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Quicksilver Therapeutic Detoxification System: Understanding Detoxification
Strategies for Mercury Intoxication
Christopher W. Shade, PhDAndrew Elias, MBA, LSSBBQuicksilver Scientific, LLC
Lafayette, CO 80026(303) 531-0861
www.quicksilverscientific.com
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Forms and Sources of Mercury
• MeHg - Methylmercury– Organomercurial; found in fish; Also formed
in gut from amalgam mercury
• Hg0 – Elemental Mercury– The metal form; liquid and gas forms; dental amalgam
• HgII – Inorganic Mercury– The salt, formed by oxidation of Hg0 in blood and mouth
• EtHg - Ethylmercury– Synthetic organomercurial; antimicrobial
– Ends up mostly as HgII
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Pathways In – Dental Amalgam
Hg0 breaks down to
inorganic mercury (HgII).
Hg0 distributes throughout body and nervous
system.
Image from the International Academy of Oral Medicine and Toxicology.
HgII accumulates in the nervous system, liver,
and kidney.
Hg0 released from amalgam and inhaled with 80% uptake in the lungs.
Amalgams: Pathway of Exposure
80% Uptake
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Pathways In – Fish Consumption
MeHg
MeHg
Chemical reactions in the gut add MeHg to an amino
acid.
Fish contaminated with methylmercury (MeHg) get
eaten.
MeHg diffuses out of the gut and circulates
throughout the body, because it gets mistaken
as an amino acid.
Methylmercury accumulates in
the body.
Seafood: Pathway of Exposure
95% Uptake
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Pathways In – Vaccines
EtHg
HgII
accumulates in the body.
EtHg distributes throughout the body and
nervous system.
EtHg probably does not leave the body, but enters tissues and breaksdown into inorganic mercury
(HgII).
Ethylmercury (EtHg) enters the blood through
vaccination.
EtHg leaves the blood after a few days.
Vaccination: Pathway of Exposure
100% Uptake
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Pathways Out – Methylmercury
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Pathways Out – Inorganic Mercury
Both Intestinal and Kidneys
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Heavy Metal Defense – Glutathione System
Antioxidant, Detoxification, Protein Repair
• Glutathione (GSH) - A thiolic tripeptide composed of glutamate, cysteine, and glycine
**Binds Inorganic and Methyl Mercury and escorts out of body**
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• Detoxification Phases I, II, III– Phase I is an activation,
– Phase II is conjugation (mobilization)
– Phase III is transport (recently delineated; control point; elimination)
The Human Detoxification System
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• Phase I – Prepares toxin for conjugation in Phase II – Not needed for metals, but very important to
have correctly coupled to Phase II • Creates Essentially Free-Radicals to be used in
Phase II
The Human Detoxification System
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• Phase II – conjugation makes toxin more water soluble and recognizable by transporters– Glutathione S-Transferases (GST)
responsible for Glutathione conjugation• Transfers Mercury (Hg) from protein-bound sites to
Glutathione for transport out
The Human Detoxification System
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• Phase III is the transport out!– Several transport proteins (cMOAT, OAT,
MRP1, MRP2, GS-X)– Same transporters for many pathways – In cells, liver, intestines, kidneys – biggest in
liver then intestines then kidneys
The Human Detoxification System
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Breakdown of the Defense System
• GSH deficiency – – Genetic (GCS polymorphisms, epigenetic dysfunction) – Environmental (oxidative consumption or inflammation)
• GST problems – – Genetic (GST polymorphisms, epigenetic dysfunction)– Environmental (Inflammatory cascade/ARE dysfunction)
• Phase III can get blocked and then downregulates Phase II enzymes – Can stop multiple detoxification pathways!
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Biggest Reason for Phase III Dysfunction
Inflammation!
