Detox FORMULA

Healthcare Professionals Product Guide

Formulated to help support the liver*
Scientifically Tested for Safety and Efficacy.
This is an educational publication provided to
help licensed healthcare professionals understand
the science upon which Detox Formula is based
and the mechanism of action by which Detox
Formula works. This guide should not be
used to sell Detox Formula and is intended
for healthcare professionals only.
The only claims that can be made for Detox
Formula are those that have been approved by
the Company.

A Scientific Product Review

COMPREHENSIVE MULTINUTRIENT SUPPLEMENT FOR LIVER DETOXIFICATION*

A Scientific Product Review

by Josh Zhu, M.D., Ph.D. and Michael Chang, Ph.D.

* These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

Detox FORMULA
For Liver Detoxification*
Summary
Pharmanex Detox Formula is a proprietary blend of
nutrients to help support the liverthe bodys detoxifying
organ. A proprietary blend of patented D-glucarate, milk
thistle extract, N-acetyl-L-cysteine and vitamin C promotes
the neutralization and elimination of toxic metabolites
and foreign chemicals in the liver. Each of these ingredients
has been shown individually to support normal liver health,
liver detoxification, bile flow, and glutathione synthesis.
Detox Formula provides scientifically supported levels of
active ingredients standardized for optimal results. Detox
Formula is recommended to be taken on a daily basis and
is intended for individuals who desire to provide dietary
support for normal liver function.*

Liver Detoxification
Toxicity is a state of excessive concentration of harmful
agents in the body. Your body defends itself from toxicity
by detoxifying harmful substances that are made in the
body, that invade our environment, or that are found in
our diet. The liver performs many important functions
including detoxification of blood, carbohydrate and lipid
metabolism, protein synthesis, and secretion of bile. The
products of digestion that are absorbed into the blood
capillaries do not directly enter general circulation. Instead,
this blood is first delivered to the liver for metabolism
and detoxification. Many of these substances must be
detoxified by the liver in order to become inactive and be
excreted from the body. These toxic metabolites and foreign
chemicals can be produced endogenously as byproducts
of normal metabolism, or can be ingested in pharmaceutical
drugs, nicotine, industrial and environmental chemicals,
food additives or cooking byproducts (nitrates, polycyclic
aromatic hydrocarbons), and alcohol. Many of the substances that must be modified by the liver are fat-soluble
nonpolar compounds that must be converted into watersoluble compounds to be excreted. Water-soluble derivatives
of these toxic metabolites and foreign chemicals are less
biologically active and, because of their increased water
solubility, are more easily excreted by the kidneys into
the urine (Fox SI, 1993).

Phase I Detoxification
The first phase of detoxification chemically alters the
composition of toxic metabolites or foreign chemicals
through the cytochrome P450 monooxygenase system.
Cytochrome p450 (CYP) enzymes are found in most tissues
but are predominantly found in the liver (Guengerich FP,
1988). According to Hardman, humans have 12 genetically determined cytochrome P450 enzyme families, of
which three, the CYP1, CYP2, and CYP3 families are
involved with most drug transformations (1996). The P450
enzymes are involved in hydroxylation reactions (addition
of OH- groups) that result in increased solubility in
metabolism and excretion of toxic compounds. In most
cases, these compounds are made inactive and are readily
excreted, primarily via the kidneys (urine), and also via the
gut (bile). However, this process occasionally leads to either
formation of the active substance or formation of even more
toxic metabolites (Guengerich FP, 1988).

Phase II Detoxification
Many substances require additional detoxification
after phase I to become inactivated and excreted. During
phase II detoxification, drugs and toxins are conjugated
with (attached to) a polar group via seven different pathways
leading to a water-soluble compound that can be excreted.
These pathways include conjugation with glutathione,
acetate, glucuronic acid, sulfate, or amino acids. Most of
these toxins undergo conjugation via glucuronidation
(Shils ME, 1999, Hardman JG, 1996). Glucuronidation
uses the oxidation of glucuronic acid to generate three
metabolites: D-glucaric acid, D-glucaro-6,3-lactone, and
D-glucaro-1,4-lactone. These compounds promote the
binding and removal of harmful substances during
phase II detoxification.
As discussed by Walaszek, Detoxification of toxins
and foreign substances is not only restricted to the rate
of conjugation, but also to the rate of glucuronidation
reversal by beta glucuronidase (1990). Beta glucuronidase
is an enzyme that has the capacity to prevent or reverse
glucuronidation. The role of glucuronidation and beta
glucuronidase in the body is very clear in the scientific
literature (Walaszek Z, 1990). Once a toxin is conjugated,
it can be taken to the kidneys or gut for excretion. Beta
glucuronidase is able to reverse the conjugation in the gut,
allowing the toxin to be reabsorbed and circulate through
the blood stream again. This reversal process can result
in re-circulation of toxins and foreign substances in an
active form, which must be re-directed through liver
detoxification before they can be excreted.

