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Metagenics

Thermophase Detox Essentials

Comprehensive Liver Detoxification

Supports Phase I, II and III of Liver Detoxification, whilst lowering toxic re-absorptions and protecting the digestive lining.

  • Supports all phases of Liver Detoxification
  • Increases Bile Production and Secretion
  • Improves Blood Detoxification

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BENEFITS

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CLINICALLY PROVEN;


  • Supports Liver Detoxification Phase I, II and III 

  • Reduces Liver Enzymes ALT, AST, GGT and ALP

  • Hepatoprotective; supports a healthy hepatic state

  • Accelerates Liver Recovery

  • Increases Bile Production and Secretion

  • Prevent deconjugation of toxins and hormones (lowering reabsorption).

  • Neutralises reactive toxins

  • Protection against toxic ‘heavy’ metals

  • Lipopolysaccharide (LPS) binding

  • Protects the gastrointestinal tract

  • Ameliorates gastrointestinal inflammation, and hyper-permiability (leaky gut)

  • Prebiotic and microbiome support

  • Antioxidant


ABOUT DETOXIFICATION


Everyone living in modern society is inevitably exposed to a wide array of toxins, both exogenous and endogenous. External toxins include the so-called ‘heavy’ metals (lead, mercury, cadmium, aluminium, etc.); herbicides, pesticides, polychlorinated biphenyls (PCBs), and other persistent organic pollutants (POPs); and plasticisers such as phthalates and bisphenol A (BPA). 


The most common endogenous toxins are lipopolysaccharides (LPS), which are gram-negative bacterial cell wall fragments, originating from the gut. Other internal toxins include metabolically-induced free radicals, and various products of glycation, maldigestion and hormonal metabolism.

Toxins exert negative effects on numerous systems (Figure 2). For example, xenobiotic compounds impact the immune, neurological, and endocrine systems, with toxicity in these systems leading to:


  • Immune dysfunction (e.g. allergies, autoimmunity, asthma, cancer);

  • Changes in mood and energy level (symptoms may include depression and/or fatigue);

  • Thyroid disorders;

  • Altered skin texture and/or hair growth;

  • Changes in reproductive function, and/or other endocrine dysfunctions; and

  • Glucose dysregulation (symptoms may include weight alterations, obesity, appetite changes, diabetes).[1]


Detoxification is the biotransformation of endogenous and exogenous toxin molecules into metabolites which can be readily excreted. This process occurs primarily in the GIT and liver, but also within individual cells and tissues. This process of detoxification has four phases:


  • Phase 0 is the uptake of a toxin into a cell;

  • Phase I reactions create an active receptor site on the molecule to prepare it for the second phase;

  • Phase II involves conjugation reactions whereby activated toxin molecules are combined with compounds to make them more water-soluble, thus easier to excrete; and

  • Phase III is the clearance (efflux) of these conjugated toxins from the cell for excretion via the GIT (in bile) or kidneys (in urine).


All detox phases must function well and in a balanced way. This avoids the accumulation of potentially harmful intermediates between phases I and II (which may be more harmful than the original toxin) as serious oxidative damage can result if phase II is unable to keep up with phase I.[2]


In addition, the effective excretion of many toxins and/or hormonal metabolites depends upon them remaining conjugated in the GIT prior to their elimination. However, dysbiotic bacterial beta-glucuronidases are capable of deconjugating these metabolites, enabling their reabsorption via enterohepatic recirculation (as opposed to their intended excretion).[3] As such, an efficient detox must ensure deconjugation is minimised.


DETOXIFICATION SUPPORT


Phase I Detoxification


A wide range of nutrients are required to support all phases of detoxification. 


For example, the relatively simple reactions of phase I (oxidation, reduction, hydrolysis, hydration and dehalogenation) utilise vitamins B2, B3, B6, B12, GSH, and the branched-chain amino acids: leucine, isoleucine and valine[73](the latter of which require a good protein source). 


In addition, antioxidants such as betacarotene, vitamin C, vitamin E, zinc and selenium help reduce oxidative stress resulting from phase I over-activity, as well as by preventing GSH depletion by ROS.[74]


Silymarin from milk thistle supports phase I pathways,[75]and provides significant protective activity against oxidative stress induced by toxin exposure, including that derived from environmental contaminants.[76]


Efficient detoxification also requires energy, and with up to 90% of intracellular magnesium associated with adenosine tri- and diphosphate (along with their associated enzymes);[77] adequate magnesium becomes vital for powering efficient detoxification processes.


Phase II Detoxification


Phase II enzymes are a group of proteins that catalyse the conjugation and neutralisation of pro-oxidant electrophiles and xenobiotics, and whose expression is regulated by the Nrf2/antioxidant response element (ARE) pathway. Phase II conjugation reactions are also heavily dependent on amino acids, and therefore dietary protein. 


Pea protein provides all the amino acids necessary for phase II toxin clearance, as well as the amino acids glutamine and glycine for the production of GSH,[82],[83],[84] to enable efficient toxin conjugation via the glutathionation pathway with cysteine.


Glutathionation targets include endogenous molecules (e.g. oestrogens),[85] cancer-inducing xenobiotics,[86],[87]paracetamol,[88]environmental toxins, household chemicals, and toxic metals.[89],[90]GSH:toxin conjugation is catalysed by the enzyme glutathione-S-transferase (GST).[91] Silymarin significantly increases GST, one of its main benefits in phase II detoxification.[92]


Taurine is also able to conjugate xenobiotics,[93] offering additional support for their detoxification in phase II. 


