Category Archives: Detoxification

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Support and Enhancement of Phase II Detoxification Pathways Using Foods, Food-Derived Components and Nutrients

Phase II Detoxification Pathways

There are 6 Phase II detoxification pathways in the body.  Each conjugation pathway serves a specific purpose of detoxifying certain toxins and requires specific nutrients to function.  These 6 detoxification pathways include:

  • Glutathione conjugation
  • Methylation
  • Sulfation
  • Acylation/Glycation
  • Acetylation
  • Glucuronidation

These 6 conjugation pathways are found primarily in the liver and in various other locations within the body:

Locations of Phase 2 Conjugation
Pathways

Conjugation System Location in Body
Acylation/Glycation conjugation liver, kidney
Glutathione conjugation liver, kidney
Glucuronidation liver, kidney, intestine, lung, skin, prostate,
brain
Acetylation liver, lung, spleen, gastric mucosa, RBCs,
lymphocytes
Sulfation liver, kidney, intestine
Methylation liver, kidney, lung,
CNS

Source:  Liston HL, Markowitz JS, DeVane CL, (October 2001). “Drug glucuronidation in clinical psychopharmacology”. J Clin Psychopharmacol 21 (5): 500–15.doi:10.1097/00004714-200110000-00008. PMID 11593076

Phase II Conjugation Enzymes

After a toxin (xenobiotic) has gone through the process of becoming hydrophilic (water-soluble) through reactions overseen by Phase I enzymes, its intermediate molecules are then conjugated with endogenous hydrophilic enzymes.  These endogenous enzymes include:  1

  • glucuronic acid (glucuronyl transferases)
  • sulfate (sulfotransferases)
  • glutathione (glutathione transferases)
  • amino acids (amino acid transferases)
  • acetyl group (N-acetyl transferases)
  • methyl group (N- and O-methyltransferases)

These enzymatic reactions result in an increase in the hydrophilicity of the metabolite leading to enhanced excretion in the bile and/or urine.

The modulation of phase II enzymes by food-based bioactive compounds can support and enhance the Phase II process, especially when there are issues with:

  • genetic polymorphisms that inhibnit Phase II
  • high toxic burden due to chronic exposure to environmental pollutants
  • overactive Phase I activity
  • hormonal imbalance

Each of the 6 Phase II pathways are supported and enhanced by various foods, food-derived components and nutrients.

Amino Acid Conjugation:  Acylation/Glycation

In acylation/glycation, toxins are attached to amino acids, especially glycine. A low protein diet can inhibit acylation/gylcation.  Acylation/glycation detoxifies compounds like benzoate, aspirin and toluene (a widely used industrial solvent).

AminoAcidConjugation

Glucuronidation

Glucuronic acid is a metabolite of glucose that can be attached to toxins. This pathway is used as a back-up for sulfation or acylation/glycination. It is used to eliminate chemical and bacterial toxins, excess steroidal hormones (like estrogen), toxins from fungal infections and a variety of chemical toxins such as nitrosamines, aromatic amines, alcohols and phenols.

Glucuronidation

Glutathione Conjugation

Attaching toxins to glutathione helps to detoxify and eliminate poisons in the liver, lungs, intestines and kidneys. Glutathione helps the body get rid of a wide variety of chemical compounds including aromatic disulphides, paththalene and anthracene.

GlutathioneNutrients

Glutathione

Methylation

Methylation attaches toxins to the amino acid methionine. This process occurs in every cell of the body and helps the body get rid of excess hormones and neurotransmitters, including steroidal hormones like estrogen, adrenaline, dopamine, melatonin, histamine and serotonin. It also helps eliminate homecysteine, a compound associated with increased risk of heart disease. A variety of chemicals (amines, phenols, etc.) are also eliminated through methylation.

Methylation

Sulfation

Sulfation eliminates toxins by attaching them to sulphate. This is the principle pathway for eliminating excess neurotransmitters, several drugs (including acetaminophen, some food additives and toxins from intestinal bacteria. It also removes many forms of environmental toxins. Reduced sulfation may be involved in Parkinson’s disease, Alzheimer’s disease and other nervous system disorders and in environmental illness.

Sulfation

Acetylation

Acetylation involves attaching acetyl co-A to toxins for elimination. People who are chemically sensitive are usually slow acetylators. Slow acetylation enhances the toxicity of drugs because it prolongs their life span in the body. Acetylation is used to eliminate excess histamine, serotonin, sulfa drugs, PABA and chemicals like sulphur amides and hydranzines.

Acetylation

Download Phase II Infographics in PDF format:  

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Glutathione conjugation (page 1)

Glutathione conjugation  (page 2)

Methylation

Sulfation

Acylation/Glycation

Acetylation

Glucuronidation

Maximizing The Sulforaphane Content of Broccoli and Broccoli Sprouts

Glucosinolates

Glucosinolates are natural components of many pungent plants that occur as secondary metabolites of most of the Brassicales family, or the cruciferous vegetables.   When these vegetables are chewed, a pungent taste arises due to the breakdown products of glucosinolates.

Each vegetable, sprout and seed usually contains more than one glucosinolate.  However, certain vegetables, sprouts and seeds may contain a predominant amount of one glucosinolate.  An example is the following:

  • Broccoli and broccoli sprouts contain large amounts of glucoraphanin
  • Mustard seeds and Brussel sprouts contain a large amount of Sinigrin
  • Garden cress and cabbage contain a large amount of glucotropaeolin
  • Watercress contains a large amount of gluconasturtiin

The total number of documented glucosinolates from nature can be estimated to around 132, as of 2011.  1  For purposes of this article, we will focus on the 4 most important glucosinolates and the ones that have been the subject of the majority of medical research.  These 4 glucosinolates include:

  • Gluconasturtiin
  • Glucoraphanin
  • Glucotropaeolin
  • Sinigrin

Gluconasturtiin, also known as phenethylglucosinolate, is a widely distributed glucosinolate in cruciferous vegetables.  The name is derived from it occurrence in watercress which has the botanical name Nasturtium officinale.

Glucoraphanin is a glucosinolate distributed in broccoli, Brussel sprouts, cabbage and cauliflower.  It is also found in large amounts in young sprouts of cruciferous vegetables, like broccoli sprouts.

Glucotropaeolin is a phytochemical from Tropaeolum majus, which is commonly known as garden nasturtium, Indian cress or monks cress.  It is also found in cabbage.