* These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

Liver Glutathione
Glutathione is the livers most important antioxidant
for both phase I and II detoxification pathways. Phase I
detoxification enzymes also rely on liver glutathione as a
cofactor and can deplete the supply of liver glutathione to
the point that there is not enough left for phase II detoxification. It is essential to have enough liver glutathione
reserves to enable detoxification of toxic metabolites and
foreign chemicals to complete detoxification by phase II
enzymes. An adequate supply of glutathione (GSH) is
necessary for the formation of glutathione S-transferase
(GST), which catalyzes the conjugation of glutathione to
water-soluble substances produced from cytochrome p450
activity. These transformed metabolites are rendered less
toxic and more soluble for excretion (Casseaud LF, 1979).

Common Limiting Factors

There are two phases of liver detoxification, as
described below. Liver enzyme activity, nutrient availability, and differences in enzyme expression due to genetics,
disease, and age can affect liver detoxification. According
to Shils (1999), there are large genetic differences in
detoxification in individuals, and this is supported by the
observed individual differences in metabolism for many
drugs. Phase II detoxification may be inhibited by the
lack of necessary cofactors or substrates; this lack may
often be attributed to the diet. The substrates needed for
detoxification include a sufficient energy source, protein,
fatty acids, iron, glucose, sulfur-containing amino acids,
and glutathione. With aging, decreases in liver blood
flow and liver mass contribute to a decline in detoxification capacity with a corresponding increase in circulating
active drug levels. The decrease in phase I detoxification
is more commonly affected than that in phase II (Shils
ME, 1999).

Milk thistle fruit consists of ripe seed of Silybum marianum (L.) Gaertner [Fam. Asteraceae]. Milk thistle seeds
contain a variety of chemical components that contribute
to its liver protective activity, including flavonoids,
flavonolignans, and others. Milk thistle seeds contain
flavonoids such as dehydrokaempferol, quercetin, and
taxifolin (Hobbs C, 1984, Morazzoni P, 1995); however, the
primary active constituents of milk thistle are the flavonolignans, also known as silymarin, which is an entire group
of active principles found only in the seeds of milk thistle.
Silymarin consists of three isomers, named silybin, silydianin,
and silychristin (Wagner H, 1974, Tittel G, 1997). Detox
Formula provides a 30:1 milk thistle extract standardized
to 80% silymarin.*
N-acetyl-L-cysteine (NAC) is a specially modified form of
the dietary amino acid cysteine. When taken orally, Nacetyl-L-cysteine is converted into the amino acids L-cysteine and glutathione. Detox Formula also provides vitamin
C as calcium ascorbate, a well-tolerated and bioavailable
form of buffered vitamin C. Vitamin C has also been
shown to promote glutathione levels in the liver*
(Nakano H, 1995).

Health Benefits
Detox Formula is a proprietary blend of nutrients to
help support the liver and liver detoxification by supporting
both phases of liver detoxification for comprehensive
protection from harmful toxins. The ingredients in Detox
Formula also protect and maintain healthy liver cells,
stimulate the normal growth of healthy liver cells, promote
liver glutathione synthesis, and stimulate normal bile flow.
These mechanisms of action address various aspects of
liver health, and are described below whenever appropriate.*

Calcium D-Glucarate
Primary Active Constiuents
Detox Formula provides a proprietary blend of calcium
D-glucarate, milk thistle extract, N-acetyl-L-cysteine and
vitamin C.
Calcium D-glucarate provides glucaric acid in a salt
form chemically bound to calcium. Glucaric acid is a
compound produced endogenously in humans and is
found in highest concentrations in grapefruit, apples,
oranges, and cruciferous vegetables (Walaszek Z, 1997).
Calcium D-glucarate has been shown to be converted to
and provide a sustained release of D-glucaro-1,4 lactone
(Wattenberg LW, 1992, Walaszek Z, 1997).*