Selenium is required for GSH activation (via glutathione-peroxidase and reductase enzymes). 


Vitamin C helps regenerate GSH.[94],[95]In addition, both animal studies and in vitro models have found that green tea polyphenols modulate several phase II enzymes (via ARE activation), as well as GSH biosynthesis enzymes.[96],[97]


Of additional note is the importance of the folate/methylation and trans-sulphation cycles to support GSH production; as homocysteine may be metabolised to cysteine for GSH synthesis. This overall process requires adequate supplies of vitamins B2, B6, B12, folate, along with the precursor amino acids glutamine and glycine.


Phase III Detoxification


Further to the aforementioned benefits of milk thistle and/or its constituents, much of milk thistle’s benefit in detoxification comes from enhancing phase III. This is due to milk thistle increasing bile salt production and excretion, therefore promoting the clearance of toxins from the liver via this mechanism. In a more supportive role, other research has revealed that silymarin increases membrane stability in the presence of xenobiotic damage;[98]not only in cells, but also in their mitochondria.[99] This adds further understanding to how this herb may be hepatoprotective. 


Glycine also plays a role in synthesising the bile salt glycocholate, along with several other compounds relevant to detoxification (GSH being the most prominent).[100]



INCREASES BILE PRODUCTION AND SECRETION


Cape jasmine has cholagogue and choleretic actions (meaning it promotes the production and secretion of bile)[52] and, as such, supports liver detoxification.[53] It has a long history of use in TCM due to its bile stimulating activity.[54],[55],[56]The choleretic action of cape jasmine is attributed to the metabolite genipin (from the active constituent geniposide), with one animal study demonstrating a highly significant increase in biliary secretion of biliary conjugates of 513% when genipin was administered.[57]


In addition, milk thistle and glycine play an important role in bile salt production. Milk thistle can increase production and excretion of bile,[58]with glycine specifically being involved in the synthesis of bile salt glycocholate[59](which is a conjugate of cholic acid and glycine).


PREVENTS DECONJUGATION OF TOXINS AND HORMONES.


β-glucuronidase is an enzyme produced by certain potentially problematic bacteria (e.g. Escherichia coli, Clostridium perfringens).[102]The enzyme breaks the bonds connecting a substrate[§] (e.g. oestrogen) to its glucuronic acid conjugate,[103]thereby freeing the substrate rather than eliminating it. 


This allows the substrate to be reabsorbed via the enterohepatic circulation and can result in significant additional exposure to that substrate. This is problematic not only in those wanting to effectively detoxify/eliminate but specifically for those prone to conditions where re-exposure to the toxin/substrate could exacerbate their symptoms or cause further harm (such as to those with hormonally driven conditions).


Silymarin has been shown to inhibit β-glucuronidase. When administered to rats at 30 mg/kg once daily (equivalent to 2.1 g/day for a 70 kg human), silymarin inhibited microsomal β-glucuronidase activity by 53% in hepatocytes.[104]This inhibitory action can help prevent the deconjugation and reabsorption of glucuronidated hormones (notably oestrogen), allowing for more effective elimination. This may have specific benefits for hormonally-dependent diseases, including some cancers.


PROTECTION AGAINST TOXIC HEAVY METALS


Silymarin has demonstrated significant benefits in reducing the toxic effects of metals, including marked reductions in lead-induced hepatotoxicity,[105]nephrotoxicity and genotoxicity, as exhibited in vivo.[106] 


The combination of silymarin with vitamin C in animal models resulted in significant decreases in serum lead, ALT, AST, GGT and ALP levels after only two weeks of treatment.[107] 


The results also revealed a remarkable prevention of histopathological findings including hepatocyte proliferation; indicating silymarin and vitamin C were highly protective against lead toxicity. 


In addition, magnesium and selenium have both demonstrated significant protective effects in an animal model of cadmium toxicity. This was achieved via antioxidant defence enhancement, with increased GSH levels and decreased lipid peroxidation.[108]


Silymarin has demonstrated significant benefits in reducing the toxic effects of heavy metals.


Moreover, green tea protects against environmental exposure to cadmium and lead,[109],[110]whilst vitamins A, C, E, zinc, selenium and magnesium are all involved in reducing the toxic effects of heavy metal exposure. An example of the beneficial effects of vitamin A in toxic metal exposure was made evident in publications by Kasperczyck et al. Over 12 weeks, 10 mg/day of betacarotene supplementation was administered to lead-exposed workers, leading to marked improvements in oxidative stress. For example, the betacarotene intervention group displayed significantly increased levels of SOD[111]and GSH,[112] as well as significant reductions in the levels of malondialdehyde[113],[114](a marker of oxidative stress), which combined indicate the beneficial effects of betacarotene in chronic lead poisoning, independent of chelation.[115]


Another study in lead-exposed workers (2014) demonstrated the protective effects of vitamins C and E. The affected workers presented with high serum lead levels, and displayed increased oxidative stress markers as a result of their chronic exposure. Over one year, the workers were provided with 400 IU vitamin E and 1 g vitamin C per day, while continuing to work in the same environment. After one year, their oxidative stress markers showed a significant overall reduction in oxidative damage, demonstrating the importance of antioxidant intake for anyone exposed to heavy metals (Figure 6).[116]


LPS BINDING


The active ingredient geniposide from cape jasmine has revealed a significant ability to directly bind and neutralise LPS both in vitro and in vivo.[118]In addition, zinc,[119] glutamine,[120],[121] and taurine[122]have all demonstrated protective properties against the effects of LPS in vitro as well as in animal models of LPS-induced damage.