Sinigrin is widely distributed in the plants of the Brassicaceae such as Brussel sprouts, broccoli, horseradish and black mustard seeds.

Myrosinase

Each of the vegetables, sprouts and seeds contain the enzyme myrosinase, which is activated when the vegetable, sprout or seeds is damaged (chopped or chewed) in the presence of water.  The glucosinolate converts to an isothiocyanate (or thiocyanate) through the enzymatic activity of myrosinase.  These isothiocyanates are the defensive substances of the plant.

Thus glucosinolates are the precursors to isothiocyanates through the breakdown of the enzyme myrosinase.  Myrosinase activity on the glucosinolate also continues in the gastrointestinal tract through intestinal bacteria which allows for some further formation and absorption of isothiocyanates. 2

Image result for glucosinolates myrosinase pathway

Figure 1:  Glucosinolates Hydrolysis by Myrosinase  (Source:  Linus Pauling Institute – Isothiocyanates)

Sulforaphane

Sulforaphane is obtained from cruciferous vegetables such as broccoli, broccoli sprouts, Brussels sprouts, and cabbages. It is produced when the enzyme myrosinase transforms glucoraphanin into sulforaphane upon damage to the plant (such as from chewing), which allows the two compounds to mix and react.

When the enzyme myrosinase acts on glucoraphanin, an unstable intermediate is produced.  This unstable intermediate is then acted on by a protein called epithiospecifier protein (ESP) to produce sulforaphane or sulforaphane nitrile.

If epithiospecifier protein (ESP) is abundant in the plant and is active, it will convert this unstable intermediate to a sulforaphane nitrile.  This sulforaphane nitrile has no anti-cancer activity.  3 

If epithiospecifier protein (ESP) is not abundant and is low-active, then it will convert this unstable intermediate into sulforaphane.  Sulforaphane has anti-cancer activity.  4

Image result for sulforaphane nitrile

Figure 2.  ESP converts into sulforaphane and sulforaphane nitrile  (Source

Decreasing Epithiospecifier Protein Activity

A research paper entitled “Heating decreases epithiospecifier protein activity and increases sulforaphane formation in broccoli”, published in Phytochemistry in 2004, examined the effects of heating broccoli florets and sprouts on sulforaphane and sulforaphane nitrile formation, to determine if broccoli contains ESP activity, then to correlate heat-dependent changes in ESP activity, sulforaphane content and bioactivity, as measured by induction of the phase II detoxification enzyme quinone reductase (QR) in cell culture.  5

Researchers experimented with cooking broccoli at different temperatures and at different times periods.  They then measured the point at which the epithiospecifier protein is destroyed. 

What they learned was that they only had to heat the broccoli for a short time in order to destroy the epithiospecifier protein thus yielding more sulforaphane and little to no sulforaphane nitrile.

Specifically, to maximize the sulforaphane in broccoli, they found that heating it for 10 minutes at 140 degrees Fahrenheit (60 degrees Celsius).  This can translate to steaming broccoli lightly for about 3 to 4 minutes.

When they heated the broccoli for 10 minutes at 158 degrees Fahrenheit (70 degrees Celsius) it not only destroyed the epithiospecifier protein but also the sulforaphane content. 

Broccoli sprouts

Broccoli sprouts are germinated from broccoli seeds for about 3 days minimum and 5 days maximum. 

Image result for broccoli sprouts

Figure 3.  Broccoli sprouts

Broccoli sprouts that are 3 days old have very concentrated sources of glucoraphanin.  It is estimated that broccoli sprouts have 10 to 100 times more glucoraphanin by weight than mature broccoli plants.  6

Three-day-old broccoli sprouts have been shown to be highly effective in reducing the incidence, multiplicity, and rate of development of mammary tumors in dimethylbenz(a)anthracene-treated rats.  7  Small quantities of crucifer sprouts may protect against the risk of cancer as effectively as much larger quantities of mature vegetables of the same variety.

The activity of the epithiospecifier protein (ESP) in broccoli sprouts fluctuates based on the number of days the sprouts have grown.  8

ESP activity increases up to day 2 after germination before decreasing again to seed activity levels at day 5.

Thus, the optimal amount of days to grow broccoli sprouts is probably 5 days since the amount of glucoraphanin in broccoli seeds remains more or less constant as those seeds germinate and grow into mature plants.  9

When the researchers heated broccoli sprouts for 10 minutes at 158 degrees Fahrenheit (70 degrees Celsius) in water, it minimized the epithiospecifier protein and maximized the sulforaphane content.

Heating broccoli sprouts in water under these exact specifications will increase the sulforaphane content for maximum anti-cancer benefit.

Compare the technique of heating broccoli sprouts in water with the study from China where they increased the sulforaphane yield by freezing the broccoli sprouts:

An example of heating broccoli sprouts in water using the specifications of the researchers can be viewed in the experiment conducted by Dr. Rhonda Patrick:

Rice Bran Fiber found to bind effectively to toxic Polychlorinated Biphenyls (PCBs) more than other tested natural substances

A polychlorinated biphenyl (PCB) is an organic chlorine compound that were used as lubricants and coolants in transformers, capacitors, and electronic equipment because of a high resistance to heat.

Unfortunately PCBs do not break down in the environment and bio-accumulate in animals and humans due to it being a very stable compound. 

As a result, and because of PCBs’ environmental toxicity and classification as a persistent organic pollutant, PCB production was banned from use in the US in 1979 by the Environmental Protection Agency (EPA). However, due to the persistence of PCBs in the environment, PCBs continue to leach into soil and groundwater from hazardous waste sites and landfills.

Humans are exposed to PCBs through our food chain by eating fish, meat and dairy products.  PCB’s are fat soluble and are not excreted by the body but instead are stored in fat cells, resulting in accumulations of PCBs over a lifetime.  This long term bio-accumulation increases a person’s body burden of PCBs.

A number of symptoms in humans of PCB exposure have been identified:

  • Severe acne
  • Rash
  • Eye irritation
  • Liver damage
  • Weakened immune system
  • Chemical sensitivity
  • Allergies
  • Obesity
  • Fatigue
  • Certain cancers
  • Developmental disorders

  

You can test for PCBs in your blood from Genova Diagnostics (GDX):

Polychlorinated Biphenyls (PCBs) Profile

A study published in the Journal Of Nutritional Biochemistry in January 2005 found that rice bran flour (RBF) was effective in binding and accelerating the fecal excretion of polycyclic biphenyl (PCBs), polychlorinated dibenzofurans (PCDFs), polychlorinated-p-dioxines (PCDDs) and various mutagens and carcinogens.  RBFs binding effects were related to its high lignan content.  1

Other dietary fibers were testing and compared to RBF.  These other dietary fibers included:

  • corn
  • wheat bran
  • spinach
  • Hijiki (a kind of seaweed)
  • sweet potatoes
  • burdock fibers

The binding effects to RBF and pulp lignin were obtained at ratios of over 90%, while corn fiber and cellulose were at ratios of 4-30%.

