Quicksilver Therapeutic Detoxification System: Understanding Detoxification Strategies for Mercury

Intoxication

Christopher W. Shade, PhDAndrew Elias, CLSSBB

Quicksilver Scientific, LLCLafayette, CO 80026

(303) 531-0861www.quicksilverscientific.com

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

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

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

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

Pathways Out – Methylmercury

Pathways Out – Inorganic Mercury

Both Intestinal and Kidneys

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**

• 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

• 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

• 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

• 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

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!

Biggest Reason for Phase IIIDysfunction

Inflammation!

Especially in Gut!-Hallmark of Autism cases

-Easily caused by heavy metal induced oxidative damage

Phase I

Phase III

Phase IIGlutathione Conjugation

Sulfation Glucuronidation

OATPBl

ood

LIVER

MRP2

Normal Small Intestine

Cellular MRP1

Oxidative Activation

Phase I

Phase III

Phase IIGlutathione Conjugation

Sulfation Glucuronidation

OATPBl

ood

LIVER

MRP2

Inflamed Small Intestine

Cellular MRP1

Oxidative Activation

Phase I

Phase III

Phase IIGlutathione Conjugation

Sulfation Glucuronidation

OATPBl

ood

LIVER

Inflamed Small Intestine

Cellular MRP1

Oxidative Activation

Inflammation causes

Downregulation of MRP2

Negative Feedback –Inhibition of Phase II

MRP2

Phase I

Phase III

Phase II

Oxidative Activation

Glutathione Conjugation

Sulfation Glucuronidation

OATPBl

ood

LIVERMRP2

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

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

Bloo

d

LIVERMRP2

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

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

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

Bloo

d

LIVERMRP2

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

Removal of Hg

Amplifying and Augmenting Natural Detoxification Systems with IMD,

Clear Way Cofactors and Nanosphere Liposomal Agents

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

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

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

Phase I

Phase III

Phase IIGlutathione Conjugation

Sulfation Glucuronidation

OATP

Bloo

d

LIVER

MRP2

Normal Small Intestine

Cellular MRP1

Oxidative ActivationPhase I

Phase III

Phase II

Oxidative Activation

Glutathione Conjugation

Sulfation Glucuronidation

OATP

Bloo

d

LIVERMRP2

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

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

Bloo

d

LIVER

MRP2

Normal Small Intestine

Cellular MRP1

Oxidative Activation

AccumulationEnterohepatic Circulation

of Hg

DrainageIMD Blocking Enterohepatic

Circulation of Hg

LOW EXCRETION HIGH EXCRETION!

Stop Reabsorption

Half-life times – Iraq Poisoning

Genetically Sensitive Population ~12%

Pathways Out – Clear Way

= Greatly Facilitated Elimination!!!

Transporters Open & Recirculation

Interrupted

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 M

eHg

(ng/

mL)

0.000

0.050

0.100

0.150

0.200

0.250

0.300

0.350

Feca

l MeH

g (n

g/g-

ww

)

blood MeHgFecal MeHg Excretion

Small Clinical Trial Results

  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

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!

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

Hg(II)

MeHg

Hg Detox Product ComparisonMaterial Area of

ActionHg-specific

Binding Safety Efficacy Risks

IMD Intestinal Yes High High Low

DMSA Blood/ Kidney Yes Low High Kidney, Liver,

Demineralization

DMPS Blood/ Kidney Yes Low High Kidney, Liver,

Demineralization

EDTA Blood/ Kid/Intest No 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!

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

Chemoprevention by Keap1-Nrf2 Signaling Pathway by Phase II Inducers

Kwak et al., 2004, Mutation Research, 555:133-148

“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

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

Flavanols (Polyphenolics)

Epicatechin – in green tea, cocoa; monomer for OPC’s from Pine Bark, Grape seeds

Ellagic Acid -Pomegranates

Quercetin – Fruit and Vegetable Skins

Clear Way Polyphenolic:

Haritaki

Coordinated Expression of Phase II and III

MRP2 and GSTπ co regulated

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

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 SupportLiposomal Vitamin C with R-Lipoic AcidLiposomal GlutathioneLiposomal EDTA with R-Lipoic Acid

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

Therasomal DetoxLiposomal 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

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