NEUTRALISES REACTIVE TOXINS


Reducing oxidative stress is an important part of detoxification, with various herbs and nutrients showing beneficial effects on reducing ROS and improving the antioxidant status in patients. One study found that drinking green tea (1.75 g dried leaf brewed in boiling water, 5 times daily for 3 weeks) significantly reduced the lipid peroxidation products malonyldialdehyde and malonyldialdehyde-4-hydroxy-2(E)-nonenal and also significantly lowered oxidative stress within red blood cells.[123]In another trial, 24 healthy female volunteers consumed 320 mg of a green tea extract taken daily (equivalent 250 mg catechins/day) for 42 days, which significantly improved overall plasma antioxidative status, and reduced plasma peroxides and DNA damage in lymphocytes.[124]


A double-blind clinical trial assessed the antioxidant effects of different doses of ascorbic acid (vitamin C) on red blood cell GSH levels. Participants ingested a placebo tablet for the first week, 500 mg ascorbic acid/day during weeks two and three, then 2 g/day ascorbic acid (500 mg QID) during weeks four and five, followed by a placebo during week six. Blood samples were analysed at baseline then at the end of weeks one, three, five and six to assess total plasma vitamin C and red blood cell GSH.


After two weeks of supplementation with 500 mg ascorbic acid/day, plasma vitamin C levels significantly increased (43% increase; p<0.05). At the three week assessment point, a 47% increase in red blood cell GSH levels was also observed. At week five (following two weeks of 2 g/day ascorbic acid) neither plasma vitamin C levels nor red blood cell GSH levels were significantly different compared to when supplementation was at 500 mg/day. It was thus concluded that 500 mg/day ascorbic acid may be an effective dose to provide significant antioxidant activity by supporting red blood cell GSH concentrations.[125]


HEPATOPROTECTIVE


Silybum marianum (milk thistle, St Mary's thistle) has a long history of traditional use for liver health, dating back to the time of the ancient Greeks (Theophrastus, 4th century BC) and Romans (Pliny the Elder, 1st century AD).[4]More recent Western herbal medicine include liver and gallbladder conditions such as jaundice, hepatitis and gallstones.


More than one-hundred clinical studies into the hepatoprotective effects of silymarin (a constituent of milk thistle) have been conducted to evaluate its efficacy in various liver diseases including acute viral hepatitis, drug- and toxin-induced hepatitis, Amanita phalloides[†]poisoning, alcoholic liver disease, and chronic hepatitis or cirrhosis.[5],[6],[7] In a meta-analysis of these studies, reviewers concluded that silymarin had the following favourable effects:[8]


  • Improvement of biochemical markers of liver function (e.g. transaminases, gamma-glutamyl-transferase (GGT), bilirubin, alkaline phosphatase (ALP), albumin and prothrombin time);

  • Amelioration of histological alterations;

  • Acceleration of recovery; and/or

  • Improvement of survival.


Importantly, silymarin has been found to be a potent anti-inflammatory agent,[9] relevant as inflammation is involved in reactive oxygen species (ROS)-induced liver damage. Silymarin has been shown to inhibit the transcription factor nuclear factor kappa B (NFκB),[10]decreasing the inflammatory response and providing significant protection against hepatic toxicity and diseases.[11]  


Gardenia jasminoides (cape jasmine) is a bitter and astringent herb which exhibits hepatoprotective properties. It has been used in traditional Chinese medicine (TCM) for jaundice and gallbladder indications as it is understood to stimulate bile.[12],[13],[14]


Antioxidant support is imperative for healthy detoxification.


Zinc has been shown to be particularly important in maintaining a healthy hepatic state.[23]Notably, decreases in zinc stores can lead to increased oxidative stress, and reduce the ability of the liver to regenerate. A vicious cycle can then develop whereby liver dysfunction leads to decreased zinc levels, and insufficient zinc increases liver dysfunction.[24]Maintaining adequate zinc levels is a significant strategy to support healthy liver function.


Camillia sinensis (green tea) has demonstrated significant hepatoprotective effects with marked decreases to elevated liver enzymes including aspartate aminotransferase (AST), alanine aminotransferase (ALT) and ALP.[15],[16],[17]In addition, green tea use has been linked with lower incidences of liver disease[18],[19]largely due to its antioxidant effects.[20]It inhibits liver oxidative DNA damage and tumour necrosis factor-α (TNF-α) expression,[21],[22]both of which can lead to liver insult.


Taurine plays many liver-supporting roles including facilitating bile acid conjugation, detoxification, osmoregulation, and reducing oxidative stress.[25] It has demonstrated significant therapeutic benefits with taurine shown to reduce elevated AST, ALT, cholesterol, triglycerides and bilirubin in chronic alcoholic patients following three months supplementation.[26]Similar hepatoprotective results have also been demonstrated in in vivo models of acute hepatotoxicity[27]with improvements in ALT, ALP and hepatic GSH levels seen.[28],[29]


Further, taurine helps reduce the impact of hepatotoxins.[30]For example, it has been shown to be effective in reducing LPS-induced hepatic damage.[31]Taurine is commonly decreased in liver diseases, with depletion of hepatic taurine stores resulting in serious liver damage.[32]It is therefore important to maintain sufficient taurine status, especially in situations of liver dysfunction.