It was also found that RBF was capable of binding even conjugates containing mutagens such as glucuronides and sulfates, as well as metabolites in urine.  

Freezing Broccoli Sprouts Increases Sulforaphane Yield

Three-day old broccoli sprouts are concentrated sources of glucoraphanin, which is the precursor to sulforaphane.  Fresh broccoli sprouts contain 10 to 100 times more glucoraphanin by weight than mature broccoli plants. 1  Fresh broccoli sprouts can contain at least 73 mg of glucoraphanin (also called sulforaphane glucosinolate) per 1-oz serving.

A study from 2015 published in the journal RSC Advances by researchers from the College of Food Science and Technology, Nanjing Agricultural University, Nanjing, People’s Republic of China and the College of Food Science and Engineering, Qingdao Agricultural University, Qingdao, People’s Republic of China, investigated whether freezing broccoli sprouts would have an effect on glucoraphanin and ascorbic acid content, myrosinase activity, sulforaphane and sulforaphane nitrile formation.  2

The researchers froze broccoli sprouts at −20 °C (DF-20), −40 °C (DF-40) and −80 °C (DF-80) or stored at −20 °C (LN-20), −40 °C (LN-40) and −80 °C (LN-80) after being frozen in liquid nitrogen for 5 min or always frozen in liquid nitrogen (LN).

The results showed the following:

  • glucoraphanin content was not significantly affected by freezing
  • myrosinase activity was enhanced
  • sulforaphane yield  was increased by 1.54–2.11 fold
  • sulforaphane nitrile formation decreased
  • ascorbic acid content was decreased

By freezing fresh broccoli sprouts, sulforaphane can be increased by on average 1.825 times its original value when fresh and not frozen. 

Eating frozen broccoli sprouts may not be very appetizing.  Instead it is recommended to use the frozen broccoli sprouts in a smoothie.  Make sure you use the broccoli sprouts straight from the freezer and do not allow them to thaw.  

Increasing Nrf2: A Master Regulator of the Aging Process

Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor. The Nrf2 pathway is “the primary cellular defense against the cytotoxic effects of oxidative stress.”

Activation of Nrf2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:

  • NAD(P)H quinone oxidoreductase 1 (Nqo1)
  • Glutamate-cysteine ligase, catalytic (Gclc) and glutamate-cysteine ligase, modifier (GCLM)
  • Heme oxygenase-1 (HMOX1, HO-1)
  • The glutathione S-transferase (GST) family
  • The UDP-glucuronosyltransferase (UGT) family
  • Multidrug resistance-associated proteins (Mrps)

A wide variety of dietary components have been shown in vitro or cell culture to activate Nrf2 and directly increase activity of phase II enzymes; these include:

  • epigallocatechin gallate (EGCG)
  • resveratrol
  • curcumin and its metabolite tetrahydrocurcumin, which has greater phase II activity
  • cinnamaldehyde
  • caffeic acid phenyethyl ester
  • alpha lipoic acid
  • alpha tocopherol
  • lycopene
  • apple polyphenols (chlorogenic acid and phloridzin)
  • gingko biloba
  • chalcone
  • capsaicin
  • hydroxytyrosol from olives
  • allyl sulfides from garlic
  • chlorophyllin
  • xanthohumols from hops

The beneficial effects of these phytochemicals have been demonstrated in numerous animal and human studies, particularly their chemopreventative and antioxidant abilities; these effects may be explained by their indirect stimulation of antioxidant enzyme production and phase II detoxification through Nrf2 signaling. (Source: Life Extension)


References:

Yuan JH, Li YQ, Yang XY. Inhibition of epigallocatechin gallate on or- thotopic colon cancer by upregulating the Nrf2-UGT1A signal path- way in nude mice. Pharmacology 2007; 80: 269 – 78

Hsieh TC, Lu X, Wang Z, Wu JM. Induction of quinone reductase NQO1 by resveratrol in human K562 cells involves the antioxidant response element ARE and is accompanied by nuclear translocation of tran-scription factor Nrf2. Med Chem 2006; 2: 275 – 85

Nayak S and Sashidhar RB. Metabolic intervention of aflatoxin B1 toxicity by curcumin. J Ethnopharmacol 2010;127 (3) : 641-4

Osawa T. Nephroprotective and hepatoprotective effects of curcuminoids. Adv Exp Med Biol 2007;595 : 407-23

Liao BC, Hsieh CW, Liu YC, Tzeng TT, Sun YW, Wung BS. Cinnamaldehyde inhibits the tumor necrosis factor-alpha-induced expression of cell adhesion molecules in endothelial cells by suppressing NF-kap- paB activation: Effects upon IkappaB and Nrf2. Toxicol Appl Pharmacol 2008; 229: 161 – 71

Lii CK, Liu KL, Cheng YP et al. Sulforaphane and alpha-lipoic acid upregulate the expression of the pi class of glutathione S-transferase through c-jun and Nrf2 activation. J Nutrition 2010;140 (5) : 885-92

Feng Z, Liu Z, Li X, et al. α-Tocopherol is an effective Phase II enzyme inducer: protective effects on acrolein-induced oxidative stress and mitochondrial dysfunction in human retinal pigment epithelial cells. J Nutr Biochem 2010;21 (12) : 1222-31

Wang H and Leung LK. The carotenoid lycopene differentially regulates phase I and II enzymes in dimethylbenz[a]anthracene-induced MCF-7 cells. Nutrition 2010;26 (11-12) : 1181-7

Veeriah S, Miene C, Habermann N et al. Apple polyphenols modulate expression of selected genes related to toxicological defence and stress response in human colon adenoma cells. Int J Cancer 2008;122 (12) : 2647-55

Liu XP, Goldring CE, Wang HY, Copple IM, Kitteringham NR, Park BK. Extract of Ginkgo biloba induces glutathione-S-transferase subunit-P1 in vitro. Phytomedicine 2009; 16(5):451–455

