IN ORTHOMOLECULAR RESEARCH The...

VOLUME 3 • ISSUE 6

ADVANCESIN ORTHOMOLECULAR RESEARCH

The TruthAbout Detoxification

research-driven botanical integrative orthomolecular innovative

The Truth

Sulforaphane

Antioxidants

Oxidation

Methylation

SAMe

Chanca Piedra

Milk Thistle


Published in Canada by

Advanced OrthomolecularResearch Inc.

Publisher/Editor-in-Chief

Dr. Traj P.S. Nibber

Research & WritingLudo Brunel, NDKeith Karamitsos, BAMegan Tracey, MScMeaghan McCollum, BScAnjan Nibber

Graphic Design/Art ProductionNeil [email protected]

1

Digital version of this magazine and back issues are available online at www.AOR.ca

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VOLUME 3 • ISSUE 6

1 The Truth about Detoxification9 Phase II Detoxification and the Role of Sulforaphane12 Antioxidants, Oxidation and the Liver18 Methylation, Detoxification and SAMe21 Chanca Piedra: Stone Breaker25 Milk Thistle: A Historical Liver Treatment


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12

Volume 3 Issue 6 ADVANCES in orthomolecular research 1

The TruthaboutDetoxificationToxins are poisonous substances capable of causingill-health, disease and death. The injurious nature oftoxins varies depending on the agent in question andincludes damage to cellular structures and inhibition ofcellular division. Detoxification, on the other hand isknown as the removal of toxic substances from thebody. Detoxification occurs mainly in the liver, theorgan responsible for the filtration of the blood andthe elimination of toxins.1 Other organs such as thekidneys, gastrointestinal tract and skin are alsoimportant when it comes to clearing toxins from thebody. Detoxification can also refer to the time periodneeded for the body to regain its natural state ofbalance after the long term use of an addictivesubstance. Unfortunately, detoxification has alsobecome synonymous with cleansing - a term looselyused to describe all sorts of treatments aimed atpurifying or purging the body. Many such treatmentsare unproven and make little sense physiologically.Although detoxification is essential for health, certaincleanses do little to enhance health and may even beharmful. It is important to understand detoxificationbefore you embark on a cleanse.

Smoke, Mirrors and Dirty WaterDetoxification has become a broad and non-specificterm used to cover a wide range of therapeuticapproaches, some of which are grounded in scienceand many of which are purely speculative in nature.Pollutant-draining foot baths, coffee enemas,cleansing diets and the use of laxatives are largelyunproven approaches that have been ascribeddetoxification properties. In many cases, suchtherapies offer little in terms of health benefits. In theworst cases, serious harm has come to those who havesubscribed to those treatments, with reports of colitisand serious burns to the gastrointestinal tract and evenliver damage in some cases.2-5

Detoxification as it is understood by many isunsupported by research. The notion that periodiccleansing promotes health is a paradox. There areobviously fundamental changes required to your dietand lifestyle if you think that you must cleanse yourbody to stay healthy. Overindulging is certainlyproblematic, but the answer is not cleansing.

The Effects of Fasting on Detoxification

The idea that fasting promotes detoxification iswidespread and many detoxification programs involvecomplete or partial fasting for this reason. The conceptis simple; if you are not eating, your body can processthe toxins it has accumulated because it is not busydigesting and processing food. However, there isanother important factor to consider – your bodyneeds nutrients and energy to support detoxification.6-8

Animal studies have shown that fish have diminisheddetoxification rates when their food supply is runninglow.9 This can have dire consequences in pollutedenvironments where animals are exposed to high toxicloads and limited food. When embarking on a cleanse, some of us are lookingto shed more than toxins. Often, weight loss is the onlything a cleanse will achieve. Weight loss is obviously agood thing for a substantial portion of the population

A Note on IonicFoot Baths

Ionic foot baths are the perfect example of adetoxification treatment that is not useful.

Although the treatment provides visual awe, thescience shows that the visual effects are the only

thing this approach provides. The electricalcurrent and electrodes used during the

treatment cause the metals in the sea water toprecipitate out of solution, leading to dirty water.The water would turn green and grey by itself.

This treatment does not detoxify the body.

2 ADVANCES in orthomolecular research Volume 3 Issue 6

given that obesity is now the second leading cause ofpreventable death in the U.S. (see figure 1).10 Manycleanses involve very low calorie diets, some evenrecommend complete fasting and this caloricdeficiency will lead to weight loss. Since losing weightis a matter of expending more calories than you areconsuming, fasting translates into rapid weight loss.Rapid weight loss is often not recommended andmaintaining a healthy weight is much better for yourhealth than yoyo dieting, which has been shown to beineffective anyway. Again, cleansing is not the answer,portion control, eating a balanced diet and exercisewill all get you much further.11

Figure 1. Preventable causes of death

During a cleanse, the weight that is lost is mainlycomprised of water and to some extent fat, but there islittle evidence showing that fasting will help to purgethe body of toxins.12 Fasting can also be dangerous,as it depletes the body of nutrients, some of which areneeded to maintain a competent immune system.13

Fasting also decreases blood glucose levels and leadsto the breakdown of muscles and lean tissue for theproduction of energy. Due to the effects it has onimmunity and muscle mass, fasting is especiallydangerous for those who are malnourished orsuffering from chronic illness. Studies also show thatfasting can increase the risk of organ injury from newtoxins because it depletes nutrients required to sustaindetoxification pathways.14

It’s the Dose that Makes the PoisonAny chemical can be toxic if you are exposed to alarge enough quantity. Similarly, a small dose of achemical that is known to be toxic in larger amountsmay be harmless. This is an important concept tounderstand because irrational fears are created whenwe assume that just because something is toxic in ahigh concentration it will be toxic at every dose. Thisargument is based on pseudoscience and is a flawedpremise. Many toxins have a threshold below which noadverse health effects are seen. This is known as thedose-response relationship (see figure 2).

Figure 2. An example of a dose response curveshowing the effect of a drug. The curve demonstrateshow different doses can have different effects, withlower doses having a desirable effect and higher doseshaving an undesirable or toxic effect.

Each contaminant is different and the threat posed bya chemical depends on how it is handled by our body.There is more to toxicity than short-term high doseexposure. Certain chemicals, such as lead, canaccumulate in our body and cause toxicity due tochronic exposure to relatively low doses ofcontaminants. Cancer causing agents, also known ascarcinogens, are much more dangerous and, in somecases, no safe exposure level can be determined. Insuch cases, exposure should be limited as much as

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possible and regulators will require the lowest feasibleexposure levels based on the technology available. Inthe case of contaminants that mimic hormones, suchas xenoestrogens, low doses can lead to disruption ofcrucial functions since hormones regulate growth,reproduction and digestion. In the case of biologicalcontaminants such as bacteria and viruses, infectionby a single organism can lead to disease, especially ifthe immune system is not functioning properly. In many cases, a chemical is beneficial or evenessential in small amounts but becomes toxic if a largedose burdens the body. Most essential mineralsbehave in this manner. For instance, iron is needed bythe immune system and for the formation of red bloodcells, but high dosages can damage the liver andblood vessels. The recommended daily intake for ironin women is 18mg per day, but iron becomes toxic inconcentrations of 10 to 20mg/Kg which is why ironsupplements should be kept away from youngchildren. The toxicity of any chemical depends on a variety offactors, the most important being how quickly the toxinenters and leaves our body. The organs involved inthe elimination process, our body composition, thephysical characteristics of the toxin, our life stage, andmany other factors determine how quickly a toxin ismetabolized by our body. Children, infants and fetusestend to be the most sensitive to toxins andcontaminants.

Detoxification in the LiverDetoxification is an extremely complex process; theimmense array of possible toxicants is such that theprocesses required to get rid of them must be intricate.

In general, water soluble exogenous compounds areexcreted by the kidneys. However, the majority oftoxins are fat soluble and need to be metabolized andtransformed into water soluble substances before theycan be eliminated – hence the importance of the liver.The liver filters blood, enzymatically breaks down andremoves toxins through phase I and phase IIdetoxification and is also responsible for theproduction of bile, which is how fat-soluble toxins andcholesterol are excreted. Different reactions areinvolved in phase I and phase II liver detoxificationand include oxidation, reduction and hydrolysis (seepages 6 and 7). During Phase I, toxins are prepared for elimination viathe phase II detoxification pathway. Phase Idetoxification leads to the production of activatedintermediates which are more reactive and can causemore harm than the initial contaminant. It is thereforeessential that phase I and phase II work synergistically.The cytochrome P450 enzyme system is central tophase I detoxification. This enzyme system canmetabolize thousands of substances including drugs,toxins and natural metabolites such as bilirubin andhormones. Free radicals are produced during phase I,which means that if antioxidants are not present insufficient quantities, liver and tissue damage canresult. Glutathione is essential for the prevention offree radical damage during phase I. Phase II is a conjugation pathway during whichanother substance is added to a toxin to make it lessharmful. The toxin is also modified to make it watersoluble which allows for excretion in bile or urine.Although several conjugation pathways are requiredfor phase II detoxification, glutathione S-tranferases arethe most prominent. Indeed, glutathione S-tranferasebinds to toxins and acts as a transport protein.Glutathione S-tranferases allow for the conjugation oftoxins to reduced glutathione, which facilitates transportin aqueous environments, thereby permitting theelimination of toxins from the organism.23


A Note onGrapefruit Juice

Our diet can also influence our ability to handlevarious chemicals. For example, grapefruit juice

contains furanocoumarins which interact withthe cytochrome P450 detoxification pathways inthe liver and intestines.21 This interaction can be

dangerous if the patient is taking prescriptionmedications as it affects the ability to handleand clear certain drugs from our system. Thiseffect lasts for up to 24 hours and leads to

higher blood concentration of the medicationthereby increasing the risk of adverse effects.22


A Note on Mercury in Vaccines

Many people are very concerned about the presenceof mercury in vaccines like the flu vaccine. It isimportant to note that the type of mercury makes asignificant difference to the toxicity of the compounddue to variations in bioaccumulation and absorption.Organic mercury or methylmercury is the mostdangerous because it accumulates in the body morethan other forms of mercury. Inorganic mercury is alot less dangerous because it is not as easilyabsorbed. Methylmercury is organic mercury andsafe exposure guidelines are usually based onexposure to methylmercury. Mercury toxicity is almostalways related to exposure to methylmercury. Theabsorption of metallic mercury is 7% of the ingesteddose whereas the absorption of methylmercury ismore than 95%. Methylmercury is also more toxiconce in the body because it can cross the blood-brain barrier and also the placental barrier.15

The Thimerosal found in vaccines, containsethylmercury which is not the same asmethylmercury, as it does not seem to bioaccumulateas much as methylmercury. Ethylmercury can betoxic but all reported instances of toxicity withethylmercury were related to long term exposure tohigh concentrations as is usually the case withmercury. It takes a relatively high SINGLE dose of mercury tokill an animal. The LD50 of oral methylmercury inguinea pigs is 16.5 mg of mercury per kg of bodyweight. For a 70 kg adult that translates to 1.155grams.In 1972, the WHO established guidelines for atolerable weekly intake of mercury andmethylmercury. This was set at 0.005 mg/kg bodyweight for mercury and 0.0033 mg/kg body weightfor methylmercury. For a 70 kg adult, this translatesto 231 mcg per week for methylmercury and 350mcg for mercury.16

The Health Canada guidelines for women ofchildbearing age, pregnant women, and youngchildren are 0.2 mcg per kg body weight per day.For the rest of the population, the recommendationis a maximum of 0.47 mcg per kg body weight perday. So again for 70 kg pregnant women, thetolerable intake is 14 mcg per day, for a nonpregnant adult, 32.9 mcg per day.17

For the sake of argument, let’s assume that ethylmercury is as toxic as methylmercury. There is 5mcgof thimerosal in a typical dose of the flu vaccine.Thimerosal contains about 49% mercury by weightwhich works out to 2.5 mcg of mercury per dose ofthe vaccine, which is well below the establishedguidelines. Studies also show that blood mercurylevels are not raised beyond safe levels aftervaccination.18

In comparison, the concentration of methylmercuryin large fish species can be much higher.