Calcium D-glucarate supports the livers phase II detoxification system by providing a dietary substrate for production
of D-glucaro-1,4 lactone. Calcium D-glucarate (as D-glucaro-1,4 lactone) is able to bind to beta glucuronidase,
which inhibits the enzyme from binding to the toxins,
allowing the conjugated toxin to be excreted from the
body (Wattenberg LW, 1992). A review published in the
August 2002 issue of Alternative Medicine Review discusses
research demonstrating that short and long-term supplementation in animals with calcium D-glucarate can inhibit as
much as 70 percent of beta glucuronidases activity (Altern
Med Rev, 2002, Dwivedi C, 1990). D-glucarate metabolites
have been identified and shown to inhibit beta glucuronidases activity in key organs such as the liver, gastrointestinal tract (small & large intestines, microflora), lungs,

* These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

and the blood (Dwivedi C, 1990). In another study,

Walaszek identified that calcium D-glucarate has been
shown to be absorbed and utilized by the body and is
held in the liver and gastrointestinal tract three to four
times higher than the blood (Walaszek Z, 1997).
Calcium D-glucarate has been studied for over 30
years and has been used in animal and in-vitro studies to
show significant effects against toxic metabolites and foreign
chemicals, including polycyclic aromatic hydrocarbons,
aromatic and heterocyclic amines, nitrates, steroid hormones,
and fungus (Dutton GJ, 1980, Dwivedi C, 1990,
Walaszek Z, 1990, Walaszek Z, 1997, Anonymous, 2002,
Walaszek Z, 1988, Walaszek Z, 1986, Walaszek Z, 1990).
Over 20 animal studies have been performed showing
that calcium D-glucarates powerful action protects normal
cell growth and replication in the presence of these toxic
metabolites and foreign chemicals (Oredipe OA, 1992,
Walaszek Z, 1990, Abou-Issa H, 1998, Walaszek Z,
1986, Walaszek Z, 1988).

Milk Thistle
Milk thistle naturally contains the antioxidant silymarin,
which helps support the liver by helping to counter the
effects of pollutants, alcohol, pesticides and other toxins
from our environment, diet and lifestyles. The therapeutic
activity of milk thistle in liver detoxification can be
attributed to multiple mechanisms of action. Key constituents in milk thistle, including silymarin, may enhance
the activity of liver enzymes involved in phase I detoxification and boost liver antioxidant glutathione levels
(Valenzuela A, 1985). In addition, milk thistle may also
promote the stimulation of normal bile flowthe livers
second line of defense against toxic chemicals. Bile manufactured by the liver acts as a carrier to effectively eliminate toxins from the body, so when bile production is
inhibited, this can lead to increased retention of toxic
substances (Lawrence Review, 1998).
A number of studies suggest that it is the antioxidant
characteristics of the silymarin-flavonolignan complex that
are primarily responsible for liver-protecting activity
(Lawrence Review, 1985, Valenzuela A, 1989, Werback M,
1994, Bindoli A, 1977, Carallini L, 1978, Valenzuela A,
1986, Muzes G, 1991, Locher R, 1998). Milk thistle can
alter and stabilize the structure of the outer cell membrane
of the hepatocytes in such a way as to prevent penetration
of a toxin, and can stimulate the regenerative ability of the
liver and the formation of new hepatocytes (Blumenthal
M, 2000, McPartland, 1996). Several reviews of double-blind
studies discuss results showing the therapeutic benefits of milk
3

thistle silymarin in protecting the liver from toxic agents

(Carallini L, 1978, Feher J, 1989, Feher J, 1990, Ferenci P,
1989, Hikino H, 1988, Bone K, 1996, Morazzoni P, 1995).
Liver toxicity induced by toxic agents produce free radicals
and lipid peroxidation and silymarin has been shown to
fight against lipid peroxidation in liver microsomes
(Bosiso E, 1992).
Several studies suggest that milk thistle provides liver
protective effects against hepatotoxic agents, including
pharmaceutical drugs and alcohol (Hahn G, 1968, Bone
K, 1996, Davila J, 1989, Fintelmann V, 1980, Grungreiff
K, 1995, Kurz-Dimitrova D, 1971, Szilard S, 1988). It was
shown that milk thistle could also counter metabolic changes
in cases of altered hepatic functions affecting the bioavailability of aspirin (Mourelle M, 1988). An in vitro study also
suggested that milk thistle has cytoprotective activity against
toxicity induced by acetaminophen (Shear N, 1995). In a
double-blind, placebo controlled trial, biochemical parameters for hepatic function returned to normal much sooner
in the milk thistle control group compared to those given
a placebo (Fintelmann V, 1980). Results of a number of
investigations have shown that milk thistle may improve
liver function in alcoholic patients without adverse side
effects and counter alcohol-induced liver damage when
administered prior to alcohol consumption (Der Marderosian
A, 1988, Desplaces A, 1975, DiMario ER, 1981, Fantozzi
R, 1986). Lastly, research over the past four decades in
Europe has confirmed repeatedly the effectiveness of milk
thistle in treating a wide array of liver conditions, with
extracts of the seed being shown to protect liver cells from
damage stemming from chronic and acute hepatitis
(Lawrence Review, 1985, Bode JC, 1977, Foster S, 1996).