Maintaining a healthy hepatic state requires a reduction of toxin burden. LPS fragments are the most common endogenously produced toxin, and can induce epithelial inflammation and hyperpermeability (‘leaky gut’) through activation of toll-like receptor-4 (TLR4).


 In vitro research has shown that geniposide from cape jasmine may reduce the amount of LPS that can bind to TLR4. This was supported by in vivo results showing geniposide reduced serum LPS concentrations in a dose-dependent manner; relevant as this has the potential to reduce the inflammatory response to LPS. Furthermore, a recent in vitro and in vivo study has confirmed the protective activity of cape jasmine on LPS-induced oxidative stress and hepatic damage, with significant decreases in AST and ALT in LPS-exposed animals.[33]


It is of note that the liver is considered the target organ for the toxic effects of lead; with toxic metal exposure playing a significant contributory role in adverse health conditions and liver damage.[34]Reducing these toxic effects is thus an important part of detoxification and homeostasis restoration. 


Many antioxidant herbs and nutrients have been shown to provide protection against toxic metal exposure, including green tea, taurine, magnesium, betacarotene,[35]vitamin E, vitamin C, selenium and zinc.[36] In the latter case, zinc and lead compete for binding sites in the GIT, therefore zinc supplementation may competitively inhibit lead absorption; further assisting in reducing lead toxicity.[37]


Vitamin E prevents free radical damage to the polyunsaturated fatty acids within the phospholipid bilayer of each cell membrane.



GASTROINTESTINAL TRACT SUPPORT


Zinc reduces and protects against intestinal permeability both in vitro and in vivo,[126],[127] with human clinical trials supporting this action. For example, an improvement in intestinal permeability was seen in one clinical trial on children with gastroenteritis.[128]


Additionally, an open label trial (n=12) in patients diagnosed with Crohn’s disease, experienced improvements in intestinal permeability with zinc supplementation. These patients received zinc sulphate three times a day (total of 75 mg elemental zinc/day) for eight weeks. Intestinal permeability was measured at baseline and after eight weeks, using the lactulose/mannitol test. The results showed 10 out of 12 patients achieved a normalisation of their lactulose/mannitol ratio following zinc treatment, with an overall significant reduction in mean score (p=0.0028).[129]


500 mg/day ascorbic acid may be an effective dose to provide significant antioxidant activity by supporting red blood cell glutathione concentrations.


In another controlled study, 7 g of glutamine administered to healthy individuals, 30 minutes prior to non-steroidal anti-inflammatory drug (NSAID) administration, was found to significantly attenuate the increase in intestinal permeability that is associated with NSAID use.[130]


GASTROINTESTINAL BARRIER RESTORATIVE


Epithelial barrier integrity is essential for optimal GIT function, which includes minimising the translocation of LPS, along with other potential toxins. However, in a suboptimal GIT environment (e.g. where there is dysbiosis or excessive LPS exposure and the resultant inflammation) epithelial cell tight junctions (TJs) become compromised. As such, it is important to repair and/or maintain a healthy GIT barrier, to prevent unnecessary systemic toxin exposure to occur.


Glutamine is an important fuel source of, and restorative for, intestinal mucosa cells, therefore contributes to epithelial barrier integrity. It has been shown to inhibit the translocation of gram-negative bacteria from the large intestine, and helps maintain secretory IgA, which prevents the attachment of potentially problematic bacteria to mucosal cells.[38],[39]Some of the mechanisms of glutamine include the promotion of enterocyte proliferation, the down-regulation of pro-inflammatory signalling pathways (Figure 3) and the regulation of TJ proteins.[40],[41],[42]Research has revealed that glutamine deprivation is linked to decreases in TJ claudin levels (a transmembrane protein), whilst epithelial glutamine restoration results in increased claudin levels via the regulation of the PI3K pathway;[43]all factors supporting the significance of glutamine for TJs, therefore epithelial barrier structure.


In addition, zinc helps maintain a healthy GIT barrier as it is involved in the initial step of wound healing, a process called epithelial cell restitution.[44]Epithelial cells deficient in zinc show a reduction in transepithelial electrical resistance (TEER) and disruption of intestinal barrier integrity; with a decreased expression of zonula occludens 1 (ZO-1) and occludin further potentiating barrier disruption.[45]Zinc is thought to promote TJ organisation and function by attenuating the pro-inflammatory mediators (TNF-α, interleukin-1β [IL-1β], NFĸB) and by reducing oxidative stress (by supporting superoxide dismutase [SOD] function); all of which can drive intestinal hyperpermeability,[46] and explaining why sufficient zinc status is important for healthy GIT structure and function.


Catechins from green tea have also been investigated for their digestive benefits, with research demonstrating that catechins may regulate TJs and stabilise the GIT environment by supporting beneficial microbiota proliferation, thus healthy digestive function via a healthy microbiome.[47]Moreover, catechins reduce inflammatory markers such as NFĸB,[48]with epigallocatechins (EGCGs) from green tea also having been shown to prevent intestinal disruption from bacterial infections.[49]


Larch arabinogalactans are a complex carbohydrate consisting of arabinose and galactose monosaccharides. Arabinogalactans are an excellent source of dietary fibre and act as a prebiotic, enhancing beneficial gut microbiota, such as bifidobacteria and lactobacilli.[50] Arabinogalactans can be fermented by intestinal bacteria to create short-chain fatty acids, particularly butyrate, that commensal microbiota may use as a fuel source. Like glutamine, butyrate is also a fuel source for epithelial cells, thereby helping with their replication.