Table 1: Methylmercury content of different fishspecies available in Canada.19

Fish Species Mean [MeHg] (μg/g)

Cod 0.06Cusk 0.35Grouper 0.45Halibut 0.31Marlin 0.69Sauger 0.46Sea Bass 0.62Shark 1.36Shrimp / Prawn 0.05Swordfish 1.82Tuna, albacore, canned 0.36Tuna, fresh or frozen 0.93Walleye / Yellow Pickerel 0.37

According to research conducted by Health Canada,there is 0.36 mcg/g of mercury in canned albacoretuna and 0.14 mcg/g in regular canned tuna. Asmall can of tuna weighs 6 oz or 170 g. So a can ofalbacore tuna contains 61.2 mcg of mercury or 24times more mercury than the flu vaccine. Regularcanned tuna contains 23.8 mcg or 9 times moremercury, and in this case we are talking aboutmethylmercury, which is the most toxic form ofmercury.The side effects and complications associated withvaccinations are likely related to the activation of theimmune system, not their Thimerosal content.20

The Effects of ToxicityWhen exposure occurs at levels that lead to toxicity, thebody systems start to break down. Depending on theoffender organ function can be affected, usuallystarting with the liver and kidneys. In some cases, theproblem can lead to cancer and hormonalimbalances.24 The effects are not limited to thephysical health of the individual; there are also effectson both mental and cognitive function, which arespecific to the contaminant. In the case of heavymetals, for example, the effects are widespread,affecting the gastrointestinal tract, kidneys, liver,airways, immunity, joints, bones, hearing,coordination, memory and reproductive system.25

Nutritional Supplementation for DetoxificationSeveral studies have now shown that many nutrientsare capable of enhancing detoxification in the liver.When detoxification systems are functioning poorly,supplementation with nutrients that enhancedetoxification will help to improve health, lifespan andrelieve symptoms associated with toxicity.26 Suchnutrients include taurine, glutathione, selenium, milkthistle, artichoke extract, sulforaphane, schizandra andvitamin E.27-30 For example, animal studies show that

selenium prolongs survival in animals exposed tomercury.31 Selenium supplementation also increasesthe mercury concentration in the liver and kidneys ofanimals preparing it for excretion.32 Selenium andvitamin E both have a similar mechanism of action;their antioxidant potential diminishes the damagecaused by the free radicals associated with exposure totoxins.33 Schizandra and sulforaphane are potentinducers of phase II liver detoxification, while milkthistle protects the liver from the injurious effects oftoxins. Artichoke has a very important role andincreases bile production and therefore stimulates theexcretion of toxins from the body.

When it comes time to detoxify your body please donot let yourself be deceived. The old saying that“things that are too good to be true usually are”definitely holds true in this case. If you are relying onperiodic cleanses or fasts to remedy the injuriouseffects of an unhealthy lifestyle you are treading inunknown waters. Remember that strength requiressupport; while eating a healthy diet, exercising andmaintaining a healthy lifestyle will promote health anddetoxification, proper nutritional support will furtherassist you in achieving your potential.

Reduce the intake of processed foods andeat more fresh, raw and whole foods.

Eat cruciferous vegetables.34

Exercise regularly.

Avoid the use of alcohol, tobacco,carbonated drinks and coffee.

Get the nutrients you need to supportyour detoxification systems.35

The Best ways to Stimulate Liver Detoxification


Protect YourHeart byLoweringHomocysteine


Phase ICytochrome P450 Enzymes

OxidationReductionHydrolysisHydration

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TOXINSFat Soluble

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environmental pollutants, pesticides, exhaust fumes,

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smoke etc.

Intermediate MetabolitesWater Soluble

Potentially Harmful

NUTRITIONAL SUPPORTPhase I: B Complex Vitamins, Folic Acid, Milk Thistle, Vitamin E, SeleniumPhase 2: Sulforaphane, Schizandra, Taurine, N-acetylcysteine, Glutamine, GlycineElimination of Toxins: Artichoke Leaf

Phase I & II Liver Detoxification

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References1. Teschke R, Nishimura M, Gellert J. Toxic and metabolic liverinjury. Leber Magen Darm. 1981 Sep;11(5):227-34.2. Lee CJ, Song SK, Jeon JH, Sung MK, Cheung DY, Kim JI, Kim JK,Lee YS. [Coffee enema induced acute colitis]. Korean JGastroenterol. 2008 Oct;52(4):251-4.3. Sashiyama H, Hamahata Y, Matsuo K, Akagi K, Tsutsumi O,Nakajima Y, Takaishi Y, Takase Y, Arai T, Hoshino T, Tazawa A, FuKI, Tsujinaka Y. Rectal burn caused by hot-water coffee enema.Gastrointest Endosc. 2008 Nov;68(5):1008; discussion 1009.4. Vanderperren B, Rizzo M, Angenot L, Haufroid V, Jadoul M,Hantson P. Acute liver failure with renal impairment related to theabuse of senna anthraquinone glycosides. Ann Pharmacother.2005 Jul-Aug;39(7-8):1353-7.5. Zhang L, Yang X, Sun Z, Qu Y. Retrospective study of adverseevents of Polygonum multiflorum and risk control. Zhongguo ZhongYao Za Zhi. 2009 Jul;34(13):1724-9.6. Miranda CL, Reed RL, Kuiper HC, Alber S, Stevens JF. Ascorbicacid promotes detoxification and elimination of 4-hydroxy-2(E)-nonenal in human monocytic THP-1 cells. Chem Res Toxicol. 2009May;22(5):863-74.7. Nakamura K, Hisaeda Y, Pan L, Yamauchi H. Chem Commun(Camb). Detoxification system for inorganic arsenic: transformationof As2O3 into TMAO by vitamin B12 derivatives and conversion ofTMAO into arsenobetaine. 2008 Nov 7;(41):5122-4.8. Antelava NA, Gogoluari MI, Gogoluari LI, Pirtskhalaĭshvili NN,Okudzhava MV. Efficacy and safety of heptral, vitamin B6 and folicacid during toxic hepatitis induced by CCL4. Georgian Med News.2007 Sep;(150):53-69. Kennedy CJ, Tierney KB.Energy intake affects thebiotransformation rate, scope for induction, and metabolite profileof benzo[a]pyrene in rainbow trout. Aquat Toxicol. 2008 Nov21;90(3):172-81.10. Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual causesof death in the United States, 2000. JAMA. 2004 Mar10;291(10):1238-45.11. Pedersen SD, Kang J, Kline GA. Portion control plate for weightloss in obese patients with type 2 diabetes mellitus: a controlledclinical trial. Arch Intern Med. 2007 Jun 25;167(12):1277-83.12. Siervo M, Faber P, Gibney ER, Lobley GE, Elia M, Stubbs RJ,Johnstone AM. Use of the cellular model of body composition todescribe changes in body water compartments after total fasting,very low calorie diet and low calorie diet in obese men. Int J Obes(Lond). 2010 Feb 9.13. Pires J, Curi R, Otton R. Induction of apoptosis in ratlymphocytes by starvation. Clin Sci (Lond). 2007 Jan;112(1):59-67.14. Adams SD, Delano BA, Helmer KS, Mercer DW. Fastingexacerbates and feeding diminishes LPS-induced liver injury in therat. Dig Dis Sci. 2009 Apr;54(4):767-73.15. Human Health Risk Assessment of Mercury in Fish and HealthBenefits of Fish Consumption. Health Canada. 16. Human Health Risk Assessment of Mercury in Fish and HealthBenefits of Fish Consumption. Health Canada. 17. Human Health Risk Assessment of Mercury in Fish and HealthBenefits of Fish Consumption. Health Canada. 18. Pichichero ME, Cernichiari E, Lopreiato J, Treanor J. Mercuryconcentrations and metabolism in infants receiving vaccinescontaining thiomersal: a descriptive study. Lancet. 2002 Nov30;360(9347):1737-41.

19. Human Health Risk Assessment of Mercury in Fish and HealthBenefits of Fish Consumption. Health Canada. 20. Stowe J, Andrews N, Wise L, Miller E. Investigation of thetemporal association of Guillain-Barre syndrome with influenzavaccine and influenzalike illness using the United Kingdom GeneralPractice Research Database.Am J Epidemiol. 2009 Feb1;169(3):382-8. Epub 2008 Nov 24.21. Edwards DJ, Bellvue FH, Woster PM. Identification of 6',7'-Dihydroxybergamottin, a cytochrome p450 inhibitor in grapefruitjuice. Drug Metabol Disp 1996; 24: 1287-90.22. Lundahl J, Regardh CG, Edgar B, Johnsson G. Relationshipbetween time of intake of grapefruit juice and its effect onpharmacokinetics and pharmacodynamics of felodipine in healthysubjects. Eur J Clin Pharmacol 1995;49:61-7.23. MM Manson, HW Ball, MC Barrett, HL Clark, DJ Judah, GWilliamson and GE Neal. Mechanism of action of dietarychemoprotective agents in rat liver: induction of phase I and II drugmetabolizing enzymes and aflatoxin B1 metabolism.Carcinogenesis, Vol 18, 1729-173824. Khan MM, Sakauchi F, Sonoda T, Washio M, MoriM.Magnitude of arsenic toxicity in tube-well drinking water inBangladesh and its adverse effects on human health includingcancer: evidence from a review of the literature. Asian Pac J CancerPrev. 2003 Jan-Mar;4(1):7-14.25. Lockitch G. Perspectives on lead toxicity. in Biochem. 1993Oct;26(5):371-81.26. Scanlan N. Altern Med Rev. Compromised hepaticdetoxification in companion animals and its correction vianutritional supplementation and modified fasting. 2001 Sep;6Suppl:S24-37.27. Barve A, Khor TO, Nair S, Reuhl K, Suh N, Reddy B, NewmarkH, Kong AN.Gamma-tocopherol-enriched mixed tocopherol dietinhibits prostate carcinogenesis in TRAMP mice. Int J Cancer. 2009Apr 1;124(7):1693-9.28. Stapleton PP, Charles RP, Redmond HP, Bouchier-HayesDJ.Taurine and human nutrition. Clin Nutr. 1997 Jun;16(3):103-8.29. Choi EH, Lee N, Kim HJ, Kim MK, Chi SG, Kwon DY, Chun HS.Schisandra fructus extract ameliorates doxorubicin-inducecytotoxicity in cardiomyocytes: altered gene expression fordetoxification enzymes. Genes Nutr. 2008 Feb;2(4):337-45.30. Yadav UC, Ramana KV, Awasthi YC, Srivastava SK. Glutathionelevel regulates HNE-induced genotoxicity in human erythroleukemiacells. Toxicol Appl Pharmacol. 2008 Mar 1;227(2):257-64.31. El-Begearmi MM, Ganther HE, Sunde ML. Dietary interactionbetween methylmercury, selenium, arsenic, and sulfur amino acidsin Japanese quail. Poult Sci. 1982 Feb;61(2):272-9.32. Kling LJ, Soares JH Jr. Mercury metabolism in Japanese quail.I. The effect of dietary mercury and selenium on their tissuedistribution. Poult Sci. 1978 Sep;57(5):1279-85.33. Park S, Kim AJ, Lee M. Synergic effects of alpha-tocopherol andbeta-carotene on tert-butylhydroperoxide-induced HepG2 cellinjury. Toxicol Ind Health. 2009 May-Jun;25(4-5):311-20.34. Angeloni C, Leoncini E, Malaguti M, Angelini S, Hrelia P, HreliaS. Modulation of phase II enzymes by sulforaphane: implicationsfor its cardioprotective potential. J Agric Food Chem. 2009 Jun24;57(12):5615-22.35. Pagonis TA, Koukoulis GN, Hadjichristodoulou CS, Toli PN,Angelopoulos NV. Multivitamins and phospholipids complexprotects the hepatic cells from androgenic-anabolic-steroids-induced toxicity. Clin Toxicol (Phila). 2008 Jan;46(1):57-66.

