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Hepatoprotection and Biliary Support
Some of the medications which improve symptoms and biochemical markers of liver injury in settings of cholestasis have mechanisms that include supporting the detoxification pathways. Ursodeoxycholic acid (UDCA), a primary medication used in settings of cholestasis, may have a protective effect via co-regulation of Phase III transporter expression. UDCA stimulates hepatic BSEP, and also co-stimulates hepatic, intestinal, and renal MRP2.115 UDCA, as well as S-adenosylmethionine (SAMe), prevents the cholestasis-induced blockage to Nrf2/ARE binding, increasing synthesis of detoxification-related enzymes and glutathione.71,116 Rifampicin, a medication that is used primarily as an antibiotic, but also for pruritis associated with cholestatic liver disease,117 enhances bile acid detoxification by increasing expression of CYP3A4 (Phase 1), UDP-glucuronosyltransferases (Phase 2), and MRP2 (Phase 3).118
Many natural substances support detoxification by improving biliary elimination of toxins. Phosphatidylcholine, the predominant phospholipid build-ing block of cellular membranes, is a crucial constituent of bile. As phosphatidylcholine comprises over 90% of the total bile phospholipids content,119 inadequate intake contributes to impaired biliary excretion of bile and toxins, and promotes cholesterol crystallization and gallstone formation.120 This further promotes liver damage by obstruction of the small bile ducts. Increased intake of phosphatidylcholine has been shown to enhance biliary lipid secretion, preventing cholestasis and subsequent liver damage.121,122 Although small amounts of choline can be synthesized from methionine or serine, it is considered an essential nutrient and must be obtained from the diet.123 A recent study showed that only 8% of US adults meet the recommended adequate intake (AI) of choline, with vegetarians, postmenopausal women, and men at greater risk of inadequacy.124,125
Well known for their generally stimulating effect on digestive system function, bitter herbs play an important role in promoting adequate biliary secretion. Digestive bitters which have hepatoprotective effects and/or support the formation and elimination of bile include gentian, dandelion, myrrh, and milk thistle. Some of these botanicals also have specific mechanisms by which they have been shown to support detoxification pathways.
Gentian (Gentiana lutea) is one of the strongest herbal bitters that is often utilized in digestive bitter formulations. Gentian has been shown to have a choleretic effect, normalizing bile volume in the setting of liver injury.126 As a liver protective agent, gentian has been observed to increase levels of GSH, GSR, GPX, and superoxide dismutase which were otherwise reduced by alcohol or acetaminophen-induced oxidative damage.127,128
Dandelion (Taraxacum officinale) simultaneously stimulates the production of bile by the liver (choleretic), the flow of bile into the small intestine (cholagogue), and also has hepatoprotective effects.129 In the setting of alcohol-induced oxidative stress, supplementation with dandelion root extract has also been observed to increase hepatic antioxidant activity, including GSH, GST, GPX, and GSR.130
Myrrh (Commiphora myrrha) has a complex profile of use and is perhaps most recognized for its antimicrobial effect.131,132 Myrrh also acts as an anesthetic, anti-inflammatory, antioxidant, and cholesterol-lowering agent.133 In Ayurvedic medicine, myrrh is used as a detoxifier and female reproductive tonifying agent, helping to move stagnant blood.134 Myrrh, and its close relative guggul (Commiphora mukul), contain molecules known as guggulsterones that have diverse biological activities. The guggulsterones are the bioactive agents responsible for the cholesterol-lowering effect, as well as anti-inflammatory and anti-oxidative properties.135 Guggulsterones have been shown to increase the transcription of BSEP as well as induction of the detoxification-promoting nuclear transcription factor PXR.
Milk thistle (Silybum marianum) has been vastly studied for its anti-oxidative, anti-inflammatory, and hepatoprotective effects.136 Silymarin is the active complex extracted from the seeds of the plant, with the flavonolignan silybin, also known as silibinin, being the most biologically active moiety comprising 50% to 70% of silymarin. One of the most important mechanisms by which milk thistle supports detoxification, in addition to its antioxidant effects, is via its anti-cholestatic properties.137 Silibinin stabilizes BSEP in its hepatocyte membrane location, preventing cholestasis caused by BSEP internalization in the presence of substances like estrogen.138 When co-administered with estrogen, silymarin was shown to prevent the estrogen-induced decrease in bile-salt dependent bile flow.139 Silibinin and silymarin also have been shown to stimulate the nuclear bile salt receptor FXR in a dose dependent manner, which increases expression of BSEP and MRP2, and also may have other positive metabolic effects.140
Completing the process of detoxification requires intestinal binders for two reasons: 1) many toxins (methylmercury, cadmium, and mycotoxins being well-known, as well as others with increased intestinal permeability) are reabsorbed after excretion into the bile, and 2) endotoxin and other dysbiotic toxins derived from the gut can be prophylactically bound with non-absorbed sorbent substances like activated carbon. As translocation of endotoxin from the gastrointestinal tract to circulation not only directly causes inflammation and oxidative damage but also has a dramatic negative effect on detoxification, it is imperative to bind and remove it from the body. Supporting reduction of intestinal permeability is also an important aspect of detoxification strategies. However, because there is no universal toxin binder that has an equal affinity for all toxins (heavy metals, molds, plastics, and more), a combination of binders that span a breadth of possible toxin chemistries is necessary (see Table 2).