PREBIOTIC AND MICROBIOME SUPPORT


As the health of the microbiome significantly impacts gastrointestinal inflammation, mucosal health and barrier integrity, it is essential to feed and diversify the microbiome. In a double-blind placebo-controlled study, human subjects consumed either 1.5 g or 4.5 g per day of arabinogalactans for 28 days, to investigate their prebiotic effects.  Lactobacillus populations were shown to increase at both the 1.5 g and 4.5 g levels, with a 47% increase in Lactobacillus populations overall. Significantly, 75% of the subjects who experienced an increase in lactobacilli began the study with no detectable lactobacilli.[131] Arabinogalactans therefore promote the growth of Lactobacillus spp, subsequently improving digestive health, protecting the gastrointestinal mucosa, and supporting a healthy microbiome.


Evidence also suggests gut bacteria-dependent metabolism of pollutants modulates the toxicity for the host and, conversely, environmental contaminants alter the composition and/or metabolic activity of the gastrointestinal bacteria.[132]This may be an important factor contributing an individual’s detoxification capacity and microbiome health.


ANTIOXIDANT


Hepatocellular insult due to drugs and/or toxins is rarely due to the drug/toxin itself, but rather to its toxic metabolites. These metabolites may exhaust conjugating mechanisms (such as GSH availability) and can be highly reactive. Free radicals (e.g. superoxide radical [O•2], hydroxyl radical [•OH], hydrogen peroxide [H2O2], and lipid peroxide radicals) have been strongly implicated in the pathogenesis of liver diseases.[61] Free radical damage also includes ROS-induced peroxidation of polyunsaturated fatty acids found within cell membranes. This leads to damage not only to the cellular membrane itself, but also to cell contents including DNA, RNA, and other cellular components.[62] As such, antioxidant support is imperative to healthy detoxification in the body.


Milk thistle is a potent antioxidant, with multiple mechanisms to protect the body against oxidative stress, particularly in the liver (Figure 4).[63]It is highly protective against lipid peroxidation with its constituent, silybin, a potent free radical scavenger - neutralising such radicals as hydroxyl (•OH), azide (N•3), dibromide (Br•2–), nitrite (NO•2), carbonate (CO•3–), and sulphate (SO•4–).[64]Another milk thistle constituent, silymarin, also increases cellular GSH content,[65]and maintains an optimal cellular redox balance by activating a range of directly antioxidant enzymes, as well as non-enzymatic antioxidant effects via nuclear factor-like 2 (Nrf2) activation.[66]


Green tea leaves are rich in antioxidant flavonoids, such as the catechins, the most abundant of which is the aforementioned EGCG. In addition to EGCG, green tea contains at least three other polyphenols that have demonstrated the ability to scavenge hydroxyl radicals and lipid free radicals: epicatechin gallate (ECG), epigallocatechin (EGC) and epicatechin (EC). The stability of their semiquinone radicals (formed through their antioxidant activity), along with their iron-chelating and free-radical scavenging abilities, contribute to green teas’ significant protective antioxidant mechanisms.[67]


The trace mineral selenium is uniquely incorporated into the structure of selenoproteins; of note due to their role in body antioxidant defences. In addition, vitamins A and C are both involved in free-radical scavenging, thus protecting cells from oxidative damage caused by ROS. Vitamin E (being lipid-soluble) prevents free radical damage to the polyunsaturated fatty acids within the phospholipid bilayer of each cell membrane;[69]whilst taurine protects a variety of cells against oxidative stress, thought to be due to its role in up-regulating cellular antioxidant defence systems via the restoration of antioxidant enzymes.[70]


As aforementioned, perhaps the most significant intracellular antioxidant is GSH, made up of glutamine, glycine and cysteine. GSH scavenges many forms of free radicals, protecting cells from hydrogen peroxides and lipid hydroperoxides, thereby protecting critical cell components.[71],[72]

INGREDIENTS

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DIRECTIONS

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Adults: 

Add 1 level scoop (19g) to 200ml of water twice daily.


Product settling occurs. Ensure lid is tightly closed and invert product twice before use.

EVIDENCE

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References


[1] Crinnion WJ. Environmental medicine, part one: the human burden of environmental toxins and their common health effects. Alt Med Rev. 2000;5(1):52-63.

[2] Liska D, Lyon M, Jones DS. Detoxification and biotransformation imbalances. In: Jones DS, Quinn S, editors. Textbook of functional medicine. Gig Harbor WA; Institute for Functional Medicine. 2005:275-98.

[3] Liska, DJ. The detoxification enzyme systems. Alt Med Rev. 1998;3(3):187-198.

[4] Saller R, Brignoli R, Melzer J, et al. An updated systematic review with meta-analysis for the clinical evidence of silymarin. Forsch Komplement Med. 2008;15(1):9-20.

[5] Hawke RL, Navarro VJ, Berman J, et al. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol. Apr 2010;50(4):434-449.

[6] Saller R, Brignoli R, Melzer J, et al. An updated systematic review with meta-analysis for the clinical evidence of silymarin. Forsch Komplement Med. 2008;15(1):9-20.

[7] Bahmani M, Shirzad H, Rafieian S, et al. Silybum marianum: beyond hepatoprotection. J Evid Based Complementary Altern Med. 2015 Oct;20(4):292-301.

[8] Crocenzi FA, Roma MG. Silymarin as a new hepatoprotective agent in experimental cholestasis: new possibilities for an ancient medication. Curr Med Chem. 2006;13(9):1055-74.

[9] Surai PF. Silymarin as a natural antioxidant: an overview of the current evidence and perspectives. Antioxidants. 2015;4:204-247.