Phase IIDetoxification andSulforaphane

Detoxification has to be distinguished from purgativeand diuretic effects. Most natural health productsaddress the cleansing of the body via purgative anddiuretic effects and by the stimulation of the liver. Theusual European, and particularly Scandinavian,“cleansers” are nothing more than stimulators of theabove effects. While this can be useful, truedetoxification can only occur at the cellular level.

The body has designed an elaborate detoxificationmechanism to deal with the thousands of toxins it isexposed to on a regular basis. These toxins come inthe form of carcinogens, environmental pollutants (likepesticides, hormones and exhaust fumes), toxicpharmaceuticals, heavy metals, cigarette smoke, UVradiation and many others.1-3 It is estimated that thereare over 500,000 chemicals currently being used andup to 25% of these may be carcinogenic! Many ofthese chemicals contribute to other diseases includingmultiple chemical sensitivities, fibromyalgia, chronicfatigue syndrome, neurological diseases (likeAlzheimer’s, Parkinson’s and MS), auto-immunediseases (like rheumatoid arthritis and lupus), diabetesand so on.1,3,4 Given the intensity of these exposures,an individual’s ability to detoxify these harmfulsubstances is now recognized as a key factor tomaintaining overall health.

Phase I vs. Phase II DetoxificationMost detoxification reactions occur in the liver and to alesser extent in the intestines and the skin. Thedetoxification process involves two steps termed phaseI and phase II. In each step a family of around 20enzymes is called into action.3 (see pages 6 and 7)

Phase I detoxification involves the well knowncytochrome P450 enzymes that catalyze a variety ofoxidation, reduction, hydrolysis and other reactions.The purpose of these enzymes is to make fat solubletoxins (called xenobiotics) more soluble by first“priming” these chemicals by incorporating an “activesite” which will ultimately be acted upon by Phase IIenzymes.5,6 By incorporating an active site themolecule becomes more reactive and thereforepotentially more damaging to the tissues. It is essentialthat Phase II enzymes are activated quickly to eliminatethe dangers of these phase I intermediates.3

Phase II reactions are also referred to as the“detoxification pathway” and involve the addition, or“conjugation” of various chemical molecules or groupsto the Phase I intermediates. Examples of such groupsare sulphydryl groups (SH), methyl groups (CH3),glutathione, glucuronide and so on. These groupsmake the xenobiotics more water soluble andtherefore more easily excreted from the body. This isimportant since this ensures that toxins are not allowedto linger too long in the body.3,5,6 While the Phase Iprocess can be a double-edged sword, Phase IIreactions are widely regarded as being highlybeneficial to health when stimulated.

Natural Stimulators of Phase II EnzymesA number of phytochemicals can stimulate Phase IIdetoxification enzymes7, but none more so thansulforaphane, a component of various cruciferousvegetables like mustard, kale, bok choy, cabbage,cauliflower and especially broccoli sprouts. Thecruciferous vegetables are a rich source of a group ofcompounds called glucosinolates that are rapidlyconverted by an enzyme called myrosinase into muchmore powerful compounds called isothiocyanates(ITC). Sulforaphane is one such compound.2,8

Sulforaphane is the most widely studied ITC, bothexperimentally and clinically. Much of the pioneeringwork has been done in Baltimore at Johns HopkinsUniversity by Paul Talalay and his group.1

Sulforaphane has hundreds of studies worldwideattesting to its very powerful Phase II stimulatingproperties.


Figure 1. Cruciferous vegetables like broccoli are richin compounds that promote phase II detoxification.

What are the Benefits of Sulforaphane?

1. AntioxidantFree radicals or reactive oxygen species are created bytoxins and carcinogens as well as by the body as abyproduct of various chemical reactions, especially inthe mitochondria. These reactive species readily attackvarious tissues in the body causing disease and aging.Sulforaphane is a potent quencher of such species,acting by stimulating various enzymes and compoundsthat neutralize these reactive species effectively.2,4,9

2. Anti-inflammatoryInflammation is now considered the hallmark of anumber of diseases like diabetes, allergies,cardiovascular disease and even obesity.Sulforaphane has an anti inflammatory effect via anumber of different mechanisms including theinhibition of COX 2 enzymes and NF-kappaB, amolecule associated with inflammation, and thepromotion of Nrf2, a powerful molecule that inhibitsinflammation.9 In a number of studies sulforaphanehas been shown to clinically reduce inflammation andpain in osteo-arthritic patients as well as improving therepair of damaged cartilage.10

3. Lowers Blood PressureHigh blood pressure has been linked to high amountsof reactive oxygen species. Animal studies havedemonstrated that sulforaphane significantly reducesblood pressure and improves other cardiovascularhealth conditions.11

4. Anti-allergic EffectsSulforaphane has been shown to reduce symptoms ofallergies including sneezing, watery eyes, itchy andrunny nose caused by a variety of allergens likedifferent types of pollen, dust, diesel fuel etc. A recenthuman study showed that sulforaphane greatlyincreased antioxidant status of the patients and theauthors suggested a potential application ofsulforaphane in conditions like asthma.2

5. Anti-cancer Effects Perhaps the most widely studied effect of sulforaphanefor over 20 years is in the field of cancer research in anumber of diverse species as well as variety of tissueslike prostate, skin, colon, breast, uterine, ovarian,bladder, pancreas etc.1,5,6,12-15 No human studies areavailable due to the large number of subjectsrequired, length of study (over 20-30 years) and thecost.The anti-cancer effect is attributed to a number ofmechanisms including the stimulation of phase IIenzymes, apoptosis (cell suicide), cell cycle arrest(preventing replication), reduction of the spread oftumours (metastases) and the inhibition of bloodsupply to cancer cells (angiogenesis).13-16

Figure 2. The chemical structure of Sulforaphane.

Detoxification at the Cellular LevelIn conclusion, stimulation of Phase II detoxificationenzymes promotes true detoxification of the body atthe cellular level. Enhanced Phase II detoxificationgreatly assists the body in reducing the overall toxicburden as well as affording substantial health benefitsin immune function, heart health, anti-inflammatoryand anti-cancer effects. Sulforaphane is an excitingnatural compound that is the most potent and widelystudied Phase II detoxifier.



References1. P Talalay et-al “Sulforaphane mobilizes cellular defenses that protect skindamage by UV radiation” PNAS,2007;104:17500-175052. S A Ritz et-al “Sulforaphane-stimulated phase II enzyme induction inhibitscytokine production by airway epithelial cells stimulated with diesel extract”Am J Physiol Lung Cell Mol Physiol,2007;292:L33-L393. Liska DJ. “The Detoxification Enzyme Systems” Altern Med Rev1998;3(3):187-198.4. R H Dashwood “Xenobiotic metabolism relevance to cancer”, JNutr,2006;136:2681S-2682S5. C S Yang “Dietary factors may modify cancer risk by altering xenobioticmetabolism and many other mechanisms” J Nutr,2006;136:2685S-2686S6. A Gopalakrishnan and T Kong “Anticarcinogenesis by dietaryphytochemicals:Cytoprotection by Nrf2 in normal cells and cytotoxicity bymodulation of transcription factors NF-kappaB and AP-1 in abnormalcancer cells”, Food Chem Toxicol,2008;46:1257-12707. J W Lampe “Health effects of vegetables and fruit: assessing mechanismsof action in human experimental studies” Am J Clin Nutr, 1999;70(suppl):475S-90S8. Nestle M. “Broccoli sprouts as inducers of carcinogen-detoxifying enzymesystems:Clinical, dietary, and policy implications” Proc. Natl. Acad. Sci.USA, 1997, 94: 11149–11151.

9. J M Han et-al “Protective effects of sulforaphane against dopaminergiccell death” J Pharmacol Exp Ther,2007;321:249-25610. Healy Z et al. “Divergent responses of chondrocytes and endothelialcells to shear stress: Cross-talk among COX-2, the phase 2 response, andapoptosis” Proc Nat. Acad. Sci. USA, 2005, 102(39):10410-10415.11. Wu L et al. “Dietary approach to attenuate oxidative stress,hypertension, and inflammation in the cardiovascular system” 2004,101(18): 7094-7099.12. A H Conney “Enzyme Induction and Dietary Chemicals as approachesto cancer chemoprevention: The seventh DeWitt S Goodman Lecture”Cancer Res, 2003;63:7005-703113. S J T Jckson and K W Singletary “ Sulforaphane inhibits human MCF-7mammary cancer cell mitotic progression and tubulin polymerization” JNutr,2004;134:2229-223614. J D Brooks et-al “Potent Induction of Phase II enzymes in humanprostate cells by Sulforaphane” Cancer Epidemiol Biomarkers andPrev,2001;10:949-95415. S Shankeret-al “Sulforaphane enhances the therapeutic potential ofTRAIL in prostate cancer orthotopic model through regulation ofapoptosis,metasis and angiogenesis” Clin Cancer Res,2008;14:6855-686616. 2.S Choi and S V Singh “Bax and Bak are required for apoptosis inducedby sulforaphane, a cruciferous vegetable-derived cancer chemopreventiveagent” Cancer Res, 2005;65:2035-43

Ortho Liver II™

Protects and Maintains aHealthy Liver

• Prevents and addresses liverdisorders

• Stimulates liver regenerationand detoxification

• Antioxidant

Antioxidants,Oxidationand the LiverWhat are Antioxidants?The term “antioxidant” is everywhere these days. Fromgreen tea to chocolate and even coffee, the media hasbecome inundated with advertising professing thebenefits of antioxidant rich-foods. And while mostpeople are aware that antioxidants are good for theirhealth, many are much less certain about what theyactually do in the body and why they are so important.

In a nutshell, antioxidants are just what their namesuggests – they are agents that prevent oxidation. Butwhat then, is oxidation and why is it so important toprevent it from occurring? In a chemical sense,oxidation is a reaction in which electrons aretransferred from one molecule to another molecule or“oxidizing agent”.1 Molecules that have been oxidizedhave therefore lost some of their electrons. There aremany normal functions and processes in the body thatrequire oxidation reactions. In fact, it has beenhypothesized that free radicals played a crucial role inthe origin of life.2 However, these reactions can alsohave harmful repercussions.

