitosan. For example, activated charcoal contains millions of tiny pores that adsorb toxins in the gut, including metals, bacterial endotoxin, and mycotoxins.16,17 Hospitals and emergency rooms have long used activated charcoal to treat cases of poisoning in children and adults. Activated charcoal is often made from coconut shells or bamboo. It is well-tolerated and readily excreted in the stool. Chitosan, another potent binding agent, is a water-soluble polysaccharide derived from the outer skeleton of shellfish. Despite being derived from shellfish, chitosan has not been found to trigger allergenicity in shellfish-allergic individuals because the allergenic proteins have been removed. Chitosan binds heavy metals and microbes and may also support the growth of beneficial gut bacteria, which play crucial roles in the immune system.18.19 When detoxing, it is best to utilize a combination of binders to capture an array of toxins, as different natural binders have different affinities and capacities for toxin removal. PC Phosphatidylcholine (PC) is the predominant lipid building block of cellular and organelle membranes. It is also an integral part of bile and is thus necessary for detoxification. PC insufficiency reduces bile flow and may slow down toxin elimination.20 Furthermore, when PC is in short supply, hepatic cell membranes suffer damage from the free radicals generated during detoxification. PC deficiency also causes lipids to accumulate in the liver, hindering detoxification and promoting inflammation.21 The Kidneys: Unsung Heroes of Detoxification The kidneys are the unsung heroes of detoxification, processing an extraordinary array of toxins via their tiny tubules. These delicate organs filter an astonishing 150 quarts of blood daily, ridding the body of various fat and water-soluble toxins including endogenous toxins like ammonia, urea, creatinine, and toxins derived from phase II hepatic detoxification. The kidneys also regulate the elimination of exogenous contaminants like heavy metals.22 Alongside the liver and the gastrointestinal system, the kidneys play a crucial role in phase III detoxification; however, their small size and fragile structure make them susceptible to damage directly by toxins and through the detoxification process. The kidneys use several processes to filter toxins from blood and prepare them for elimination in the urine. First, the glomeruli, tiny clusters of looped blood vessels in the kidneys, filter out many small- and medium-sized substances. The proximal tubules of the kidneys harbor active transporters, including the vital MRPs that usher toxins from the blood into the urine. Finally, passive diffusion of some toxins, namely fat-soluble toxins, also occurs in the renal tubules. Botanicals for Kidney Support Incorporating kidney-supporting botanicals to detoxification protocols may protect them from toxin-induced damage and support the urinary elimination of toxins. Several Western herbs and herbs from Traditional Chinese Medicine (TCM) have been found to support the kidneys, including dandelion leaf, Fu ling, and He Shou Wu. In TCM, dandelion leaf is considered an anti-toxin herb. It is rich in phytochemicals, including β-sitosterol, α-amyrin, l, quercetin glycosides, chicoric acid, and sesquiterpene lactones. Β-sitosterol has been found to inhibit kidney damage in rats exposed to toxic industrial solvents, while chicoric acid prevents chemotherapy-induced kidney damage by upregulating the antioxidant Nrf2 pathway.23 Fu ling (Poria cocos) is a medicinal mushroom used for over 2,000 years in TCM.24 Fu ling has diuretic effects and aids detoxification by inhibiting the kidney’s water transporter, renal aquaporin-2.25 QUICKSILVERSCIENTIFIC.COM *These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease. Information provided by this website or this company is not a substitute for individual medical advice. ® 2 He Shou Wu (Polygonum multiflorum), another treasured herb in the TCM herbal compendium, also supports the kidneys. It contains a compound called 2,3,5,4’-Tetrahydroxystilbene-2‐O‐β‐D-glucoside (THSG) that is structurally similar to resveratrol and has been shown to protect the kidneys against synthetic chemical toxicity while reducing the expression of genes involved in kidney fibrosis through the Nrf2 antioxidant pathway.26 Interestingly, He Shou Wu also demonstrates hepatoprotective effects, decreasing inflammatory activity in the liver.27 Conclusion Phase III detoxification is the culmination of numerous biochemical and physiological processes that transform harmful contaminants, making them available for elimination. However, when phase III detoxification and the excretion pathways are overlooked, toxins may recirculate in the body, continuing to degrade health. By supporting phase III detoxification and the two primary excretion pathways, bile and kidney elimination, we can improve detoxification outcomes dramatically. 