[10] Morishima C, Shuhart MC, Wang CC, et al. Silymarin inhibits in vitro T-cell proliferation and cytokine production in hepatitis C virus infection. Gastroenterology. 2010 Feb;138(2):671-81.

[11] Surai PF. Silymarin as a natural antioxidant: an overview of the current evidence and perspectives. Antioxidants. 2015;4:204-247.

[12] Hempen C-H, Fischer T. Gardenia fructus/Zhi zi. In: A material medica for chinese medicine. Sydney: Elsevier/Churchill Livingstone. 2009:126-127.

[13] Xu L, Wang W. Herbs for clearing heat: Zhi zi. In: Chinese materia medica: combinations and applications. United Kingdom: Donica Publishing. 2002:72-5.

[14] Lee S-J, Oh P-S, Lim K-T. Hepatoprotective and hypolipidaemic effects of glycoprotein isolated from gardenia jasminoides ellis in mice. Clin Exp Pharmacol Physiol. 2016 Oct;33(10):925-33.

[15] Ojo OO, Ladeji O, Nadro MS. Studies of the antioxidative effects of green and black tea (Camellia sinensis) extracts in rats. J Med Food. 2007;10(2):345-9.

[16] Pezeshki A, Safi S, Feizi A, et al. The effect of green tea extract supplementation on liver enzymes in patients with non-alcoholic fatty liver disease. Int J Prev Med. 2016;7:28.

[17] Sakata R, Nakamura T, Torimura T, et al. Green tea with high-density catechins improves liver function and fat infiltration in non-alcoholic fatty liver disease (NAFLD) patients: a double blind placebo-controlled study. Int J Mol Med. 2013 Nov;32(5):989-94.

[18] Jin X, Zheng R-H, Li Y-M. Green tea consumption and liver disease: a systematic review. Liver International. 2008 Aug;28(7):990-996.

[19] Ni C-X, Gong H, Liu Y, et al. Green tea consumption and the risk of liver cancer: a meta-analysis. Nutr Cancer. 2017 Feb-Mar;69(2):211-220.

[20] Hayakawa S, Saito K, Miyoshi N, et al. Anti-cancer effects of green tea by either anti- or pro-oxidative mechanisms. Asian Pac J Cancer Prev. 2016;17(4):1649-54.

[21] Jin X, Zheng R-H, Li Y-M. Green tea consumption and liver disease: a systematic review. Liver International. 2008 Aug;28(7):990-996.

[22] He P, Noda Y, Sugiyama K. Green tea suppresses lipopolysaccharide-induced liver injury in d-galactosamine-sensitized rats. J Nutr. 2001;131(5):1560-7.

[23] Grungreiff K, Reinhold D, Wedemeyer H. The role of zinc in liver cirrhosis. Annals of Hepatology. 2016;15(1):7-16.

[24] Grungreiff K, Reinhold D, Wedemeyer H. The role of zinc in liver cirrhosis. Annals of Hepatology. 2016;15(1):7-16.

[25] Miyazaki T, Matsuzaki Y. Taurine and liver diseases: a focus on the heterogeneous protective properties of taurine. Amino Acids. 2014;46:101-110.

[26] Hsieh Y-L, Yah E-H, Lee Y-T, et al. Effect of taurine in chronic alcoholic patients. Food Funct. 2014;5:1529-1535.

[27] Nagai K, Fukuno S, Oda A, et al. Protective effects of taurine on doxorubicin-induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses. Anticancer Drugs. 2016 Jan;27(1):17-23.

[28] Heidari R, Jamshidzadeh A, Keshavarz N, et al. Mitigation of methimazole-induced hepatic injury by taurine in mice. Sci Pharm. 2014 Sep;83(1):143-158.

[29] Heidari R, Rasti M, Yeganeh BS, et al. Sulfasalazine-induced renal and hepatic injury in rats and the protective role of taurine. Bioimpacts. 2016;6(1):3-8.

[30] Miyazaki T, Matsuzaki Y. Taurine and liver diseases: a focus on the heterogeneous protective properties of taurine. Amino Acids. 2014;46:101-110.

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[182] Natural Medicines. Arabinogalactan. [Online]. 2016. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=974. [Cited 12/01/2017].

[183] Natural Medicines. Glutamine. [Online]. 2015. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=878.   [Cited: 18/01/2017].

[184]  Natural Medicines. Niacinamide. [Online]. 2015. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1534.   [Cited: 09/03/2017].

[185] Braun L, Cohen M. Vitamin B3 In: Herbs & Natural Supplements: An evidence-based guide. 3rd edition. Sydney: Elsevier/Churchill Livingstone. 2010:936-45.

[186] Natural Medicines. Chromium. [Online]. 2016. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=932. [Cited: 09/03/2017].

[187]  Braun L, Cohen L. Chromium In: Herbs & natural supplements: an evidence-based guide. 4th Edition. Sydney: Elsevier/Churchill Livingstone. 2015:180-90.

[188] Natural Medicines. Zinc. [Online]. 2016. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=982. [Cited: 16/03/2017].

[189] Stargrove MB, Treasure J, McKee DL. Silybum marianum In: Herb, nutrient, and drug interactions. Clinical implications and therapeutic strategies. St Louis, USA: Mosby Elsevier; 2008:123-30.

[190] Gardner Z, McGuffin M, editors. Silybum marianum. In: American herbal products association’s botanical safety handbook. 2nd ed. Boca Raton (FL): CRC Press. 2013:815-18.