The Danger of Free RadicalsWhen a molecule loses an uneven number of electronsit becomes a “free radical”. Free radicals are highlyunstable and reactive molecules that possess anunpaired electron in their outermost shell. Thesemolecules react within a very short time with anothermolecule in order to gain or lose another electron.However, this produces another free radical, and kicksoff a chain reaction of free radical production that canhave deleterious effects.1,3

Figure 1. Antioxidants and Free Radicals

One of the most common, and most damaging, typesof free radicals are reactive oxygen species (ROS) oroxygen free radicals, and include a number ofchemically reactive species derived from oxygen,1,3

such as the superoxide anion and the hydroxyl radical.These highly reactive molecules readily react withother molecules in the body, initiating a cascade offree radical producing reactions.1,3 However, theproduction of ROS is required for the generation ofcellular energy, creating a difficult situation for thebody, which must first produce these molecules, andthen eliminate them before they can cause damage.High levels of ROS are associated with oxidative stress,a dangerous condition that can result in a great dealof damage to the molecules and organs of the body.Because of this, ROS are also potentially toxic,carcinogenic and mutagenic. The damage caused byROS has been linked to the development of cancer,atherosclerosis, heart disease and autoimmunediseases.3

ROS can attack various different molecules in thebody, including DNA, lipids and proteins. DNAdamage can result in replication errors and can play arole in the initiation of cancer. In fact, studies haveshown a high prevalence of cancer in individualsexposed to chronic oxidative stress.4,5 Lipidperoxidation, or the oxidation of low density


Normal Oxygen Atom

Electron Loss

Creates a Free

RadicalCell Membrane

Free Radicals Set off a

Chain Reaction

This Leads to Erosion

and Damage to the

Cell Membrane

Antioxidants Neutralize

Free Radicals


lipoprotein (LDL) cholesterol is another well knownand dangerous effect of ROS. Lipid peroxidation leadsto blood vessel damage and has been associated withthe development of atherosclerosis and heartdisease.6,7

The Antioxidant SolutionIf ROS are so dangerous, the obvious question thatarises is how this damage can be prevented? Theanswer to this question is simple - antioxidants.Antioxidants are vitally important molecules that playthe role of free radical scavengers. They are moleculesthat, in one way or another, react with ROS or otherfree radicals, stopping the uncontrolled free-radicalchain reaction in its tracks, and preventing additionaldamage and oxidative stress.1,3

Antioxidants come in many forms, and act in manydifferent ways. Some antioxidants, like vitamin E,vitamin C, beta-carotene and numerous flavonoids,are able to form stable radicals themselves thateventually undergo reactions to form non-radicalproducts.1 Others are enzymes or molecules involvedin enzymatic reactions that convert the ROS intodifferent, non-radical products.1

Antioxidants in the Liver Antioxidants play an especially important role in theliver. The liver is essential for a wide variety of functionsincluding metabolism, detoxification, protein synthesis,glycogen storage and the production of somehormones. With the liver being a major site of cellularmetabolism and energy production it is not a surprisethat oxidative stress and free radicals are a seriousproblem for this critical organ. However, the liver isalso a major site of detoxification and is well equippedfor dealing with toxic and harmful substances,including free radicals.

The Importance of Glutathione (GSH)The most important molecule for eliminating freeradicals in the liver, and in the whole body for thatmatter, is glutathione (GSH). GSH is a molecule that isfound in all healthy cells, and is composed of threeamino acids – glutamine, cysteine and glycine.8 Theproduction of GSH is catalyzed by the enzymes γ-glutamylcysteine synthetase (GCS) and GSHsynthetase, and occurs in all cell types, although theliver is by far the greatest producer and exporter ofGSH.1

Figure 2. The production and recycling of glutathione(GSH)

GSH is considered the most important antioxidant inthe human body8, and its role as an exceptionalantioxidant is made possible by various importantcharacteristics. First of all, GSH is able to scavengefree radicals both directly and indirectly through avariety of different enzymatic reactions.8,9 It’santioxidant capabilities are thus extremely potent andversatile. Furthermore, when oxidized, GSH forms theglutathione radical, but this then reacts with anotherglutathione radical to produce GS-SG, a stable, non-radical compound. This reaction prevents additionaldamage and quickly halts the chain of free radicalproduction. GS-SG can then be recycled back intoGSH by the enzyme glutathione reductase.9

GSH is not merely an antioxidant; it is one of the mostimportant molecules in the body, and is involved innumerous different cellular reactions and processes.8-10

In addition to its antioxidant role, GSH, along with theenzyme glutathione-S-transferase (GST), is anessential component of the Phase II enzymedetoxification system in the liver. Together GSH andGST react with various toxic and potentiallycarcinogenic waste products or molecules, detoxifyingthem, and protecting the body.8,9 GSH is also involvedin the proper utilization of lipids, glucose and aminoacids by the liver11, the removal of formaldehyde fromthe body12, normal cellular growth13, proper immunefunction12 and sperm production.14

GSH Deficiency and Liver HealthIt is apparent that GSH is a vitally important molecule forthe maintenance of both liver and whole body health.

Glutamine + Glycine + Cysteine

-glutamylcysteine synthetase& GSH synthetase

GSH

GSSGNADPH

NADP Free Radical

GSH Reductase

Stable Molecule

GlyGlutamine + + Cysteineycine

slcysteiney-glutam ynthetases

NADP

GSH R

GSSH

& GSH synthetase

Free Radical

NADPH GSSG Stable Moleccule

Deficiencies in GSH place the body in a situation ofoxidative stress, increasing the likelihood of cellulardamage and disease.12 GSH imbalances have beenlinked to a variety of conditions and disease, includingcancer, neurodegenerative disorders, cystic fibrosis(CF), HIV and aging.12

In regards to the liver specifically, a great deal ofresearch has shown that GSH is intimately linked toliver health. The situation can be fairly complex,however, as low GSH levels can be either the cause orthe resulting effect of a condition.12 For example,inherited disorders in GSH metabolism cansignificantly disrupt liver function, and can even leadto death.12 Nutritional amino acid deficiency can alsoresult in depleted GSH.8 Alternatively, certainconditions, like excessive alcohol consumption, candeplete glutathione, putting serious stress on the liver.12

Overall, there are two primary mechanisms by whichGSH can be depleted. First, excessive production ofROS can lead to GSH depletion. Excessive ROSproduction is often associated with inflammation, a

common manifestation of many disease conditions.15

GSH can also be depleted by the metabolism of largequantities of drugs or other chemicals. For example,acetaminophen overdose is known to deplete GSH.GSH is required for the detoxification of substanceslike acetaminophen, so high levels can lead to GSHdepletion.15

In the case of alcohol-induced liver disease, ethanolconsumption puts a strain on the liver’s detoxificationsystems while also inducing inflammatory pathwaysand promoting lipid peroxidation.16,17 It is thereforenot surprising that alcohol consumption has beenshown to deplete GSH levels in the liver. It has alsobeen associated with reduced activity of the enzymeglutathione reductase, which is essential for theregeneration of GSH from GS-SG.16 The earliest stageof alcohol-induced liver disease is a fatty liver, whichthen can progress to alcoholic hepatitis and finally,cirrhosis and eventually death.

Glutathione depletion and oxidative stress have alsobeen implicated in the pathogenesis of non-alcoholicfatty liver disease (NAFLD).17 NAFLD is oftenassociated with obesity, diabetes and high cholesterollevels, and follows a progression similar to that ofalcohol-induced liver disase.18,19 Abnormal antioxidantstatus has been reported in 90% of NAFLD patients,and glutathione levels have been found to be reducedby as much as 57%.17

Oxidative stress can induce a number of extremelydamaging events in the liver. Hepatotoxicity byoxidative stress may be achieved through a directattack of ROS on essential biomolecules, resulting in aloss of biological function and cellular death. It mayalso occur through the activation of proinflammatorymolecules or Kupffer cells.17 Kupffer cells are a specialtype of macrophage that reside only in the liver, andare involved in the liver’s response to toxiccompounds.20 Prolonged activation of Kupffer cells (bytoxic agents, for example) stimulates the cells torelease inflammation causing compounds and ROS.This results in an exacerbation of liver injury.20 Recentresearch also suggests that chronic activation ofKupfer cells can result in the release of molecules thatpromote excessive liver cell proliferation, therebycontributing to the development of liver cancer.20


Roles ofGlutathione8

Antioxidant Defense• Scavenging free radicals and other reactive

species• Removing hydrogen and lipid peroxides• Preventing oxidation of biomoleculesMetabolism• Synthesis of leukotrienes and prostaglandins• Removal of formaldehyde• Involved in Phase 1 and II detoxification of toxins• Utilization of cellular lipids, glucose and

amino acids• Storage and transport of cysteineRegulation• Intracellular antioxidant status• Signal transduction and gene expression• DNA and protein synthesis, and proteolysis• Cell proliferation and apoptosis• Cytokine production and immune response• Mitochondrial function and integrity

Figure 3. The Causes and Effects of GlutathioneDepletion

The Problem with Glutathione SupplementationThe importance of adequate GSH is undeniable, andsupplementing with this essential antioxidant wouldseem to be a very good idea. There is a problem,however. Although oral GSH supplementation seemsto be effective in rodents21, research has shown that ithas very poor bioavailability in humans. In one study,a single administration of a 3g dose of glutathione didnot significantly increase circulating glutathionelevels.22

The problem seems to occur somewhere between thedigestive tract and the liver. Research suggests thatGSH can be effectively absorbed by the body from thegastrointestinal tract via a specialized uptakemechanism. However, once absorbed GSH in the

bloodstream is broken down by enzymes before itreaches the liver.23 It is possible, therefore, that oralGSH may still be beneficial for conditions of theintestinal tract, like Crohn's disease, but not for otherconditions requiring GSH supplementation.23 In onetrial, for example, a 300 mg/day dose of GSHadministered to cirrhosis patients for 28 days did notimprove GSH status.24

N-Acetyl-Cysteine (NAC) as a SolutionThe good news is that there is another way to increaseGSH levels. GSH is composed of three amino acids –cysteine, glutamine and glycine.8 Research has shownthat the availability of cysteine is rate-limiting for GSHsynthesis.25 For instance, human subjects given acysteine-free diet for 10 days showed a significantdecrease in GSH synthesis and turnover, compared towhen they received a cysteine-containing diet.25 These


Glutathione (GSH)

Depletion

Free

Radicals

Oxidative

Stress Toxic

Buildup

Stress

Aging

Infection

Pollution Injury

RadiationDrugsPoor Diet

Liver Cell

Damage


findings suggest that cysteine is most likely to be inshort supply, thereby limiting cellular production ofGSH, and that supplementation with cysteine couldpotentially boost GSH levels. L-cysteine is an extremelyunstable molecule, and is not suitable forsupplementation.23 N-Acetyl-Cysteine, on the otherhand, is a safe and orally bioavailable source ofcysteine.23,26 Following absorption in the intestines,NAC is converted to cysteine and can be used toincrease GSH production.NAC supplementation has been shown to effectivelyreplenish GSH in depleted patients.23 NACsupplementation has been demonstrated to haveclinical benefits to HIV patients, and was associatedwith a significant improvement in their depleted GSHlevels.27

Figure 4. The Chemical Structure of N-Acetylcysteine

In terms of liver health, NAC is well-established as atreatment for acetaminophen poisoning. When givenwithin 8 hours of overdose, 140 mg of oral NAC perkilogram of body weight was protective and reducedthe incidence of hepatotoxicity regardless of initialacetaminophen concentration.28 Furthermore, nodeaths were clearly caused by acetaminophen amongpatients in whom NAC therapy was begun within 16hours.28 NAC’s actions in preventing acetaminopheninduced hepatotoxicity has been linked to itsantioxidant effects and its ability to replete GSH.29

NAC is also beneficial in cases of liver failure notrelated to acetaminophen. In 170 children with acuteliver failure NAC was found to be a safe and effectivetreatment option. Children receiving NAC had ashorter length of hospitalization, a greater survival withthe native liver and a better survival rate after livertransplant than those not receiving NAC.29

In addition to its ability to increase GSH production,NAC is also beneficial for respiratory conditions, andhas been shown to help reduce mucous in the lungs,reduce cough severity and improve pulmonaryfunction.30 NAC also has cardiovascular benefits, andresearch has demonstrated that it is able to lowerlevels of the toxic amino acid homocysteine by 45%31

and lipoprotein(a) levels by 70%.32 Finally, NACappears to have anti-cancer properties as well. In vitrostudies have shown that NAC has direct anti-carcinogenic effects. In animal and cellular studiesNAC was found to selectively protect normal cells, butnot malignant ones, from chemotherapy and radiationtoxicity.30,33

ConclusionsAntioxidants are vital for protection from free radicaldamage, whether the free radicals are producedthrough biochemical processes or as the result of adisease condition. The liver is particularly vulnerableto free radical damage, which occurs when the mostimportant liver antioxidant, glutathione, is depleted.Oxidative stress in the liver can lead to liver cell death,inflammation of the liver, liver diseases and possiblyeven liver cancer. Increasing glutathione levels iscritical, especially in conditions where it has beendepleted. NAC supplementation is by far the safestand most effective method to naturally increaseglutathione levels, thereby enhancing the health of theliver and the entire body.