Especially in Gut!-Hallmark of Autism cases
-Easily caused by heavy metal induced oxidative damage
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Phase I
Phase III
Phase IIGlutathione Conjugation
Sulfation Glucuronidation
OATPB
lood
LIVER
MRP2
Normal Small Intestine
Cellular MRP1
Oxidative Activation
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Phase I
Phase III
Phase IIGlutathione Conjugation
Sulfation Glucuronidation
OATPB
lood
LIVER
MRP2
Inflamed Small Intestine
Cellular MRP1
Oxidative Activation
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Phase I
Phase III
Phase IIGlutathione Conjugation
Sulfation Glucuronidation
OATPB
lood
LIVER
Inflamed Small Intestine
Cellular MRP1
Oxidative Activation
Inflammation causes
Downregulation of MRP2
Negative Feedback – Inhibition of Phase II
MRP2
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Phase I
Phase III
Phase II
Oxidative Activation
Glutathione Conjugation
Sulfation Glucuronidation
OATPB
lood
LIVER
MRP2
Inflamed Small Intestine
Cellular MRP1
Negative Feedback – Inhibition of Phase II
Inflammation causes
Downregulation of MRP2
Oxidative Stress From Phase I/Phase II mismatch
Build-up of both cellular and blood-borne toxins
Oxidative Activation
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Pathways Out – Amalgam Poisons Intestinal Function
Corrosion Products of Amalgam (Inorganic Hg) are swallowed with saliva
and create inflammation
Phase I
Phase III
Phase II
Oxidative Activation
Glutathione Conjugation
Sulfation Glucuronidation
OATP
Blo
od
LIVER
MRP2
Inflamed Small Intestine
Cellular MRP1
Negative Feedback –Inhibition of Phase II
Inflammation causes
Downregulation of MRP2
Build-up of both cellular and blood-borne toxins
Oxidative Activation
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Pathways Out – Gut Blocked
Toxin Retention and High Stress on
Kidneys
Then Kidneys Weaken from Constant Load and Can’t Filter Hg
= Even More Retention
Intestinal Load Goes to Kidneys
Excretion Rates Decrease
Kidney Load Increases
Gut Inflames, Blocking Exit
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Pathways Out – Amalgam Poisons Intestinal Function
Corrosion Products of Amalgam (Inorganic Hg) are swallowed with saliva
and create inflammation
Phase I
Phase III
Phase II
Oxidative Activation
Glutathione Conjugation
Sulfation Glucuronidation
OATP
Blo
od
LIVER
MRP2
Inflamed Small Intestine
Cellular MRP1
Negative Feedback –Inhibition of Phase II
Inflammation causes
Downregulation of MRP2
Build-up of both cellular and blood-borne toxins
Oxidative Activation
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Removal of Hg
Amplifying and Augmenting Natural Detoxification Systems with IMD,
Clear Way Cofactors and Nanosphere Liposomal Agents
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Biochemical Hg Removal Requirements
1. Intracellular Glutathione Sufficiency
2. Effective GST Activity (Phase II-Mobilization)
3. Effective Phase III Clearance including intestinal binding and Elimination
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System for Intestine-Based Metals Detoxification
1. IMD Intestinal Cleanse
- Opens Phase III and Stops Reabsorption
2. Clear Way Cofactors Phytonutrients - Upregulate Synthesis of Phase II enzymes and Intra-Cellular Antioxidants
3. Nanosphere Glutathione Support
- Liposomal EDTA with R-Lipoic Acid
- Liposomal Vitamin C with R-Lipoic Acid
- Liposomal Glutathione
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System for Therapeutic Metals Detoxification
• Intestinal Metals Detox (IMD)– Use Intestines NOT Kidneys for Metal Removal
– NON-ABSORBED silica particles saturated with strong (thiol) binding groups
– Binds Mercury in the intestines and moves out of body
• Opens Phase III transporters
• Stops Enterohepatic Circulation (Reabsorption)
• Restores and Amplifies on the Natural Detoxification System
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Phase I
Phase III
Phase IIGlutathione Conjugation
Sulfation Glucuronidation
OATP
Blo
od
LIVER
MRP2
Normal Small Intestine
Cellular MRP1
Oxidative Activation
Phase I
Phase III
Phase II
Oxidative Activation
Glutathione Conjugation
Sulfation Glucuronidation
OATP
Blo
od
LIVER
MRP2
Inflamed Small Intestine
Cellular MRP1
Negative Feedback –Inhibition of Phase II
Inflammation causes
Downregulation of MRP2
Oxidative Stress From Phase I/Phase II mismatch
Build-up of both cellular and blood-borne toxins
Oxidative Activation
Correct Phase III Elimination
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Phase III EnhancementBilirubin (unrelated to GSH) falls too
Table 2. Bilirubin Levels on Select Patients with Elevated Blood Bilirubin (From Clinics 1 & 2, 7-10 interventions)
Before After % Change
2 1.1 -45
1.7 0.9 -47.1
1.4 1.3 -7.1
1.2 0.9 -25.0
3.4 2.6 -23.5
1.7 1.2 -29.4
Phase I
Phase III
Phase IIGlutathione Conjugation
Sulfation Glucuronidation
OATP
Blo
od
LIVER
MRP2
Normal Small Intestine
Cellular MRP1
Oxidative Activation
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AccumulationEnterohepatic Circulation
of Hg
Drainage IMD Blocking Enterohepatic
Circulation of Hg
LOW EXCRETION HIGH EXCRETION!