[191] Natural Medicines. Taurine. [Online]. 2015. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1024.   [Cited: 09/03/2017].

[192] Stargrove MB, Treasure J, McKee DL. Zinc IN: Herb, nutrient, and drug interactions. Clinical implications and therapeutic strategies. St Louis, USA: Mosby Elsevier; 2008:619.

[193]Braun L, Cohen M. Zinc. In: Herbs & Natural Supplements: An evidence-based guide. 4th edition. Sydney: Elsevier/Churchill Livingstone. 2015:1197-1223.

[194] Gardner Z, McGuffin M (eds). Gardenia jasminoides In: American Herbal Products Association’s Botanical Safety Handbook. 2nd edn. USA. 2013:393-4.

WARNINGS

+

Contraindications


  • Allergies and sensitivities:

  • Avoid with known allergy or hypersensitivity to cobalamin and/or cobalt.[136]L-Cysteine is contraindicated in those hypersensitive to any component of the preparation.[137]
    Avoid in individuals with known allergy or hypersensitivity to members of the Asteraceae/Compositae family (Milk Thistle).[138],[139]
    Use with caution in patients with known allergy/hypersensitivity to monosodium glutamate (MSG) or glutamine. Glutamine may be metabolised to glutamate in the body and in theory may precipitate symptoms of MSG sensitivity. Use with caution and monitor patient symptoms.[140],[141]

  • Severe liver disease such as cirrhosis and hepatic encephalopathy: Glutamine, which is metabolised to ammonia, may lead to accumulation of nitrogen/ammonia waste in the blood increasing the risk of ammonia-based encephalopathy and coma. Avoid use. [142],[143]

  • Traditional Chinese Medicine (TCM) Spleen deficiency picture and diarrhoea: Gardenia jasminoides is a traditional Chinese herb and several TCM texts state that it is contraindicated in cases of diarrhoea or loose stools due to spleen deficiency. Do not use in those with spleen deficiency (see justification) or diarrhoea. [144],[145],[146],[147]


Moderate Level Cautions


  • Allergy to peanut: Pea protein may have cross-reactivity in those with peanut allergy (as may other legumes such as lentils, chick pea and soy bean).[148],[149] Though this is rare, it has been noted in young children and in a small study using RAST testing.[150]  Use with caution in patients with verified peanut allergy.

  • Anticoagulant/antiplatelet drugs: The catechins in green tea have antiplatelet effects. Concomitant use alongside anticoagulant or antiplatelet agents such as aspirin and warfarin might increase the risk of bleeding. Use with caution and monitor INR in patients taking warfarin. [151],[152]

  • Bleeding disorders: Due to the anticoagulant properties of green tea, there have been safety concerns in regards to the risk of increased bleeding tendency in patients with bleeding disorders. Although this theoretical possibility is not reflected functionally in human studies, it would still warrant caution in situations which carry a high risk of bleeding such as haemorrhagic stroke and postoperative events. To minimise the risk of exacerbation of these bleeding events it is recommended to discontinue use of green tea during acute bleeding episodes, such as during and immediately after a haemorrhagic stroke, or in patients who are at high risk for haemorrhagic stroke.[153],[154]

  • Chemotherapy/Radiotherapy: It has generally been thought that antioxidants may interfere with chemotherapy and/or radiotherapy by decreasing the efficacy of the treatment, recent studies have found that antioxidants are safe to use in conjunction with these treatments. However, it is still advisable to check with a patient’s oncologist before recommending a formula containing antioxidants.[155],[156] (Vitamin C, Betacarotene, vitamin E, selenium, green tea, milk thistle)

  • Levodopa/Carbidopa (Sinemet): Magnesium may reduce the bioavailability of levodopa.[157] A pharmacokinetic interaction study of magnesium and levodopa found that 1g of magnesium oxide was shown to significantly reduce the bioavailability of levodopa by 80.9% in healthy volunteers.[158] Closely monitor those who are taking supplemental magnesium alongside levodopa and separate dosing by at least two hours.

  • Renal stones:  Cysteine tends to precipitate out of urine and form stones (calculi) in the urinary tract. Cysteine kidney stones are due to cysteinuria, a genetic disorder of the transport of an amino acid called cysteine that results in an excess of cysteine in the urine (cysteinuria) and the formation of cysteine stones. Although the incidence of cysteine renal stones is low, they occur occasionally.  Those who do form renal calculi, particularly cysteine stones, should avoid L-cysteine supplements.[159],[160],[161]

  • Stimulant laxatives: Evidence from animal research suggests that geniposide, a glucoside found in gardenia fruit, may function as a laxative and cause diarrhoea when taken orally. Theoretically, concomitant use of gardenia with stimulant laxatives might compound fluid and electrolyte loss. Some stimulant laxatives include bisacodyl, cascara, castor oil, senna and others.  Monitor use with concommitant laxatives due to additive effects and discontinue use if there is compounded fluid and electrolyte loss or diarrhoea.[162]

  • Surgery: Due to the anticoagulant properties of green tea, there have been safety concerns in regards to the risk of increased postoperative bleeding. Although this theoretical possibility is not reflected functionally in human studies, it would still warrant caution in postoperative events. To minimise the risk of exacerbation of these bleeding events it is recommended to discontinue use of green tea 4-7 days before elective procedures which have a high risk for bleeding complications.[163],[164]


Low Level Cautions


  • Amiodarone: Conflicting information exists regarding potential interactions between amiodarone and pyridoxine. Case reports suggest that that pyridoxine could exacerbate amiodarone-induced photosensitivity. Mechanisms for this effect are unknown. Monitor patient for signs of photosensitivity.[165],[166]

  • Antibiotics: Magnesium[167],[168] and zinc[169],[170] may form insoluble complexes with some antibiotics. Separate doses by at least 2 hours.