Liu YC, Hsieh CW, Wu CC, Wung BS. Chalcone inhibits the activation of NF-kappaB and STAT3 in endothelial cells via endogenous electrophile. Life Sci 2007; 80: 1420 – 30

Joung EJ, Li MH, Lee HG, Somparn N, Jung YS, Na HK et al. Capsaicin in- duces heme oxygenase-1 expression in HepG2 cells via activation of PI3K-Nrf2 signaling: NAD(P)H:quinone oxidoreductase as a potential target. Antioxid Redox Signal 2007; 9: 2087 – 98

Zhu L, Liu Z, Feng Z et al. Hydroxytyrosol protects against oxidative damage by simultaneous activation of mitochondrial biogenesis and phase II detoxifying enzyme systems in retinal pigment epithelial cells. J Nutr Biochem 2010;21 (11) : 1089-98

Gong P, Hu B, Cederbaum AI. Diallyl sulfide induces heme oxygenase-1 through MAPK pathway. Arch Biochem Biophys 2004; 432: 252 – 60

Zhang Y, Guan L, Wang X, Wen T, Xing J, Zhao J. Protection of chloro- phyllin against oxidative damage by inducing HO-1 and NQO1 ex- pression mediated by PI3K/Akt and Nrf2. Free Radic Res 2008; 42: 362–71

Dietz BM, Kang YH, Liu G et al. Xanthohumol isolated from Humulus lupulus Inhibits menadione-induced DNA damage through induction of quinone reductase. Chem Res Toxicol 2005;18 (8) : 1296-305

Surh YJ, Kundu JK, Na HK. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 2008;74 (13) : 1526-39


Informational Reference:

Nrf2.com  

Free E-Book: The Health and Medicinal Benefits of Ashitaba

Ashitaba, which is the common name used in Japan, is botanically known as Angelica keiskei or Angelica Keiskei Koidzumi. The English translation of the Japanese word “Ashitaba” (アシタバ or 明日葉) is “Tomorrow’s Leaf”. Ashita means ‘tomorrow and ba means ‘leaf.’ The name stems from the plant’s ability to quickly regenerate new leaves after taking cuttings. This give an indication of its potential for longevity of life.

asitab_5

Ashitaba plant

There are two separate substances (products) that are derived from the Ashitaba plant.

The first is the hot-air dried powder of Ashitaba from the leaves and stems. The color of this powder is bright green. The leaves of the Ashitaba plant contain approximately 0.25% to 0.35% chalcones.

The second is the powder made from the unique yellow sap which is collected from the Ashitaba’s stem. It is commonly called Ashitaba Chalcone Powder which consists up to 8% chalcones. The color of Ashitaba Chalcone Powder is bright yellow and is a fat-soluble substance.

Although the green Ashitaba powder from the leaves and stems provide nutritional and health benefits, it is the Ashitaba Chalcone Powder (bright yellow powder from the sap of the stem) that is the Chalconoids are natural phenols related to chalcone. They form the central core for a variety of important biological compounds.

997422_orig

Chalcone sap from Ashitaba stem

Chalcones are the active factors in Angelica Keiskei Koidzumi. At least 20 chalcones have been identified in Angelica Keiskei.

Ashitaba contains a thick, sticky yellow sap, which is not found in other celery plants, and are unique to this strain of angelica. This yellowish element in Ashitaba contain the chalconoids.

 

Download the Free E-Book (PDF): The Health and Medicinal Benefits of Ashitaba

Left-click to download into new window, then right-click (in new window) to save as PDF file.

The Detoxification and Biotransformation System in the Human Body

Detoxification Pathways

There are 6 main detoxification organs or systems in the human body:

  • Liver (processes and packages toxins) (70% of detoxification)
  • Lungs (gas exchange of oxygen and carbon dioxide)
  • Gastrointestinal Tract (excretes waste)
  • Skin (sweat)
  • Kidneys (urination)
  • Endothelial cells of the blood brain barrier

The intestines, liver and kidneys are the primary organs of detoxification.

Biotransformation enzymes exist in the smooth endoplasmic reticulum, cystosol (intracellular fluid) and to a lesser degree in the membranes of the mitochondria, nuclei and lysosomes (small spherical organelles) of the liver’s hepatocytes. The kidneys and lungs are the next major biotransformation sites, but only at 10 – 30% of the livers capacity. The skin, nasal mucosa and intestinal mucosa also have some biotransformation capacity.

Other sites of detoxification metabolism include epithelial cells of the gastrointestinal tract, lungs, kidneys, and the skin. These sites are usually responsible for localized toxicity reactions.

Once an unwanted compound has been completely bio transformed and removed from the cell, it will then be eliminated from the body via – kidneys, bowels, breath, sweat, saliva or hair – completing the detoxification process.

Toxins that the body is unable to eliminate build up in the tissues and typically stored in the adipose (fat) tissue.

Liver Detoxification

Almost 2 quarts of blood pass through the liver every minute for detoxification. Filtration of toxins is absolutely critical for the blood from the intestines because it is loaded with bacteria, endotoxins, antigens – and tight body complexes, and various other toxic substances.

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Figure 1:  Detoxification pathways

Intermediary Metabolites  and Pathological Detoxifiers

The transformation of xenobiotics into more chemically active toxins can cause several problems. A significant side effect of all this metabolic activity is the production of free radicals as xenobiotics are transformed by phase 1. Without adequate free radical defenses, every time the liver neutralizing toxins, it is damaged by the free radicals that are produced.

The most important antioxidant for neutralizing free radicals produced by phase 1 byproducts is glutathione. In the process of neutralizing free radicals glutathione is oxidized to glutathione disulfide. Glutathione is required for one of the phase 2 detoxification processes namely glutathione conjugation. When high levels of toxic exposure produces so many free radicals from phase 1, all of glutathione is used up, and glutathione conjugation stops working.

Another potential problem occurs because the toxins transformed into intermediary metabolites by phase 1 can be more toxic than the original toxin. Unless these intermediary metabolites are quickly removed from the body by phase 2 detoxification pathways, they can cause widespread problems. Therefore, the rate at which phase 1 produces intermediary metabolites must be balanced by the rate at which phase 2 finishes the process. Unfortunately, some people have a very active phase 1 detoxification system but very slow phase 2 enzymes. These people are described as “pathological detoxifiers” because they’re over active phase 1 results in a buildup of more harmful intermediate products, which phase 2 cannot detoxify quickly enough. The end result is that these people suffer severe toxic reaction to environmental poisons.