Stop Reabsorption
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Half-life times – Iraq Poisoning
Genetically Sensitive Population ~12%
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Pathways Out – Clear Way
= Greatly Facilitated Elimination!!!
Transporters Open & Recirculation
Interrupted
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IMD Decreases Half-Life in Blood
With IMD
½-Life ~ 17 days
To Baseline = 40 days
No Treatment (Walleye)
½-Life = 46-66 days
Up to 120 days - Iraq
To Baseline = 160+ days
0
0.2
0.4
0.6
0.8
1
1.2
1.4
08/10/08 08/20/08 08/30/08 09/09/08 09/19/08 09/29/08 10/09/08 10/19/08 10/29/08
Blo
od
Me
Hg
(n
g/m
L)
0.000
0.050
0.100
0.150
0.200
0.250
0.300
0.350
Fe
ca
l Me
Hg
(n
g/g
-ww
)
blood MeHg
Fecal MeHg Excretion
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Small Clinical Trial Results
Table 3.1 Changes in blood mercury levels during 7-10 day intervention with amalgam revision and nutritional support.
Clinic 1 IMD (n=8) No Treatment (n=4) %Decr HgT 23.9 0.4 %Decr MeHg 22.9 5.1 %Decr HgII 12.4 -4.1
Changes in Blood Mercury Levels during 7-10 day intervention with amalgam removal and nutritional treatment
~20% change typical in first 1-2 weeks followed by gradual lowering as mercury is displaced from cells into blood following initial rapid lowering
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Individual Cases
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 9.5 10 10.5
Concentration of Mercury (ng/mL or ug/L)
HgT
Hg(II)
MeHg
Before Blood Mercury Comparison
3/14/200912/10/2008QS Average
Methylmercury
Inorganic Hg
Total Hg
Patient #1: Fish Consumption Ceased
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7
Concentration of Mercury (ng/mL or ug/L)
HgT
Hg(II)
MeHg
Before Blood Mercury Comparison
8/8/20081/23/2009QS Average
Methylmercury
Inorganic Hg
Total Hg
Patient #2: Fish Consumption ContinuedEven with Continuous Exposure, Levels Fall!
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Patient – Methylmercury Suspected Detox Enzyme Deficiency
30% Removal of MeHg in 2 months
80% Removal of MeHg in 6 months
90% Removal of HgII in 6 months
0 2 4 6 8 10 12 14 16 18 20
1
2 2/12/209
4/16/2009
5/7/2009
7/8/2009
8/25/2009
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 9.5 10 10.5
HgT
Hg(II)
MeHg
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Hg Detox Product ComparisonMaterial
Area of Action
Hg-specific Binding
Safety Efficacy Risks
IMD Intestinal Yes High High Low
DMSABlood/ Kidney
Yes Low HighKidney, Liver,
Demineralization
DMPSBlood/ Kidney
Yes Low HighKidney, Liver,
Demineralization
EDTABlood/
Kid/IntestNo Moderate Moderate Demineralization
Zeolite Intestinal No High Low Demineralization
Chlorella Intestinal No High Low Low
Combines Strength of Pharmaceuticals (DMSA and DMPS) with the Safety of Zeolite and Chlorella!