References1. Bender DA. Introduction to Nutrition and Metabolsim, 4thEdition. 2008. CRC Press, Taylor & Francis Group. Boca Raton, FL.pp: 189-203.2. McCord JM. The evolution of free radicals and oxidative stress.Am J Med. 2000;108:6523. Nordberg J and Arnér ESJ. Reactive oxygen species, antioxidantsand the mammalian thioredoxin system. Free Radical Biology andMedicine. 2001; 31(11): 1287-1312. 4. Marnett LJ. Oxyradicals and DNA damage. Carcinogenesis.2000; 21:361–370.5. Mates J M, Perez-Gomez C, Nunez de Castro I. Antioxidantenzymes and human diseases. Clin. Biochem. 1999; 32:595–603.6. Halliwell B. The role of oxygen radicals in human disease, withparticular reference to the vascular system. Haemostasis. 1993;23(Suppl. 1):118–126.7. Frei B. On the role of vitamin C and other antioxidants inatherogenesis and vascular dysfunction. Proc. Soc. Exp. Biol.Med.1999; 222:196–204.8. Wu G, Fang Y, Yang S, Lupton JR, and Turner ND. GlutathioneMetabolism and Its Implications for Health. J. Nutr. 2004; 134:489–492.9. Fang Y Z, Yang S and Wu G. Free radicals, antioxidants, andnutrition. Nutrition. 2002; 18: 872–879.10. Lei X G. In vivo antioxidant role of glutathione peroxidase:evidence from knockout mice. Methods Enzymol. 2002; 347:213–225.11. Guarino MP, Afonso RA, Raimundo N, Raposo JF and MacedoMP. Hepatic glutathione and nitric oxide are critical for hepaticinsulin-sensitizing substance action. Am. J. Physiol. 2003; 284:G588–G594.12. Townsend DM, Tew KD and Tapiero H. The importance ofglutathione in human disease. Biomed. Pharmacother. 2003; 57:145–155.13. Aw T Y. Cellular redox: a modulator of intestinal epithelial cellproliferation. News Physiol. Sci. 2003;18: 201–204.14. Sies H. Glutathione and its cellular functions. Free Radic. Biol.Med. 1999; 27: 916–921.15. Han D, Hanawa N, Saberi B, and Kaplowitz N. Mechanisms ofLiver Injury III. Role of glutathione redox status in liver injury. Am JPhysiol Gastrointest Liver Physiol. 2006; 291: G1–G7.16. Das SK and Vasudevan DM. Effect of ethanol on liverantioxidant defense systems: a dose dependent study. IndianJournal of Clinical Biochemistry. 2005; 20(1): 80-84.17. Situnayake RD, Crump BJ, Thurnham DI, Davies JA, Gearty J,and Davis M. Lipid peroxidation and hepatic antioxidants inalcoholic liver disease. Gut. 1990; 31:1311-1317.

18. Ludwig J, Viggiano RT and McGill DB. Nonalcoholicsteatohepatitis: Mayo Clinic experiences with a hitherto unnameddisease. Mayo Clin. Proc. 1980; 55:342–34819. Matteoni C, Younossi ZM and McCullough A. Nonalcoholicfatty liver disease: a spectrum of clinical pathological severity.Gastroenterology. 1999; 116:1413–141920. Roberts RA, Ganey PE, Ju C, Kamendulis LM, Rusyn I andKlaunig JE. Role of the Kupffer Cell in Mediating Hepatic Toxicityand Carcinogenesis. Toxicological Sciences. 2007; 96(1): 2-15.21. Aw TY, Wierzbicka G, Jones DP. Oral glutathione increasestissue glutathione in vivo. Chemico-biological interactions.1991;80(1):89-97.22. Witschi A, Reddy S, Stofer B, and Lauterburg BH. The systemicavailability of oral glutathione. Eur J Clin Pharmacol. 1992;43:667-66923. Glutathione, Reduced (GSH). Monograph. Alternative MedicineReview. 2001; 6(6): 601-607.24. Cook GC, Sherlock S. Results of a controlled clinical trial ofglutathione in cases of hepatic cirrhosis. Gut. 1965; 6:472-476.25. Lyons J, Rauh-Pfeiffer A, Yu YM, Lu XM, Zurakowski D, TompkinsRG, Ajami AM, Young VR and Castillo L. Blood glutathionesynthesis rates in healthy adults receiving a sulfur amino acid-freediet. PNAS. 2000; 97(10): 5071–5076.26. Olsson B, Johansson M, Gabrielsson J, and Bolme P.Bioavailability of Reduced and Oxidized N-Acetylcysteine. Eur JClin Pharmacol. 1988; 34:77-82.27. De Rosa SC, Zaretsky MD, Dubs JG, Roederer M, Anderson M,Green A, Mitras D, Watanabe N, Nakamura H, Tijoe I, DeresinkiSC, Moore WA, Ela SW, Parks D, and Herzenberg LA. N-acetylcysteine replenishes glutathione in HIV infection. EuropeanJournal of Clinical Investigation. 2000; 30:915-929.28. Smilkstein MJ, Knapp GL, Kulig KW, and Rumack BH. Efficacyof oral N-acetylcysteine in the treatment of acetaminophenoverdose. Analysis of the national multicenter study. The NewEngland Journal of Medicine. 1988; 319:1557-1562.29. Kortsalioudaki C, Taylor RM, Cheeseman P, Bansal S, Mieli-Vergani G, and Dhawan A. Safety and Efficacy of N-Acetylcysteinein Children with Non-Acetaminophen-Induced Acute Liver Failure.Liver Transplantation. 2008; 14: 25-30.30. N-acetylcysteine Monograph. Alternative Medicine Review.2000; 5( 5): 467-471. 31. Wiklund O, Fager G, Andersson A, et al. N-acetylcysteinetreatment lowers plasma homocysteine but not serum lipoprotein(a)levels. Atherosclerosis. 1996;119:99-106.32. Gavish D, Breslow JL. Lipoprotein(a) reduction by N-acetylcysteine. Lancet. 1991; 337:203-204.33. De Flora S, D’ Agostini F, Masiello L, et al. Synergism betweenN-acetylcysteine and doxorubicin in the prevention oftumorigenicity and metastasis in murine models. Int J Cancer.1996; 67:842-848.

Promotes EmotionalWell Being


Methylation,Detoxificationand SAMeMethylation is one of the most fundamental biologicalfunctions of the human body. It occurs at the rate ofapproximately one billion times per second, affectingeverything from fetal development to the immunesystem to nerve transmission. It is also essential forover 100 different metabolic reactions involvingcritical molecules such as nucleic acids, DNA, RNA,proteins, phospholipids, myelin, polysaccharides,creatine, and catecholamines to name a few.Methylation has an acute relationship with

homocysteine, and the balance of this relationship canquite literally make the difference between life anddeath.

The Relationship between Homocysteine andMethylationIt is impossible to properly define homocysteinewithout clearly defining methylation, such is therelationship between the two. Biochemically speaking,methylation is a metabolic process that involves theaddition of methyl groups to various molecules. Thatprocess begins with the amino acid methionine.

1 Methionine: an essential yet relatively ubiquitousamino acid found in most sources of dietary protein. Itis the building block of all polypeptide (multiple-aminoacid chain) proteins, containing both sulfur and methylgroups.

2 Methionine Bonds with ATP: ATP is adenosinetriphosphate, a nucleotide that is the primary energycurrency of the cell – and therefore the source of allimmediate short-term energy for the human body.This bonding then creates SAMe.

H3C

Methionine1

2ATP

Methyl

group

3

Methyl

Acceptor

SAMe4 Homocysteine

Vitamin B12 &

Folic AcidVitamin B6

BATrans-

sulfuration

Glutathione

Re-methylation

M

ninehioetM

neohitautlG

M

pougr

Methyl

ninehioetM

PAT

6BinmaitVVi

nioturaulffus

-nsraT

idc

12 &Bn

iotlahyet

no

comoH

einetscy

eSAM

ccA

Met

rotep

lyht

Figure 1. The Methylation Cycle


3 SAMe (s-adenosylmethionine): SAMe is a coenzymewhose creation results in the chemical reaction ofdonating its methyl group inherited from methionine toa methyl receptor. The transfer of methyl groups is thereactive process that sparks the entire methylationcycle. After SAMe donates its methyl group to a methylacceptor (which can include folate or vitamin B12), itbecomes s-adenosylhomocysteine (SAH). SAH then israpidly transformed into homocysteine.

4 Homocysteine: This is the critical stage of themethylation cycle. Although technically an amino acid,homocysteine is in effect a by-product of proteinmetabolism, to which the methylation cycle isintrinsically connected via methionine. This by-product, left unconverted, can accumulate andbecome toxic. Elevated homocysteine levels havebeen linked to cardiovascular disease and a myriad ofother ailments.

The Critical JunctureIt is at this point where the alternatives to homocysteineaccumulation become critical. These alternativesconsist of two metabolic pathways: A) the “re-methylation” pathway or B) the “trans-sulfuration”pathway.

A The “re-methylation” pathway is wherehomocysteine is converted back to methionine. Thisprocess is dependent on adequate serum levels offolate and vitamin B12, which will safely recyclehomocysteine back into methionine. They will do thisby donating methyl groups that they themselves haveaccepted.

B The “trans-sulfuration” pathway is vitamin B6-dependent, and if adequate levels of this nutrient arepresent, then it (among other substances) will actuallytransform homocysteine into either the non-toxicamino acid cysteine or the ubiquitous glutathione, themost important antioxidant produced by the body.

Supplemental SAMe, Homocysteine, and DetoxificationUpon first examining SAMe’s biological ‘place’, onecan be forgiven for failing to make the immediateconnection between it and the health conditions forwhich supplemental SAMe is clinically demonstrated tobe effective, namely mood, joint and (to a lesserextent) liver health. The connection, however, doesexist and is based on detoxification.Homocysteine can be described as a naturallyoccurring toxic agent. High levels of homocysteinehave been connected to correspondingly high levels ofinflammation, and both have a long-establishedinverse relationship with joint health and a morerecently established one with mood health. In thiscontext, the value of lowering homocysteine levelsbecomes apparent, and since homocysteine is a by-product of the methylation process, improving themethylation process is key to lowering homocysteinelevels. In effect, homocysteine can be thought of as a“waste product” of methylation, and thus improvingthe efficiency of the methylation process is a form ofdetoxification. The question now becomes: how doesSAMe, which is an integral part of methylation,contribute to detoxification?