Gastrointestinal Tract Detoxification

About 25% of detoxification occurs within the cells lining the intestines, the remainder occurs in the liver.

Most literature on detoxification refers to liver enzymes, as the liver is the site of the majority of detoxification activity for both endogenous and exogenous compounds. However, the first contact the body makes with the majority of xenobiotics is the gastrointestinal tract. the gastrointestinal tract is the second major site in the body for detoxification. Detoxification enzymes such as Cyp3A4 and the antiporter  activities have been found in high concentrations at the tip of villi in the intestine.

Adequate first pass metabolism of xenobiotics by the gastrointestinal tract requires integrity of the gut mucosa. Compromised barrier function of the mucosa will easily allow xenobiotics to transit into the circulation without opportunity for detoxification. Therefore, support for healthy gut mucosa is instrumental in decreasing toxic load.

The gastrointestinal tract influences detoxification in several other ways. Gut microflora can produce compounds that either induce or inhibit detoxification activities.

Pathogenic bacteria can produce toxins that can enter circulation and increase toxic load.

Detoxification through the intestinal tract is enhanced by fasting, mono, high fiber and mucus-less diets, ingestion of substances such as charcoal, mud and grasses, and in some cases by the use of cathartics that either lubricate, increase fluidity, add bulk or stimulate peristaltic motion.

Gastrointestinal health and gut permeability also play a role in detoxification. Increased gut permeability allows for increased absorption of xenobiotics and toxins, which are processed and removed by the liver, thus increasing the demands on the liver detoxification system. Impaired gastrointestinal integrity can be improved via dietary support as well as prebiotics and probiotics.

Fiber is particularly important for supporting detoxification. Dietary fibers bind not only carcinogens, bile acids, and other potentially toxic agents, it also promotes a faster transit time and therefore less opportunity for toxin interaction with the intestinal lining and reabsorption. In addition, increased fiber intake helps positively balance the intestinal microflora, which minimizes endotoxin production from pathogenic bacteria.

Brain Detoxification: The Glymphatic System

The cytochrome P450 enzyme system is found in other parts of the body, especially the brain cells.

The glymphatic system (or glymphatic clearance pathway) is a functional waste clearance pathway for the mammalian central nervous system (CNS). The brain is not part of the body’s lymphatic system which is responsible for removing extracellular proteins, excess fluid, and metabolic waste products from peripheral tissues.

Glymphatic flow answers the long standing question of how the sensitive neural tissue of the CNS functions in the absence of a conventional lymphatic circulation. The pathway consists of a para-arterial influx route for cerebrospinal fluid (CSF) to enter the brain parenchyma, coupled to a clearance mechanism for the removal of interstitial fluid (ISF) and extracellular solutes from the interstitial compartments of the brain and spinal cord. Exchange of solutes between the CSF and the ISF is driven by arterial pulsation and regulated during sleep by the expansion and contraction of brain extracellular space.

Clearance of soluble proteins, waste products, and excess extracellular fluid is accomplished through convective bulk flow of the ISF, facilitated by astrocytic aquaporin 4 (AQP4) water channels.

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Figure 2:  Mammalian Gymphatic System

A publication by L. Xie and colleagues in 2013 explored the efficiency of the glymphatic system during slow wave sleep and provided the first direct evidence that the clearance of interstitial waste products increases during the resting state. Xia and Nedergaard demonstrated that the changes in efficiency of CSF–ISF exchange between the awake and sleeping brain were caused by expansion and contraction of the extracellular space, which increased by ~60% in the sleeping brain to promote clearance of interstitial wastes such as amyloid beta.

During the night, we experience sleep cycles that average about 90 minutes. In the first half of the night we cycle through all of the stages, N1, N2, N3, and REM sleep. Slow wave sleep or delta sleep is N3. We start at N1 and go deeper into N2, then deeper into N3, the stage where brain cleansing occurs. In the second half of the night, REM sleep increases and alternates with N1 and N2 sleep, so it appears most of the cleanup is done in the first half of the night.

The interstitial space makes up about 20% of the brain volume but that fraction varies over the course of the day and night. During sleep this space increases by up to 60% in volume. This flushing of the glymphatic system removed waste metabolic products that are potentially neurotoxins. These products include β-amyloid proteins which are strongly suspected to play a part in Alzheimer’s Disease.

This is a two part process:

  • 1. After the brain cells shrink 60 %  cerebral spinal fluid is pumped through the brain’s tissue, then 
  • 2. The waste is flushed back into the circulatory system where it enters the blood circulation system and goes to the liver

Cerebral spinal fluid quickly flows into the space, aided by the pulse of the arteries. It mixes with the interstitial fluid and washes the waste toward the veins and carries it to the liver. This process occurs during slow wave sleep, the deepest sleep.

Another startling finding was that the cells in the brain “shrink” by 60 percent during sleep. This contraction creates more space between the cells and allows CSF to wash more freely through the brain tissue. In contrast, when awake the brain’s cells are closer together, restricting the flow of CSF. 

The researchers observed that a hormone called noradrenaline is less active in sleep. This neurotransmitter is known to be released in bursts when brain needs to become alert, typically in response to fear or other external stimulus. The researchers speculate that noradrenaline may serve as a “master regulator” controlling the contraction and expansion of the brain’s cells during sleep-wake cycles.

Using these techniques, researchers were able to observe in mice – whose brains are remarkably similar to humans – what amounts to a plumbing system that piggybacks on the brain’s blood vessels and pumps cerebral spinal fluid (CSF) through the brain’s tissue, flushing waste back into the circulatory system where it eventually makes its way to the general blood circulation system and, ultimately, the liver.

Skin Detoxification

Detoxification through the skin is facilitated by the promotion of sweating. This can be accomplished by ingesting sudorific (diaphoretic) herbs like ginger, mustard and cayenne, either by themselves or in conjunction with fasting, saunas, baths and sweats.

Packs of clay, mud, salt, charcoal, seaweed, volcanic ash and castor oil have also proven useful in increasing the elimination of toxins through the skin.

Physiological Factors that Affect Detoxification

There are various physiological and pathological factors that affect the detoxification process. Physiological factors that can influence detoxification include:

  • Age
  • Genetic Factors
    • Polymorphisms (SNPs)  

Aging

The activity of phase I detoxification enzymes decreases in old age. Aging also decreases blood flow through the liver, further aggravating the problem. Lack of the physical activity necessary for good circulation, combined with the poor nutrition commonly seen in the elderly; add up to a significant impairment of detoxification capacity, which is typically found in aging individuals.