  • Anticonvulsant medications: Theoretically, glutamine may reduce seizure threshold in those taking anticonvulsant medication. Glutamine may be converted to glutamate, an excitatory neurotransmitter.  Medications include Carbamazepine, Phenobarbital, Phenytoin, Primidone, Valproate. Use with caution and monitor patient symptoms.[171]

  • Autoimmune diseases: Larch arabinogalactan seems to stimulate immune function. Theoretically, larch arabinogalactan might exacerbate autoimmune diseases by stimulating disease activity.[172] Advise patients with autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, or others to avoid or use larch arabinogalactan with caution.

  • Bipolar disorder: Theoretically, glutamine may affect behaviour in people with bipolar disorder.  Glutamine may be converted to glutamate, an excitatory neurotransmitter.  Use with caution and monitor patient symptoms.[173]

  • Bisphosphonates: Magnesium may form insoluble complexes with bisphosphonates. Separate doses by at least 2 hours.[174],[175]

  • Epilepsy and seizure disorders: Theoretically, glutamine may reduce seizure threshold in those with epilepsy or seizure disorders. Glutamine may be converted to glutamate, an excitatory neurotransmitter.  Use with caution and monitor patient symptoms.[176]

  • Hemochromatosis and other diseases of iron accumulation:

  • Vitamin C increases iron absorption; use with caution in cases of uncontrolled haemochromatosis, thalassaemia, sideroblastic anaemia or erythrocyte G6PD deficiency.[177]

  • Riboflavin is involved in mobilising iron from its storage form (ferritin), for heme and globin synthesis, thereby increasing haemoglobin levels. However, riboflavin does not seem to significantly influence iron absorption.  The effect of riboflavin on iron utilization is probably only significant in people with riboflavin deficiency and has only been examined in a few small studies, including one on 123 women who were given 2 – 4 mg riboflavin/day.[178],[179],[180] Iron overload is a risk in people with haemoglobinopathies, such as haemochromotosis, or other refractory anaemias erroneously diagnosed as iron deficiency anaemia. Use riboflavin with caution in cases of uncontrolled haemochromatosis, thalassaemia, sideroblastic anaemia or erythrocyte G6PD deficiency. Consider using iron studies to monitor patient iron levels in these patients.

  • Hypertension/antihypertensive medication: Preliminary clinical evidence suggests that taking taurine reduces both systolic and diastolic blood. Taurine may have additive effects when used in combination with antihypertensive drugs and may increase the risk of blood pressure becoming too low. Use with caution and monitor blood pressure. [181]

  • Immunosuppressants: Theoretically, larch arabinogalactan might interfere with immunosuppression therapy due to immunostimulant effects. Immunosuppressant drugs include azathioprine, basiliximab, cyclosporine, daclizumab, muromonab-CD3, mycophenolate, tacrolimus, sirolimus, prednisone, corticosteroids (glucocorticoids), and other drugs. Use cautiously in patients on this medication and monitor symptoms changes.[182]

  • Insulin and other hypoglycaemic medications:Glutamine may have insulin sensitising effects and may theoretically reduce the requirement for hypoglycaemic medications (consequently increasing the risk of hypoglycaemia). Interaction may be beneficial but individuals should continue to monitor their blood glucose. [183]
    Niacin and nicotinamide can interfere with blood glucose control requiring dosing adjustment of antidiabetic agents. May cause hyperglycemia, abnormal glucose tolerance, and glycosuria in diabetic patients. In non-diabetic patients, changes in blood glucose are generally small and levels remain within the normal range.
    About 10% to 35% of diabetic patients may need adjustments in hypoglycemic therapy when niacin/nicotinamide is added to their regime. Monitor symptoms in diabetic patients.[184],[185]
    Chromium may have insulin sensitising effects and may reduce the requirement for hypoglycaemic medications (consequently increasing the risk of hypoglycaemia). Interaction may be beneficial but individuals should continue to monitor their blood glucose.[186],[187]
    Zinc can lower blood glucose levels and have additive effects in patients treated with antidiabetic agents. Some antidiabetes drugs include glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, Micronase), insulin, metformin (Glucophage), pioglitazone (Actos), rosiglitazone (Avandia), and others. Use with caution as dose adjustments to diabetes medications might be necessary.[188]
    Milk thistle may modify glucose regulation and can reduce insulin requirements. Those with diabetes are advised to monitor their blood sugar levels.[189],[190]

  • Lithium: Theoretically, taurine may reduce the excretion of lithium. Taurine is thought to have diuretic properties which might reduce excretion and increase levels of lithium. The dose of lithium might need to be altered and use should be supervised by the pharmaceutical prescriber.[191]

  • NSAIDs: Zinc may form insoluble complexes with certain NSAIDs. Separate doses by at least 2 hours.[192],[193]


Pregnancy and Breastfeeding

  • Pregnancy: Not appropriate for use. Detoxification is not recommended during pregnancy.

  • Breastfeeding: Not appropriate for use.The ingredients are safe to use in breastfeeding, with the exception of Gardenia jasminoides on which there is no information[194], however detoxification is not recommended during breastfeeding. Weigh the potential risks against the benefits.

MGXTDE

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