1. Hodges RE and Minich DM. Modulation of metabolic detoxification pathways using foods and food-derived components: A scientific review with clinical application. J Nutr Metab. 2015; 2015: 760689. 2. Klaassen CD, Aleksunes LM. Xenobiotic, bile acid, and cholesterol transporters: Function and regulation. Pharm Rev. 2010; 62(1): 1096. 3. Garcia M, et al. Nuclear receptor metabolism of bile acids and xenobiotics: A coordinated detoxification system with impact on health and diseases. Int J Mol Sci. 2018; 19(11): 3630. 4. Pan X, Jeong H. Estrogen-induced cholestasis leads to repressed CYP2D6 expression in CYP2D6-humanized mice. Mol Pharmacol. 2015; 88(1): 106-112. 5. Chan KM, et al. De novo endotoxin-induced production of antibodies against the bile salt export pump associated with bacterial infection following major hepatectomy. BioMed Res Int. 2018; 2018: 6197152. 6. Urdaneta V, Casadesus J. Interactions between bacteria and bile salts in the gastrointestinal and hepatobiliary tracts. Front Med. 2017. 4: 163. 7. Chen H et al. Application of herbal medicines with bitter flavor and cold property on treating diabetes mellitus. Evid Based Complement Alternat Med. 2015; 2015: 529491. 8. Ahnfelt NO and Fors H. Making early modern medicine: Reproducing Swedish bitters. Ambix. 2016; 63(2): 162-183. 9. Deng R et al. The hypolipidemic agent Guggulsterone regulates the expression of human bile salt export pump: Dominance of transactivation over farsenoid X receptor-mediated antagonism. J Pharmacol Exp Ther. 2007; 320(3): 1153-1162. 10. Alnouti Y. Bile acid sulfation: A pathway of bile acid elimination and detoxification. 11. Crocenzi FA et al. Effect of silymarin on biliary bile salt secretion in the rat. Biochem Pharmacol. 2000; 59(8): 1015-1022. 12. Crocenzi FA et al. Silibinin prevents cholestasis-associated retrieval of the bile salt export pump, Bsep, in isolated rat hepatocyte couplets: possible involvement of cAMP. Biochem Pharmacol. 2005; 69(7): 1113-1120. 13. Victorova J et al. Antioxidant, anti-inflammatory, and multidrug resistance modulation activity of Silychristin derivatives. Antioxidants (Basel). 2019; 8(8): 303. 14. Mohammad S and Thiemermann C. Role of metabolic endotoxemia in systemic inflammation and potential interventions. Front Immunol. 2020; 11: 594150. 15. Thomson CA et al. Sustained exposure to systemic endotoxin triggers chemokine induction in the brain followed by a rapid influx of leukocytes. J Neuroinflamm. 2020; 17: 94. 16. Pegues AS et al. The removal of 14C labeled endotoxin by activated charcoal. Int J Artif Organs. 1979; 153-158. 17. Devreese M et al. Efficacy of active carbon towards the absorption of deoxynivalenol in pigs. Toxins (Basel). 2014; 6(10): 2998-3004. 18. Zhang L et al. Removal of heavy metal ions using chitosan and modified chitosan: A review. J Mol Liq. 2016; 214: 175-191. 19. Davydova VN et al. Interaction of bacterial endotoxins with chitosan. Effect of endotoxin structure, chitosan molecular mass, and ionic strength of the solution on the formation of the complex. Biochemistry Biokhimiia. 2000; 65(9): 1082-1090. 20. Wan S et al. Impaired hepatic phosphatidylcholine synthesis leads to cholestasis in mice challenged with a high-fat diet. Hepatol Commun. 2019; 3(2): 262-276. 21. Wan S et al. Impaired hepatic phosphatidylcholine synthesis leads to cholestasis in mice challenged with a high-fat diet. Hepatol Commun. 2019; 3(2): 262-276. 22. Pizzorno J, et al. The kidney dysfunction epidemic, part 1: Causes. Integr Med (Encinitas). 2015; 14(6): 8-13. 23. El-Twab SMA. Chicoric acid prevents methotrexate-induced kidney injury by suppressing NF-κB/NLRP3 inflammasome activation and upregulating Nrf2/ARE/HO-1 signaling. Inflamm Res. 2019; 68(6): 511-523. 24. Li X et al. Molecular basis for Poria cocos mushroom polysaccharide used as an antitumour drug in China. J Cell Mol Med. 2019; 23(1): 4-20. 25. Wu ZL et al. Sclederma of Poria cocos exerts its diuretic effect via suppression of renal aquaporin-2 expression in rats with chronic heart failure. J Ethnopharmacol. 2014; 155(1): 563-571. 26. Lin EY, et al. The natural compound 2,3,5,4’-tetrahydroxystilbene-2-O-β-d glucoside protects against adriamycin-induced nephropathy by activating the Nrf2-Keap1 antioxidant pathway. Environ Toxicol. 2018; 33(1): 72-82. doi: 10.1002/tox.22496. 27. Xue X et al. A review of the processed Polygonum multiflorum (Thunb.) for hepatoprotection: Clinical use, pharmacology and toxicology. J Ethnopharmacol. 2020; 261(28): 113121. QUICKSILVERSCIENTIFIC.COM *These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease. Information provided by this website or this company is not a substitute for individual medical advice. ® 3