Genetic Factors

Biochemical individuality is a simple concept that states all humans differ biochemically from others. And that biochemical individuality directly affects the degree to which a chemical compound is bio-transformed from person to person. Some of the factors that determine a person’s level of biochemical individuality and therefore biotransformation capacity are:

The structure, amount of or complete lack of a specific biotransformation enzyme may differ among individuals and this can give rise to differences in rates of biotransformation.  Genetic differences in the ability of an individual to metabolize xenobiotics are related to the presence of different versions of the gene encoding that activity, or genetic polymorphism.

A Single Nucleotide Polymorphism, also known as Simple Nucleotide Polymorphism, is a DNA sequence variation occurring commonly within a population (e.g. 1%) in which a single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes.

Polymorphisms (SNPs) in the genes coding for a particular enzyme can increase or, more commonly, decrease the activity of that enzyme. Both increased and decreased activity may be harmful. As mentioned above, increased Phase I clearance without increased clearance in Phase II can lead to the formation of toxic intermediates that may be more toxic than the original toxin. Decreased Phase I clearance will cause toxic accumulation in the body.

Genova Diagnostics offers a comprehensive test of the Polymorphism (SNPs) in its DetoxiGenomic(TM) Profile. 

Click the link to view a Sample Report


 

Amino Acid Conjugation Pathway in Metabolic Detoxification: Glycine is the Main Amino Acid

Phase 1 Biotransformation Process

The primary function of the Phase I biotransformation process is to either:

  • Biotransform a toxic lipophilic compound directly to a more hydrophilic compound so it can be directly excreted in the kidneys (e.g. caffeine). Though, Phase I usually results in only a small amount of direct hydrophilicity and excretion
  • The bulk of Phase I enzymatic activity takes place in the form of altering unwanted compounds in a way as to either expose or introduce a functional group. Functional groups such as: Carboxyl group (–COOH), hydroxyl group (– OH), amino group (-NH2), or sulfhydryl group/thiol (-SH)

In the Phase 1 detoxification process a toxic chemical is converted into a less harmful chemical through various chemical reactions.  Phase 1 is essentially responsible for breaking fat-soluble toxins down and then sending the raw materials to Phase 2 detoxification process.  Phase 2 is the addition or conjugation phase where new substances are added/conjugated to the toxic metabolites produced in Phase 1 in order to make them easier to transport, more stable and/or more functional for the body.

Phase 2 Conjugation Pathways

There are 6 Conjugation Pathways in the human body and they include:

  • Sulphation (sulfation) pathway
  • Glucoronidation pathway
  • Glutathione conjugation pathway
  • Acetylation pathway
  • Methylation (& Sulfoxidation) pathway
  • Amino Acid conjugation pathway (glycine, cysteine, glutamine, methionine, taurine, glutamic acid and aspartic acid)

These 6 conjugation pathways occur in different organs of the body.  The locations of the Phase 2 conjugation pathways are listed in Table 1.

  Table 1 Locations of Phase 2 Conjugation Systems

Conjugation System

Location in Body

Glycine conjugation

liver, kidney

Glutathione conjugation

liver, kidney

Glucuronidation

liver, kidney, intestine, lung, skin, prostate, brain

Acetylation

liver, lung, spleen, gastric mucosa, RBCs, lymphocytes

Sulphation

liver, kidney, intestine

Methylation

liver, kidney, lung, CNS

(Source:   Liston HL, Markowitz JS, DeVane CL (October 2001). “Drug glucuronidation in clinical psychopharmacology”. J Clin Psychopharmacol 21 (5): 500–15.)

Amino Acid Conjugation Pathway

The Amino Acid conjugation pathway is less utilized by the body, yet is still a very important conjugation pathway. 

The conjugation of toxins with amino acids occurs in this pathway. The amino acids commonly used in this pathway include:

  • Glycine
  • Taurine
  • Glutamine

but arginine, and ornithine are also used.

image

Figure 1:  Amino acid conjugation pathways

(Source:  Wikipathways)

The Amino Acid Conjugation Pathway often includes the Acylation Pathway.  Acylation uses acyl CO-A with the amino acids glycine, glutamine and taurine. Conjugation of bile acids in the liver with glycine or taurine is essential for the efficient removal of these potentially toxic compounds.  

The main amino acid in the Amino Acid Conjugation Pathway is glycine.  Glycine is the smallest of the 20 amino acids commonly found in proteins.  Glycine is a colorless, sweet-tasting crystalline solid. It is unique among the proteinogenic amino acids in that it is achiral. It can fit into hydrophilic or hydrophobic environments, due to its minimal side chain of only one hydrogen atom.

Since it plays such an important role in the Amino Acid Conjugation Pathway, it is also known as the Glycination Pathway.  Salicylates and benzoate are detoxified primarily through glycination. Benzoate is present in many food substances and is widely used as a food preservative.

In humans, there is a wide variation that exist in the activity of the glycine conjugation, which is primarily due not only to genetic variations, but also to the availability of glycine in the diet.

High-protein rich foods should be consumed in the diet to ensure that the amino acid conjugation is functioning properly.  There are a number of natural substances that induce the

Amino Acid Conjugation Pathway and act as co-factors in the conjugation process.  These substances are listed in Table 2. 

Table 2 Natural Substances that Induce the Amino Acid Conjugation Pathway

 

Category

Food

Minerals

 

 

Magnesium

 

Iron

Vitamin

 

 

B Complex Vitamins (particularly

Vitamin B3 and Vitamin B6)

Amino Acids

 

 

Glycine

 

Methionine

 

Taurine

 

Cysteine

 

Glutamine


Resources:

Life Extension – Glycine (Capsules)

NOW – Glycine (Powder)


Cover Photo Source:  Perfect Health Diet


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Detoxifying Heterocyclic aromatic amines (HCAs) and Polycyclic aromatic hydrocarbons (PAHs) with Chlorella vulgaris

Heterocyclic aromatic amines (HAAs) and polycyclic aromatic hydrocarbons (PAHs) have been identified by scientific research as carcinogenic chemicals in the diet. 

Heterocyclic aromatic amines (HAAs)

Heterocyclic aromatic amines are a group of 20 chemical compounds formed during cooking. They are found in meats that are cooked to the well done stage, in pan drippings, and in meat surfaces that show a crispy brown crust.