Table 2: Toxic Substances Bound by Common Binders
- Activated charcoal: Endotoxin, mycotoxins, pesticides and herbicides, volatile organic compounds (VOCs)
- Bentonite clay: Mycotoxins, bisphenol A (BPA), pesticides and herbicides, some metal binding, also has antibacterial activity
- Chitosan, a molecular mimic of Welchol: Ochratoxin, polychlorinated biphenyls (PCBs), phthalates, BPA, endotoxin, metals, also has prebiotic activity
- Thiol-functionalized silica: Heavy metals specific binder including mercury, lead, arsenic, and cadmium
Activated charcoal is well known for its ability to adsorb a wide variety of toxic substances, and is used for this purpose in many emergency settings when poisonous substances or medication overdoses have been ingested.141 One of the most important things about charcoal is that it is very effective at binding and removing endotoxin, a major contributor to blocked detoxification pathways.142-144 Activated charcoal also effectively adsorbs pesticides and herbicides,145 volatile organic compounds (VOCs) such as benzene,146 mycotoxins,147 and the intestinal precursor to indoxyl sulfate, a uremic toxin.148 Charcoal has also been observed to reduce pro-inflammatory cytokine production in settings of infection.149
Bentonite clay is particularly good at absorbing mycotoxins, including food-borne aflatoxin; aflatoxin's precursor mycotoxin sterigmatocystin, commonly found in water-damaged buildings;150,151 zearalenone, a mycotoxin with estrogenic effects commonly found on stored grains152; and fumonisin B1, a mycotoxin most often found on corn.153 Bentonite clay also strongly binds bisphenol A (BPA),154 as well as pesticides and herbicides,155,156 and cyanotoxins, a product of harmful algal blooms that may be found in contaminated drinking water or food.157 Bentonite clay has an affinity for some heavy metals such as lead,158 cadmium,159 and nickel,160 and has been shown to reduce the cadmium-induced toxicity and pro-inflammatory response in vivo as well.161,162 Bentonite clay also has intrinsic broad-spectrum antibacterial properties and has a healing effect on the gastrointestinal lining.163
Derived from shellfish, chitosan is the result of enzymatic treatment of chitin, a component of the shell. As a biomaterial with use in a variety of applications including as a vaccine adjuvant, chitosan has been observed to be safe for use in individuals with shellfish allergies.164,165 Chitosan acts similarly to the bile acid sequestrants cholestyramine (Questran) and colesevelam (Welchol),166 preventing the absorption of lipids by effectively binding to bile salts,167 but most importantly where detoxification is concerned, removing the many conjugated toxins excreted in the bile. One extremely harmful and common toxin, ochratoxin, a mold toxin found in many foods as well as water-damaged buildings,168,169 is very effectively bound and removed by chitosan.170,171 Chitosan also binds metals including mercury172,173 as well as polychlorinated biphenyls (PCBs), phthalates,174 and BPA.175 Chitosan, like charcoal, also is able to bind endotoxin.176,177 Chitosan also has a prebiotic effect, promoting the growth of Bifidobacterium and Lactobacillus.178 Like bentonite clay, chitosan also has been demonstrated to have an antimicrobial effect.179
Although chitosan and bentonite clay have an ability to bind some heavy metals, they are not the most effective tools for this purpose. Thiolated resins are substances with covalently attached thiolic metal-binding groups which very tightly bind metals including lead, mercury, cadmium, and arsenic.180,181 The use of thiolated resins dates back to the 1970s when they were used to address methylmercury (MeHg) poisoning in Iraq, and were found to significantly reduce the half-life of MeHg from 61 to 20 days, performing even better than penicillamine, a medical metal-chelating agent.182,183 The thiol-functionalized silica intercepts MeHg and other metals trapped in enterohepatic circulation, binding them and escorting them out of the intestines.184
Because binders act locally in the gastrointestinal tract, they allow tissue-bound toxins such as metals to safely drain into the blood at a natural rate. This contrasts with many blood metal chelating agents, which may increase circulatory levels of metals and place a greater burden on the kidneys and liver in the process of elimination.185 With gastrointestinal binders, the work of the liver and kidneys to eliminate toxic substances including metals is diminished as enterohepatic reabsorption is interrupted. The ability of charcoal and chitosan to block initial absorption of endotoxin is an important aspect of the role of binders in effective detoxification protocols.
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