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System for Therapeutic Metals Detoxification
1. Intestinal Metals Detox (IMD)
-Opens Phase III and Stops Reabsorption
2. Clear Way Cofactors Phytonutrients
- Upregulate Synthesis of Phase II enzymes and Intracellular Antioxidants
1. Glutathione Support
-N-Acetyl Cysteine, Vitamin C, Alpha Lipoic Aced, Phytonutrients
-Liposomal GSH
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Chemoprevention by Keap1-Nrf2 Signaling Pathway by Phase II Inducers
Kwak et al., 2004, Mutation Research, 555:133-148
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“Phytogenomics”• Certain Phytochemicals upregulate Phase II
enzymes as well as GSH, SOD (cellular antioxidants)
• The Anti-Inflammatory Cascade• Polyphenolic Antioxidants• Sulfur compounds
– Alpha Lipoic Acid – Crucifers– Garlic oil
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Polyphenolics
• Anti-inflammatory cascade• Upregulate Phase II enzymes through
binding to membrane and nuclear receptors (transcription factors)
• Vascular protective effects (strengthen capillaries and improve oxygen delivery)
• Anti-carcinogenic• Cross Blood-Brain Barrier
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Flavanols (Polyphenolics)
Epicatechin – in green tea, cocoa; monomer for OPC’s from Pine Bark, Grape seeds
Ellagic Acid - Pomegranates
Quercetin – Fruit and Vegetable Skins
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Clear Way Polyphenolic:
Haritaki
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Coordinated Expression of Phase II and III
MRP2 and GSTπ co regulated
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Clear Way CofactorsIngredient per 3 caps % DV
Vitamin B1 100 mg 6667 Vitamin B6 125 mg 6250 Vitamin B5 100 mg 1003 Iodine 450 mcg 300 as Kelp Extract Selenium 200 mcg 286 as Selenomethionine
Na-form R-Lipoic Acid 150 mg - Lumbrokinase 20 mg - 20,000 units/mg Kelp Extract 100 mg -
Proprietary Blend: 1205 mg Haritaki Extract ** - 45% Tannins Pomegranate Extract ** - 40% Ellagic Acid Quercetin ** - Pine Bark Extract ** - 95% OPC Gotu Kola Extract ** - 10:1 Dandelion Extract ** - 12:1 Other Ingredients: Gelatin (capsule), rice bran
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System for Therapeutic Metals Detoxification
1. Intestinal Metals Detox (IMD)
-Opens Phase III and Stops Reabsorption
2. Phytonutrients – Clear Way Cleanse Cofactors
- Upregulate Synthesis of Phase II enzymes and Intracellular Antioxidants
3. Nanosphere Glutathione Support
Liposomal Vitamin C with R-Lipoic Acid
Liposomal Glutathione
Liposomal EDTA with R-Lipoic Acid
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Liposomes
Liposomal Encapsulation•Nanosphere Essential Phospholipid (EPL) bilayer (100-150 nanometers)
•Bypasses peptidases that break down glutathione and barrier to EDTA and high-dose Vitamin C
•Direct absorption in upper intestine
•Evidence of cellular absorption
•Macrophage oxidative damage protection
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Therasomal Detox
Liposomal Encapsulation•Same Essential Phospholipid (EPL) source as Lipostabil – injectable grade
•1.8g/tsp.
•Near complete absorption
•R-Lipoic Acid (much stronger and more anti-inflammatory than RS-ALA)
•Mix of Na, Ca, Mg, and K-EDTA
Strengthen effect on Pb, Cd, As, and Ni
Extend Detox out to the Hard metals – Al
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Can L-GSH Improve GSH Concentration across Membranes?• Neuron cell culture depleted of GSH by DEM (diethyl
maleate)
• L-GSH was > 100-fold more potent than plain GSH in solution (non-L-GSH) in replenishing intracellular
GSH
EC50 GSH
Plain GSH 575
µM
Mol Wt. GSH - 304
Liposomal GSH 4.75
µM
Zeevalk G, Guilford F, Bernard L. Liposomal glutathione for replenishment and maintenance of intracellular glutathione in mesencephalic cultures. Abstract Neuroscience 2009: Soc. for Neuroscience 2009 Chicago, Oct 17, 2009