SAMe, Mood and Detoxification

It is important to emphasize the difference between thepresence of high levels of homocysteine in peoplesuffering from conditions such as depression (andother mood disorders) and determining those levels tobe causative factors in such condition(s). While it is stilla subject of some speculation, it is believed thatelevated homocysteine may cause depression by


altering the function of neurotransmitters.1 Moodhealth is one of the areas where SAMe has beenclinically proven (and officially recognized) to beeffective. At least a dozen clinical trials involvinghundreds of patients diagnosed with major depressionhave experienced significant alleviation of theirsymptoms with supplemental SAMe.2 While theprecise mechanism of action for this remains elusive,an inverse relationship between plasma levels ofhomocysteine and SAMe has been established.3

SAMe, Joint Health and Detoxification

Homocysteine has recently been identified as both arisk indicator of osteoporosis as well as a factor inbone metabolism.4 Less conclusive but ongoingresearch is connecting elevated homocysteine levels toosteoarthritis as well.5 Supplemental SAMe has beensuccessfully used to treat the latter, with numerousclinical studies demonstrating both efficacy and safetyto its credit.6 Among the mechanisms of action behindthis efficacy are increased glutathione production andDNA methylation (assuming B-vitamin levels areadequate).7

SAMe, Liver Health and DetoxificationSAMe also has an established reputation in thetreatment of liver health, and this is due in large partto its role as a glutathione precursor (once again,dependent on sufficient levels of B-vitamins).Furthermore, the enzyme that acts as the catalyst tocombine methionine with ATP to produce SAMe isseverely inhibited in cases of liver dysfunction.8

The Bottom LineIn summary, healthy methylation will have a high ratioof glutathione production and remethylationcompared to homocysteine production. This is theessence of detoxification in the context of methylation.While the effects of supplemental SAMe alone arerelatively neutral with respect to homocysteine levels9,combining it with a synergistic B-complex amounts tostrong theoretical evidence for enhancedcardiovascular health. Healthy levels of SAMe helpensure that the methylation process remains robust,and concurrently adequate levels of B12, Folic acid,and B-6 help ensure that it remains efficient.

References 1. Bryer JB, Starkstein SE, Votypka V, Parikh RM, Price TR, RobinsonRG: Reduction of CSF monoamine metabolites in poststrokedepression: a preliminary report. J Neuropsychiatry Clin Neurosci1992; 4:440–442.2. Williams AL, Girard C, Jui D, Sabina A, Katz DL. S-adenosylmethionine (SAMe) as treatment for depression: asystematic review. Clin Invest Med. 2005 Jun;28(3):132-9.3. Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW,Reynolds EH: Homocysteine, folate, methylation, and monoaminemetabolism in depression. J Neurol Neurosurg Psychiatry 2000;69:228–232. 4. Herrmann M, Widmann T, Herrmann W. Homocysteine - a newlyrecognised risk factor for osteoporosis. Clin Chem Lab Med.2005;43(10):1111-7. 5. Fayfman M, Niu J, Zhang YQ, Felson DT, Sack B, Aliabadi P,Selhub J, Hunter DJ. The relation of plasma homocysteine toradiographic knee osteoarthritis. Osteoarthritis Cartilage. 2009Jun;17(6):766-71.6. Soeken KL, Lee WL, Bausell RB, Agelli M, Berman BM. Safety andefficacy of S-adenosylmethionine (SAMe) for osteoarthritis. J FamPract. 2002 May;51(5):425-30.7. Hosea Blewett HJ. Exploring the mechanisms behind S-adenosylmethionine (SAMe) in the treatment of osteoarthritis. CritRev Food Sci Nutr. 2008 May;48(5):458-63.8. Lieber CS. S-adenosyl-L-methionine: its role in the treatment ofliver disorders. Am J Clin Nutr. 2002 Nov;76(5):1183S-7S.9. Thompson MA, Bauer BA, Loehrer LL, Cha SS, Mandrekar JN,Sood A, Wahner-Roedler DL. Dietary supplement S-adenosyl-L-methionine (AdoMet) effects on plasma homocysteine levels inhealthy human subjects: a double-blind, placebo-controlled,randomized clinical trial. J Altern Complement Med. 2009May;15(5):523-9.


ChancaPiedraStone BreakerPhyllanthus niruri, is affectionately referred to asChanca Piedra – Spanish for Stone breaker. Quite aname to live up to, but that is what Phyllanthus nirurihas been used for traditionally: to break stones of thekidney and gallbladder. This stone breaking herb hasbeen known in Indian ayurvedic tradition for the last2000 years but being indigenous to many tropical andsubtropical areas worldwide it is also known inTraditional Chinese Medicine and Brazilian,Indonesian and Malaysian traditional folk medicinesystems. “Budhatri” as it is called in India is found inmany Indian homes and is often used for tuberculosis,asthma, bronchitis, jaundice, and anemia.1 In Brazilwhere it is referred to as “Quebra Pedra” it has beenused successfully for urinary tract disorders.1 InIndonesia it has been used for epilepsy, hypertension,toothache, malaria, fever, tetanus and urolithiasis(kidney stones).2 More traditional uses for Chancapiedra include dysentery, influenza, diabetes,jaundice, dyspepsia, gonorrhea, and diarrhea.3

Figure 1. Phyllanthus niruri is affectionately referred toas Chanca Piedra – Spanish for Stone breaker.

The abundance of traditional and widespread use hasled researchers to investigate these famed properties.Research has focused on its anti-viral, stone breakingand liver protecting properties, but P. niruri has alsobeen shown to exhibit diuretic, hypotensive andhypoglycemic actions in humans4, suggesting it as atreatment for hypertension and diabetes. As wellpreliminary research in vitro and in vivo with mice hasshown anti-malarial action5, supporting its potentialas an anti-malarial agent.

Anti-viralAnti-viral activity in Phyllanthus niruri has gained a lotof attention particularly around hepatitis B. Hepatitis Bis a virus that causes inflammation of the liver andoften leads to jaundice. Many who get infected withHepatitis B can become chronic carriers, putting themat risk for liver cirrhosis, cancer and even death. In factmore than one million people die each year fromhepatitis B.6 P. niruri has been commonly usedworldwide as a treatment for jaundice and other liverdisorders.7 In 1987 it was demonstrated that anaqueous extract of Phyllanthus niruri was effective invitro and in vivo on woodchuck livers (woodchuckshave a similar hepatitis carrier state to that of humans)at decreasing the surface antigen of hepatitis B(HBsAg).8 Hepatitis B is monitored by the presence ofthese surface antigens. This spurred much interest inanti-hepatitis B activity within the Phyllanthus genus.Another study, this time on humans, looked at a veryclosely related species9, Phyllanthus amarus, previouslyclassified as P. niruri until they were shown to be twodistinct species. They treated 37 chronic hepatitis Bcarriers with 600mg of P.amarus daily for one monthand found that 59% of the subjects had completely losttheir surface antigen compared to only 4% of theplacebo-treated controls.10

Not only does the Phyllanthus species showeffectiveness against hepatitis B but P. niruri also hasaction against the HIV virus. Extracts of P. niruri haveshown inhibition of HIV-1 reverse transcriptase, whichis an important enzyme in the HIV virus’ replicationprocess.11,12 Niruriside, a phenylpropanoid from P.niruri also has been found to have anti-HIV activity.13 Itdoes this by preventing viral RNA from beingtransported to the cytoplasm, and thus halts thereplication of HIV.


Stone BreakerKidney stones affect many people, approximately 10-12% of the population in developed countries.14 Theestimated cost of healthcare for these numbers was$2.1 billion in the US in 2000.15 There are not manydrug therapies that address kidney stones with successmaking this a substantial healthcare problem.However Phyllanthus niruri works to break these stonesin their tracks. Chanca Piedra acts in more subtle waysthan its name may suggest. Instead of crushing orpounding stones it works to dissolve, allowing passingor prevent these stones from forming in the first place.

Kidney stones, also known as urolithiasis ornephrolithiasis, occur when crystals in urine form fromsalts and accumulate along the inner surface of thekidney, ureter or bladder. Calcium oxalate stonesmake up the majority as they account for 70-80% ofall kidney stones. But stones made of struvite and uricacid can also occur. Many stones are small enough topass unnoticed through the urine, however they canbecome large enough to block the flow of urine or beextremely painful to pass. Many have likened thepassing of kidney stones with the pain of childbirth –making it one of the most painful human experiences.There are inhibitors and promoters of stone formationthat can be monitored in the urine: glycoaminoglycans(GAGs), citrate and magnesium are all consideredendogenous inhibitors of calcium oxalate stoneformation. Excessive calcium in the urine(hypercalcuria) is a marker of increased risk of calciumoxalate stone formation and so is considered apromotor. Factors such as genetics, low fluid intake,high protein and high salt diets are all factors inwhether a person will develop stones.

Studies have shown P. niruri aqueous extract to inhibitcalcium oxalate crystal growth and aggregation bothin vitro and in animal studies.16 In a Brazilian study onstone formation in rats, P. niruri prevented calciumoxalate growth, decreased the number of stones andlowered stone weight.17 Glycoaminoglycans (GAGs),citrate and magnesium were monitored in this study.What they found was a decrease in urinary GAGs,suggesting the mechanism at work was from uptake ofGAGs into the stones resulting in their dissolution.

Figure 2. Cross Section of Kidney with stone

Human studies on P. niruri’s effectiveness to treaturolithiasis have also surfaced. P. niruri was found tonormalize elevated calcium levels in individuals thatwere predisposed to forming calcium stones.18 In thisstudy they were investigating urinary excretion ofpromotors and inhibitors of calcium stones in humans.There was a significant reduction in urinary calciumexcretion thought to be due to the reduction of calciumoxalate crystallization within the kidney tubules.1 Inanother very interesting study, P. niruri was shown toreduce kidney stones in patients receivingextracorporeal shock wave lithotripsy (ESWL), aminimally invasive procedure for breaking up andremoving stones.19 Patients received either the ESWLalone or in combination with 2g of P. niruri daily, theresults showed 93.5% stone free rate in thecombination group compared with 83.3% stone freerate in those treated with just ESWL alone.

Other significant actions of P. niruri that contribute tostone reduction are its antispasmodic effect due to thepresence of alkaloids.20 These help smooth muscle torelax thus allowing stones to pass with greater ease.As well P. niruri has been shown to have analgesicaction21, reducing the pain associated with passingstones. With these stone crushing, smooth musclerelaxing and pain relieving effects, Chanca Piedra is awell-rounded approach for treating stones of theurinary tract.


DetoxificationSo what does Chanca Piedra have to do withdetoxification? The kidneys and the liver are two of ourmain detoxification organs, both of which are targetedby P. niruri. We have already discussed how P. nirurihelps detoxify the kidneys through stone dissolution. P.niruri is also gaining recognition for itshepatoprotection (liver protection) qualities. We haveseen how it works to protect the liver from the hepatitisB virus, but it has also shown effectiveness inprotection from various liver toxins.