Related image

Epidemiological studies show associations between intakes of heterocyclic aromatic amines and cancers of the:

  • colon
  • rectum
  • breast
  • prostate
  • pancreas
  • lung
  • stomach
  • esophagus

The U.S. Department of Health and Human Services Public Health Service labeled several heterocyclic aromatic amines as likely to be carcinogenic to humans in its most recent Report on Carcinogens.  1 

The most common types of Heterocyclic Aromatic Amines (HAAs) include:

  • 4,8-DiMelQx 2-Amino-3,4,8-Trimethylimidazo [4,5-f]Quinoxaline
  • 8-MelQx 2-Amino-3,8-Dimethylimidazo [4,5-f]Quinoxaline
  • IQ 2-Amino-3-Methylimidazo [4,5-f]Quinoline
  • MelQ 2-Amino-3,4-Dimethylimidazo [4,5-f]Quinoline
  • PhIP 2-Amino-1-Methyl-6-Phenylimidazo [4,5,b]Pyridine
  • TMIP 2-Amino-N,N,N-Trimethylimidazopyridine

HAAs form when Amino Acids and Creatine present in muscle Meats react at high temperatures (above 100° C). Temperature is the most important factor in formation of HAAs. Frying, Grilling, and Barbecuing produce the largest amounts of HAAs because the Meats are cooked at very high temperatures. Roasting and Baking are done at lower temperatures, so lower levels of HAAs are likely. Microwaving, Stewing, Boiling, or Poaching are done at or below 100° and cooking at this low temperature creates negligible amounts of HAAs.

Polycyclic aromatic hydrocarbons (PAHs)

Polynuclear aromatic hydrocarbons (PAH) are potent atmospheric pollutants. Some compounds have been identified as carcinogenic, mutagenic, and teratogenic.

Image result for polycyclic aromatic hydrocarbons

The EPA has classified seven PAH compounds as probable human carcinogens:

  • benz[a]anthracene,
  • benzo[a]pyrene,
  • benzo[b]fluoranthene,
  • benzo[k]fluoranthene,
  • chrysene,
  • dibenz(a,h)anthracene, and
  • indeno(1,2,3-cd)pyrene

The source of PAH’s include:

  • Car exhaust
  • The smoke generated by various cooking methods
    • High heat grilling
    • Barbequing
    • Smoked foods (meats, fish,etc.)
  • Tobacco smoke

Detoxifying Heterocyclic aromatic amines (HAAs) and Polycyclic aromatic hydrocarbons (PAHs) with Chlorella vulgaris

A randomized, double blind, placebo-controlled crossover study from January 2015 assessed the ability of Chlorella vulgaris to detoxify carcinogenic HAAs and PAHs.   Researchers analyzed urine specimens of 6 females with ages around 27 years for 2 weeks.  Urine specimens showed high levels of three HAAs, specifically:  2

  • MeIQx                 323.36±220.11ng/L
  • PhIP                    351.59±254.93ng/L
  • IQx-8-COOH       130.85±83.22ng/L

Consumption of Chlorella vulgaris significantly reduced urinary levels of MeIQx:

  • Before    430±226.86pg/mL
  • After       174.45±101.65pg/mL

Urinary levels of PhIP or IQx-8-COOH, a major metabolite of MeIQx, were not changed by chlorella supplementation.  

Natural Substances that May Potentially Detoxify Certain Environmental Toxins

Environmental toxins or toxicants are universal and are virtually impossible to avoid anywhere in the world.  There are, of course, more pristine areas of the world than others, but in this day and age your exposure to environmental toxins, to a certain extent, are inevitable.

Having a good understanding of the most prevalent and health damaging environmental toxins is important to maintaining overall health and avoiding possible disease pathologies, especially cancer and neurological disorders. 

There are a number of online resources that can educate you on these environmental toxins.  Four important resources are listed below:

Toxicology and Environmental Health Information Program (TEHIP)

The National Library of Medicine (NLM) Toxicology and Environmental Health Information Program (TEHIP) evolved from the Toxicology Information Program (TIP) that was established in 1967 at the (NLM) in response to recommendations made in the 1966 report “Handling of Toxicological Information,” prepared by the President’s Science Advisory Committee.

TEHIP maintains a comprehensive web site that provides access to resources produced by it and by other government agencies and organizations. This web site includes links to databases, bibliographies, tutorials, and other scientific and consumer-oriented resources. TEHIP also is responsible for the Toxicology Data Network (TOXNET®), an integrated system of toxicology and environmental health databases that are available free of charge on the web.

The Agency for Toxic Substances and Disease Registry (ATSDR)

The Agency for Toxic Substances and Disease Registry (ATSDR), based in Atlanta, Georgia, is a federal public health agency of the U.S. Department of Health and Human Services. ATSDR serves the public by using the best science, taking responsive public health actions, and providing trusted health information to prevent harmful exposures and diseases related to toxic substances.

U.S. Environmental Protection Agency’s Toxics Release Inventory (TRI) Program

TRI is a resource for learning about toxic chemical releases and pollution prevention activities reported by industrial and federal facilities. TRI data support informed decision-making by communities, government agencies, companies, and others.

The Environmental Working Group

The Environmental Working Group’s mission is to empower people to live healthier lives in a healthier environment. With breakthrough research and education, we drive consumer choice and civic action. We are a non-profit, non-partisan organization dedicated to protecting human health and the environment. 