The liver, being responsible for detoxifying toxins anddrugs, can become overloaded and be unable todetoxify appropriately leading to elevated liverenzymes (a marker of liver damage) and can inextreme cases lead to acute liver failure. One exampleis Acetaminophen, which causes more overdosehospitalizations than any other medication and its useis the leading cause of acute liver failure in the UnitedStates and the United Kingdom.22 It has beendemonstrated that the protein fraction of P. niruri wasprotective against liver damage induced in mice fromacetaminophen.23 The damage caused by drugs likeacetaminophen is a result of a drastic increase in toxicmetabolites as the liver attempts to detoxify the excessdrug. These toxic metabolites are too great and resultin depletion of the main liver antioxidant: glutathione,allowing the metabolites to cause damage to liver cellsthrough oxidative stress. As Bhattacharjee et al.demonstrated in a rat model, P. niruri protein fractionworked to boost levels of antioxidant enzymes such assuperoxide dismutase (SOD) and catalase (CAT)thereby neutralizing the excessive amounts of freeradicals causing damage.23 Similar studies usingprotein fractions were found to providehepatoprotection against toxin induced liver damagefrom compounds such as carbon tetrachloride24,thioacetamide25, and nimesulide.26 Markers of toxicityfrom these toxins are elevated liver enzymes and withadministration of P. niruri the liver enzymes returned tonormal levels.24

Secret Ingredient?A long list of health benefits such as that claimed byP. niruri, lends the question: what exactly does itcontain that allows for such a diverse range of uses? Itwould be easy if there were one answer to thisquestion, however, as could be expected, ChancaPiedra contains a variety of biologically activeconstituents that allow this plant to exhibit the manyhealth benefits that it does. Among these are: lignans,

tannins, coumarins, terpenes, flavonoids, alkaloids,saponins, and phenylpropanoids.20 Although wholeplant extracts were used traditionally and in manyscientific investigations, several constituents have beenisolated from Chanca Piedra that help to elucidate it’shealing qualities.

Two biologically active lignans are main contributors tothe hepatoprotective and anti-hepatotoxic qualities:phyllanthin and hypophyllanthin.7 These same lignans,as well as two others, niranthin and nirtetralin, arethought responsible for the anti-hepatitis B activity.27

The anti-HIV activity of P. niruri is attributed to a tanninknown as repandusinic acid11 as well as niruriside, aphenylpropanoid.13 P. niruri’s stone breaking actionsare associated with a variety of lignans, alkaloids andflavonoids.1 Some of the alkaloids present also showanti-malarial actions.3 This is naming but a few in along list of compounds while researchers arecontinually isolating others.

Figure 3. Biologically active lignans isolated from P.niruri. Phyllanthin and Hypophyllanthin have beenidentified as the main contributors to P. niruri’s liverprotective and anti-hepatotoxic properties. Niranthinand Nirtetralin have been associated with anti-hepatitis B activity.

This plethora of compounds is working in concert tocreate a diversely acting herb used for millennia totreat a multitude of conditions. Through its action inprotecting the liver against damage induced from livertoxins, oxidative stress, and viral stress, and its abilityto clear the urinary tract through its stone breakingproperties, Chanca piedra is an important addition toany detoxification effort for the liver and kidneys.


References1. Kieley, S., Dwivedi, R. & Monga, M. Ayurvedic medicine andrenal calculi. Journ Endourology 2008; 22(8): 1613-1616.2. Subeki, H.M., Takahashi, K., Yamasaki, M., Yamato, O., Maede,Y., Katakura, K., Kobayashi, S., Chairul, T., Yoshihara, T. Anti-babesial and anti-plasmodial compounds from Phyllanthus niruri.J.Nat.Prod. 2005; 68:537-539.3. Bagalkotkar, G., Sagineedu, S.R., Saad, M.S. & Stanslas, J.Phytochemicals from Phyllanthus niruri Linn. And theirpharmacological properties: a review. J. Pharm. and Pharmac.2006; 58: 1559-1570. 4. Devi, M.V., Satyanarayana, S., Rao, A.S. Effect of Phyllantusniruri on the diuretic activity of Punarnava tablets. J.Res. Edu. Med.1986; 5: 11-12.5. Mustofa, Sholikhah, E.N., Wahyuono, S. In vitro and in vivoantiplasmodial activity and cytotoxicity of extracts of Phyllanthusniruri L. herbs traditionally used to treat malaria in Indonesia.Southeast Asian J. Trop. Med. Public Health. 2007; 38(4): 609-615.6. Liu, J., Lin, H., McIntosh, H. Genus Phyllanthus for chronichepatitis B virus infection a systematic review. J. Viral Hepatitis.2001; 8:358-366.7. Symasundar, K.V. Singh, B., Thakur R.S, Husain, A., Kiso, Y.,Hikino, H. Antihepatotoxic principles of Phyllanthus niruri herbs. J.Ethnopharmacol. 1985; 14: 41-44.8. Venkateswaran, P.S. Millman, I., Blumberg, B.S. Effects of anextract from Phyllanthus niruri on hepatitis B and woodchuckhepatitis viruses: In vitro and in vivo studies. Proc. Natl. Acad. Sci.1987; 84:274-278.9. Lee, S.K. Li, P.T, Lau, D.T, Yung, P.P, Kong, R.Y, Fong, W.F.Phylogeny of medicinal Phyllanthus species in China based onnuclear ITS and chloroplast atpB-rbcL sequences and multiplex PCRdetection assay analysis. Planta Med. 2006; 72:721-726.10. Thyagarajan, S.P., Subramanian, S., Thirunalasundari, T.,Venkateswaran, P.S., Blumberg, B.S. Effect of Phyllanthus amaruson chronic carriers of hepatitis B virus. Lancet 1988: 764-766.11. Ogata T, Higuchi H, Mochida S, Matsumoto H, Kato A, Endo T,Kaji A, Kaji H. HIV-1 reverse transcriptase inhibitor from Phyllanthusniruri. AIDS Res. Hum. Retroviruses 1992;8(11): 1937-44.12. Naik, A.D, Juvekar, A.R. Effects of alkaloidal extract ofPhyllanthus niruri on HIV replication. Indian. J. Med. Sci. 2003;57(9):387-393.13. Qian-Cutrone, J., Huang, S., Trimble, L., Li, H., Lin, P.F., Alam,M., Klohr, S.E., Kadow, K.F. Niruriside, a new HIV REV/RRE bindinginhibitor from Phyllanthus niruri. J.Nat.Prod. 1996; 59:196-199.14. Sowers MR, Jannuasch M, Wood C, Pope SK, Lalhance LL,Peterson B. Prevalence of renal stones in a population based studywith dietary calcium, oxalate and medication exposures. Am JEpidemiol 1998; 147:914

15. Lotan, Y. Economics and cost of care of stones disease. Adv.Chronic Kidney Dis. 2009; 16(1): 5-10.16. Barros, M.E., Lima, R., Mercuri, L.P., Matos, J.R., Schor, N.,Boim, M.A. Effect of extract of Phyllanthus niruri on crystaldeposition in experimental urolithiasis. Urol Res 2006;34:351–357. 17. Freitas AM, Schor N, Boim MA. The effect of Phyllanthus nirurion urinary inhibitors of calcium oxalate crystallization and otherfactors associated with renal stone formation. BJU Int 2002;89:829–834.18. Nishiura JL, Campos AH, Boim MA, Heilberg IP, SchorN.Phyllanthus niruri normalizes elevated urinary calcium levels incalcium stone forming (CSF) patients. Urol Res 2004; 32:362–366.19. Micali S, Sighinolfi MC, Celia A, et al. Can Phyllanthus niruriaffect the effacacy of extracorporeal shock wave lithotripsy forrenal stones? A randomized, prospective, long-term study. J Urol2006; 176:1020–1022.20. Calixto, J.B., Santos, A.R., Filbo, V.C., Yunes, R.A. A review ofthe plants of the genus Phyllanthus: Their chemistry, pharmacologyand therapeutic potential. Med. Res. Rev. 1998; 18(4): 225-258.21. Santos, A.R. Analgesic effects of callus culture extracts fromselected species of Phyllanthus in mice. J Pharm Pharmacol 1994;46:75522. Chun, L.J, Tong, M.J., Busuttil, R.W. Hiatt, J.R. Acetaminophenhepatotoxicity and acute liver failure. J. Clin. Gastroenterol. 2009;43(4): 342-349.23. Bhattacharjee, R. & Sil, P.C. The protein fraction of Phyllanthusniruri plays a protective role against Acetaminophen inducedhepatic disorder via its antioxidant properties. Phytother. 2006; 20:595-601. 24. Bhattacharjee, R. & Sil, P.C. Protein isolate from the herb,Phyllanthus niruri L. (Euphorbiaceae), plays hepatoprotective roleagainst carbon tetrachloride induced liver damage via itsantioxidant properties. Food and Chem. Toxic. 2007; 45:817-826. 25. Sarkar, M.K. Sil, P.C. Hepatocytes are protected by herbPhyllanthus niruri protein isolate against thioacetamide toxicity.Pathophys. 2007; 14:113-120. 26. Chatterjee, M., Sarkar, K., & Sil, P.C. Herbal (Phyllanthus niruri)protein isolate protects liver from nimesulide induced oxidativestress. Pathophys. 2006; 13:95-102. 27. Huang, R.L., Huang, Y.L., Ou, J.C., Chen, C.C., Hsu, F.L.,Chang, C. Screening of 25 compounds isolated from Phyllanthusspecies for anti-human hepatitis B virus in vitro. Phytother. Res.2003; 17:449-453.

Supports the Healthof the Kidneys, Liver

and Gall bladder


Milk ThistleA Historical LiverTreatment

Milk thistle is a plant with a long history in medicine,having been mentioned in every important medicinalrecord of herbs.1 It was widely used as a medicinalplant in traditional European medicine, and its seedshave been used for over 2000 years for a variety ofpurpose.2 Traditional uses have mainly focused on thetreatment of liver diseases, but have also includedgallbladder disorders such as hepatitis, cirrhosis andjaundice.1 Milk thistle was brought to North Americawith European immigration, and was used there as atreatment for such various ailments as gallstones,morning sickness, uterine hemorrhage, andcongestion of the liver, spleen or kidneys.3

Figure 1. Milk Thistle

Currently, milk thistle is still a staple in naturalmedicine. It is commonly included in detoxificationregimes due to its ability to support and protect theliver.4 However, its applications have been extended toother purposes including support for the pancreas, thelungs and the kidneys, prostate disorder, and

dermatology and cosmetics.1 It has also begun to gainattention for its activities against cancer cells and for itseffects in the regulation of cholesterol levels.1 Althoughits actions are somewhat disputed and still not fullyunderstood, the potentials of this remarkable plant fordealing with a wide variety of disorders have caused itto become one of the most studied plants in naturalmedicine.