Despite the fact that there have been hundreds of environmental toxins identified and categorized, this article will only focus on eleven (11) common environmental toxins and examine their various sources and possible disease pathologies that may develop as a result of exposure.  These eleven environmental toxins include:

  • Aluminum
  • Asbestos
  • Benzo[a]pyrene (Polycyclic aromatic hydrocarbon)
  • Bisphenol A (BPA)
  • Chloroform
  • Cyanide
  • Dioxins
  • Formaldehyde
  • Heterocyclic amines
  • Perchlorate
  • Polycyclic aromatic hydrocarbons

The Table below lists the eleven environmental toxins and their sources and possible disease states based on ongoing exposure:

List of Certain Environmental Toxins

ToxinSourcesPotential Diseases
AluminumAluminum is used for beverage cans, pots and pans, airplanes, siding and roofing, and foil. Aluminum is often mixed with small amounts of other metals to form aluminum alloys, which are stronger and harder. Aluminum compounds have many different uses, for example, as alums in water-treatment and alumina in abrasives and furnace linings. They are also found in consumer products such as antacids, astringents, buffered aspirin, food additives, and antiperspirants.Musculoskeletal (Muscles and Skeleton), Neurological (Nervous System), Respiratory (From the Nose to the Lungs)
AsbestosInsulation on floors, ceilings, water pipes and heating ducts from the 1950s to 1970sAsbestos is linked to increased risk of lung cancer, and development of mesothelioma (cancer of the thin lining surrounding the lung (pleural membrane) or abdominal cavity (the peritoneum)) and laryngeal cancer. Cancer may appear 30 to 50 years after exposure.
Bisphenol A (BPA)It is used in making all kinds of plastics and resins, including water bottles and food containers. It is used in hard plastics, food cans, drink cans, receipts, and dental sealants.BPA is an endocrine disruptor linked to breast and prostate cancer.
ChloroformAir, drinking water and food can contain chloroform. Other names for chloroform are trichloromethane and methyl trichloride.Cardiovascular (Heart and Blood Vessels), Developmental (effects during periods when organs are developing) , Hepatic (Liver), Neurological (Nervous System), Renal (Urinary System or Kidneys), Reproductive (Producing Children)
DioxinsDioxins are a group of chemicals formed as unintentional byproducts of industrial processes involving chlorine, such as waste incineration, chemical manufacturing, and pulp and paper bleaching. Dioxins include polychlorinated dibenzo dioxins (PCDDs), polychlorinated dibenzo furans (PCDFs), and the polychlorinated biphenyls (PCBs). Exposure is through the ingestion of contaminated foods and, to a lesser extent, dermal contact. Farm-raised salmon. Most farm-raised salmon, which accounts for most of the supply in the United States, are fed meals of ground-up fish that have absorbed PCBs in the environment. Polychlorinated biphenyls (PCBs) are commonly found in foods of animal origin (meat, dairy, and fish, depending on the country of origin)cancer classification depends on the dioxin: 2,3,7,8-TCDD (Agent Orange) is a known human carcinogen; some other dioxins are probable or possible human carcinogens.
FormaldehydeFormaldehyde can be found in a variety of building and home decoration products (as urea-formaldehyde resins and phenol-formaldehyde resin). It is also used as a preservative and disinfectant.Exposure is through inhalation and dermal contact. Automobile exhaust is the greatest contributor to formaldehyde concentrations in ambient air. Construction materials, furnishings, and cigarettes account for most formaldehyde in indoor air.Formaldehyde has caused nasal cancer in rats after long term exposure; it is linked to leukemia and nasopharygeal cancer in humans. It is a known human carcinogen.
Heterocyclic aminesChemicals that form when meat is cooked at high temperatures (e.g., grilled or broiled)Some heterocyclic amines (HCAs) found in cooked and especially burned meat are known carcinogens. Harmane, a β-carboline alkaloid found in meats, has been shown to have strong neurotoxic characteristics, and in particular, is "highly tremorogenic" (tremor inducing).
PerchlorateThe dominant use of perchlorates are for propellants in rockets. Of specific value is Ammonium perchlorate composite propellant as a component of solid rocket fuel. Low levels of perchlorate have been detected in both drinking water and groundwater in 26 states in the U.S., according to the Environmental Protection Agency.Perchlorate is a potent competitive inhibitor of the thyroid sodium-iodide symporter. Some studies suggest that perchlorate has pulmonary toxic effects as well.
Polycyclic aromatic hydrocarbonsThey are products of fossil fuel combustion, particularly petrochemicals, and are a major source of cancer-causing chemicals in polluted air. Polycyclic aromatic hydrocarbons (PAHs) form as a result of incomplete combustion of organic compounds: combustion from wood and fuel in residential heating, coal burners, automobiles, diesel-fueled engines, refuse fires, and grilled meats. They are found in coal tar and coal tar pitch, used for roofing and surface coatings. Exposure to these lipophilic substances results from inhalation of polluted air, wood smoke, and tobacco smoke, and ingestion of contaminated food and water. PAHs are reasonably anticipated to be a human carcinogen. PAHs have been linked to skin, lung, bladder, liver, and stomach cancers in well-established animal model studies. 1

In addition to the conscious avoidance and non-exposure to these eleven environmental toxins, (e.g., non-exposure to polycyclic aromatic hydrocarbons can be avoiding or minimized by not consuming grilled, barbequed or fried meats), there are a number of natural substances that have been researched for their ability to counteract the environmental toxin and/or assist the body in detoxifying the toxin from the body by stimulating the Phase I or II metabolic detoxification system.

The Table below lists those natural substances that may potentially assist in the detoxification of the eleven environmental toxins:

Natural Substance that Detoxify Certain Environmental Substances

ToxinPotential Substances that DetoxifyReference
Aluminum
N-acetylcysteine (NAC)1
Ethylene-Diamine-Tetra-Acetate (EDTA)2
Melatonin3
Selenium4
Silicon5
Malic acid6
Citric acid7
Folic acid (folate)8
Vitamin C9
Vitamin E10
Ginko Biloba11
Propolis12  13
Magnesium14
Centrophenoxine15  16  17
Bacopa monniera18
Cnidium monnieri19
Asbestos
Green Tea20
Garlic21
Benzo[a]pyrene (Polycyclic aromatic hydrocarbon)
Calcium D-Glucaric Acid22
Quercetin23
Vitamin C24
Vitamin E25
Blueberries, raspberries, strawberries26
Bisphenol A (BPA)
Sage (Salvia)27
ChloroformN-acetylcysteine (NAC)28
Dioxins
Chitosan31
Curcumin32
Resveratrol33
Chlorophyllin34
Vitamin A35
Vitamin E36
Chlorella38 39  
Green Tea40
Korean Ginseng41
Wakame seaweed42
Formaldehyde
Melatonin43
Vitamin C44
Vitamin E45
Heterocyclic amines
Indole-3-Carbinol46
Caffeic Acid47
Curcumin48
Epigallo-Catechin-Gallate (EGCG)49
Luteolin50
Quercetin51
Chlorophyllin52 53  
Natto54
Rosemary55
Broccoli56
Brussels Sprouts57
Perchlorate
Iodine58
Polycyclic aromatic hydrocarbons
Lycopene59
Resveratrol60
Chlorophyllin61
Green Tea62
Vitamin C63
Vitamin E64


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