Silymarin- the Active IngredientThe active ingredient in milk thistle is a flavonoidcomplex known as silymarin, which is extracted fromthe seeds of the plant.1,2 The standardized seed extractcontains approximately 70-80% of silymarinflavolignans, and around 20-40% of a fraction ofpolymeric and oxidized polyphenolic compoundswhich has not been chemically defined.1 The six majorflavolignans are silybin A and B, isosilybin A and B,silychristin, and silydianin. These compounds are likelythe main contributors to silymarin’s beneficial effects.5

In particular, silybin, also known as silibinin, has beenstudied for its effectiveness in liver treatment and otherapplications.1

Figure 2. Active components present in milk thistle


The precise mechanism of action of silymarin iscurrently not well defined, although severalmechanisms have been suggested in scientific studies.1

Silymarin is known to have antioxidant qualities,stopping the damage caused by free radicals, whichare highly reactive by-products of cellularmetabolism.1 It also has anti-inflammatory andimmunomodulatory effects.5 Furthermore, it appearsto have an influence on cholesterol metabolism.1

The Effects of Milk ThistleProtection for the LiverSilibinin’s effectiveness as a liver protective agent hasbeen documented throughout history. Its protectiveeffects appear to be at least partially mediated by itsantioxidant activity.1 It is also thought to intercede withcell signaling pathways, blocking the production ofpro-inflammatory molecules in order to avoid anexcessive inflammatory response. It has been found todo so at a lower concentration than the well-knownanti-inflammatory agent salicylate.1 Furthermore, itsantioxidant effect helps to decrease the damagingcytotoxic effects of various drugs and othercompounds that can damage the liver.1 In animalstudies, silymarin and silibinin were found to be ableto protect mice or rats against liver damage caused bysuch factors as acute ethanol intoxication, carbontetrachloride, cisplatin and acetaminophen.2 Milkthistle is currently recommended by the GermanCommission E for dyspeptic complaints, toxin-inducedliver damage, and hepatic cirrhosis as well as for asupportive therapy for chronic inflammatory liverconditions.6

Effects on Cholesterol LevelsSilibinin has been found to have beneficial effects oncholesterol levels. It is thought that its antioxidantactivity helps to protect cholesterol-transportinglipoproteins.1 It has also been found to influencecholesterol metabolism, and can block a key enzymeinvolved in the synthesis of cholesterol.7 In rats, milkthistle seed oil was found to reduce serum totalcholesterol and triglyceride levels by 84 and 60%.4

Silibinin’s potential in helping to deal with cancer hasbeen the focus of many recent studies. Its ability tointeract with cellular pathways includes the ability tomodulate various regulators of the cell cycle.1 This isimportant in cancerous cells, which have deranged cellcycles and divide too quickly. Cell studies with silibininhave found that it is able to inhibit and to kill abnormalcells of various forms of cancer without damaging

healthy cells.1,8 It is also thought to block theproliferation of cancerous cells.8 For instance, prostatecancer cells incubated with silibinin showed a doseand time-dependent decrease in viability and motility.8

Silibinin’s antioxidant effects also help to protectagainst cellular damage, such as in the case of skindamage caused by UV radiation. This has been testedin both cell and animal studies, in which silibinin wasfound to have beneficial effects when used bothtopically and when fed in the diet.9 Other studies havesuggested that silibinin’s ability to protect against thetoxicity of various drugs may be able to lessen thetoxicity of anticancer agents and enhance theeffectiveness of chemotherapy treatments.2 Studieshave suggested several areas of potential for silibinin,including cleansing and detoxification afterchemotherapy, the prevention of chemotherapy-caused liver damage, and dealing with liver damageafter chemotherapy.2 While the results that have beendiscovered so far suggest that silibinin has a fairlystrong anticancer effect, more studies are needed toconfirm these results.10

Other EffectsSilibinin’s effects may be beneficial in other areas aswell. Its anti-inflammatory effects can help protectneurons from over inflammation, as well as fromtoxicity associated with drugs such as acetaminophen,cisplatin and cyclosporin.10 Silibinin has beensuggested to have protective effects in allergic asthma,likely due to its interference with pro-inflammatorypathways, and its ability to help stabilize cellularmembranes, thus blocking the release of pro-inflammatory molecules.1 Other studies havesuggested that silibinin may help to reduce insulinresistance.11

Clinical TrialsThe effectiveness of milk thistle has been tested inseveral scientific studies and clinical trials.

Its liver protective effects have been the area of themost research. A study of patients with hepatitis Cfound that milk thistle, along with the antioxidantalpha lipoic acid and selenium and with dietary andlifestyle changes, helped to reduce disease markerssuch as serum transaminase levels and viral load.12 Ina randomized double-blind study, patients sufferingfrom alcoholic cirrhosis of the liver were found to havea significantly higher survival rate when givensilymarin compared to control groups.13


Silibinin’s effects on cholesterol have also been tested.In 15 patients who had had their gallbladdersremoved, the administration of 420 mg of milk thistleextract per day for 30 days resulted in a significantdecrease in the concentrations of biliary cholesterolcompared to patients who were given a placebo.Researchers suggested that the silibinin may havehelped to decrease cholesterol synthesis in the liver.12

In another study, 14 type II hyperlipidemic patientswere given 420 mg of milk thistle extract per day forseven months. The milk thistle was suggested to havean effect on decreased total cholesterol in the serumand an increase in high-density (good) cholesterollevels in the blood.14

In a controlled study of insulin-treated patients, 600mg of milk thistle extract per day for 12 monthsappeared to significantly reduce fasting glucose levels,mean daily glucose levels and decrease fasting insulinlevels compared to controls.11 In a randomizedcontrolled trial of alcoholic diabetic patients, 600 mgof milk thistle extract per day for 6 months wasassociated with significant decreases in the meanlevels of fasting blood glucose, daily blood glucoseand daily insulin need compared with controls and thepatients’ own baseline levels.13

In 30 patients with end-stage diabetic nephropathy,milk thistle extract appeared to help normalize theregulatory effects in the immune system, for instance,by helping to activate T cells and significantly decreasethe release of a key pro-inflammatory molecule.15

Safety Profile Overall, milk thistle is considered to be extremelysafe.1 Side effects in clinical trials have been mainlylimited to a very low frequency of gastrointestinalsymptoms.1 The majority of people have no adversereactions. It has been suggested that up to 1.44 g ofsilibinin administered daily in an oral form for over aweek is safe.2

Silibinin undergoes metabolism by both phase I andphase II enzymes. Its interaction with these enzymeshas led to fears of its effect on the metabolism of otherdrugs. Most studies in this area have found thatsilibinin does not interact significantly with many otherdrugs. Studies with several common drugs found ageneral lack of associated toxicity and a lowinterference in their metabolism when combined withmilk thistle16; however, a physician should be consultedbefore taking milk thistle with other medications due tothe potential for interference.2

Milk Thistle- the Past and the FutureWhile milk thistle has a long history of medicinal use,its effectiveness in human studies has been somewhatcontroversial because of occasionally conflictingresults in scientific literature.1 This is likely due to thefact that studies in the past have tended to use variablycomposed silymarin preparations.1 As the ingredientbecomes more standardized, and as its mechanism ofaction becomes better understood, its effectiveness willbe more clearly determined. Thus far, its potential isacknowledged by many clinical trials, as well as by itshistorical record. It is a plant that will continue to holdinterest for those looking to optimize the health of theirliver.

References1. Gazak R, Walterova D and Kren V. Silybinin and silymarin- newand emerging applications in medicine. Current MedicinalChemistry. 2007;14:315-338.2. Wu JW, Lin LC and Tsai TH. Drug-drug interactions of silymarinon the perspective of pharmacokinetics. Journal ofEthnopharmacology. 2009;121:181-193.3. Abascal K, Yarnell E. The many faces of silybum marianum (milkthistle) part I. Altern Complement Ther. 2003;9:170-175.4. Greenlee H, Abascal K, Yarnell E and Ladas E. Clinicalapplications of silybum marianum in oncology. Integrative CancerTherapies. 2007;6:158-165.5. Schrieber SJ, Wen Z, Vourvahis M, Smith PC, Fried MW, KashubaADM, Hawke RI. The pharmacokinetics of silymarin is altered inpatients with hepatitis C virus and nonalcoholic fatty liver diseaseand correlates with plasma caspase-3/7 activity. Drug Metabolismand Disposition. 2008;36(9):1909-1916.

Beneficial Actions ofMilk Thistle

• Liver protection• Support for liver disorders,

including hepatitis C and cirrhosis• Reduction of the toxicity of

chemotherapy drugs• Anti-cancer effects• Anti-inflammatory actions• Cholesterol reduction• Blood sugar balancing effects• Immune system support


6. The Complete German Commission E Monographs: TherapeuticGuide to Herbal Medicines 1st Ed. Baltimore, MD: LippincottWilliams & Wilkins:1998.7. Nassuato G, Iemmolo RM, Strazzabosco M, Lirussi F, Deana R,Francesconi MA, Muraca M, Passera D, Fragasso A, Orlando R etal. Effect of Silibinin on biliary lipid composition. Experimental andclinical study. J Hepatol. 1991;12(3):290-295.8. Mokhtari MJ, Motamed N, Shokrgozar MA. Evaluation ofsilibinin on the viability, migration and adhesion of the humanprostate adenocarcinoma (PC-3) cell line. Cell BiologyInternational. 2008;32:888-892.9. Gu M, Dhanalakshmi S, Singh RP and Agarwal R. Dietaryfeeding of silibinin prevents early biomarkers of UVB radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis. CancerEpidemiology Biomarkers and Prevention. 2005;14:1344-1349.10. Dietzmann J, Thiel U, Ansorge S, Neumann KH, Tager M. Thiol-inducing and immunoregulatory effects of flavonoids in peripheralblood mononuclear cells from patients with end-stage diabeticnephropathy. Free Radic Biol Med. 2002;33(10):1347-1354.11. Velussi M, Cernigoi AM, De Monte A, Dapas F, Caffau C, ZiliM. Long-term (12 months) treatment with an anti-oxidant drug(silymarin) is effective on hyperinsulinemia, exogenous insulin needand malondialdehyde levels in cirrhotic diabetic patients. J Hepatol1997;26(4):871-879.

12. Berkson BM. A conservative triple antioxidant approach to thetreatment of hepatitis C: combination of alpha lipoic acid (thiocticacid), silymarin, and selenium: three case histories. Med Klin.1999;94(suppl 3):84-89.13. Velussi M, Cernigoi AM, Viezzoli L, et al. Silymarin reduceshyperinsulinemia, malondialdehyde levels, and daily insulin need incirrhotic diabetic patients. Curr Ther Res 1993;53(5):533-545.14. Somogyi A, Ecsedi GG, Blazovics A, Miskolczi K, Gergely P,Feher J. Short term treatment of type II hyperlipoproteinaemia withsilymarin. Acta Med Hung. 1989;46:289-295.15. Tamayo C and Diamond S. Review of clinical trials evaluatingsafety and efficacy of milk thistle (silybum marianum Gaertn.).Integrative Cancer Therapies. 2007;6:146.16. Sridar C, Goosen TC, Kent UM et al. Silybin inactivatescytochromes P450 3A4 and 2C9 and inhibits major hepaticglucuronosyltransferases. Drug Metabl. Dispos. 2004;32(6):587-594.

NAC Sustained™

An Important Antioxidant

• Protects the heart

• Boosts levels ofGlutathione

• Improves immunity

• Protects against toxins

Comprehensive Liver Support• Promotes Detoxification

• Stimulates Liver Regeneration

Increases Antioxidant Levels• Stimulates Glutathione Production

• Assists Liver Detoxification

Reduces Harmful Homocysteine Levels• Supports Detoxification of the Amino Acid Homocysteine

• Supports Liver and Cardiovascular Health

Supports Liver and Kidney Health• Protects the Liver from Toxins

• Helps Eliminate Gallstones and Kidney Stones

Supports Mood and Liver Function• Promotes Detoxification

• Relieves Mood Disorders

www.aorpro.caAdvancedOrthomolecular Research

Innovative Research& Scientific Integrity

AOR 3900 12th Street NE, Calgary, Alberta T2E 8H9 Canada

30 Vegi‑CapsServing Size: 1 CapsuleSGS 300 mg(standardized to contain 30 mg glucoraphaninglucosinolate)Wasabia japonica extract 80 mgNon‑medicinal ingredients:Capsule; hypromellose, water.

Produced under patent US2006/010032licensed from Caudill Seed Inc.

Caution: Take with a light mealPregnancy/Nursing: Do not use.Key Feature: Supports phase IIdetoxification.

SGS is a precursor to sulforaphaneSulforaphane is a potent inducer of phase II liverdetoxification

See p.9 for more information

D‑Tox 2™

AOR Professional is only available to registeredmedical practitioners

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