N-Acetyl-L-Cysteine
N-acetyl-L-cysteine boosts liver glutathione levels for
both phase I enzyme activity and phase II glutathione
conjugations. N-acetyl-L-cysteine is an excellent source
of sulfhydryl groups and is converted in the body into
metabolites capable of stimulating glutathione synthesis,
promoting detoxification and acting directly as a free radical
scavenger. Studies have provided evidence that multiple
mechanisms contribute to N-acetyl-L-cysteines role in
liver detoxification and liver protection. These include
detoxification of reactive compounds due to the antioxidant
and nucleophilic properties and replenishment of liver
glutathione stores (De Flora S, 1995).
N-acetyl-L-cysteine and vitamin C administration have
been shown to improve levels of phase I detoxification
enzymes, including total CYP content (+35%) and

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CYP3A content (+100%), in animal studies (Clarke J,

1996, Berg-Candolfi M, 1996). Results from animal studies
suggest that N-acetyl-L-cysteine enhances concentrations
of L-cysteine within hepatocytes providing a substrate for
glutathione synthesis (Nakano H, 1995, Sener G, 2003).
In an eight-week double blind, placebo-controlled trial,
blood glutathione levels significantly increased after
N-acetyl-L-cysteine administration in HIV patients. These
findings suggests that N-acetyl-L-cysteine therapy could
be valuable for other clinical situations in which glutathione
deficiency or oxidative stress play a role in disease pathology
including hepatitis, rheumatoid arthritis, liver cirrhosis,
diabetes, Parkinsons disease and septic shock (De Rosa
SC, 2000). Interestingly, acetaminophen poisoning causes
liver damage by depleting liver glutathione; a high dose
treatment course (i.e. 20 grams) of N-acetyl-L-cysteine is
currently the mainstay as an acetaminophen antidote
(Kelly GS, 1998).

Vitamin C
Vitamin C is also involved in glutathione synthesis
and has also been shown to boost liver glutathione levels
for phase I enzyme activity and phase II glutathione conjugations. A study by Das et al, found that administration
of vitamin C in animals resulted in a remarkable improvement of glutathione, lipid peroxide, superoxide dismutase,
glutathione peroxidase, and catalase (Das KK, 2001). The
total liver content of P-450 enzymes has been shown to
correlate with the excretion of D-glucaric acid in the urine,
and is a method for evaluation of the livers functional
reserve (Hanaue H, 1993). A clinical trial found that after
vitamin C administration (1 g), the excretion of urinary
D-glucaric acid was significantly lower, suggesting vitamin
C-induced activation by P-450 enzymes.

Proprietary Processing
Manufacturing standards are strictly followed to ensure
the creation of natural supplements with pharmaceutical-like
quality. Detox Formula provides standardized ingredients
with known content and uniform consistency. All ingredients are tested for purity, and where applicable, ingredients are certified pure by microbial testing, such as tests
for Salmonella, E. coli, other coliforms, Staphylococcus
aureus, total plate counts, yeasts, molds and pesticide
residues. Our manufacturers go through a detailed selection
and certification process to assure their compliance with
Good Manufacturing Practice (GMP) standards set by the
Food and Drug Administration (FDA).

Side Effects
Detox Formula has no side effects when used as recommended. However, a mild laxative effect has been observed
in occasional instances with milk thistle administration
(Blumenthal M, 1998).

Safety and Toxicity

Detox Formula is safe when used as recommended.
Calcium D-glucarate has been shown to be safe for human
consumption (Walazsek Z, 1990, Heerdt AS, 1995).
Studies have shown that there is no toxicity with levels
of calcium D-glucarate at doses up to 10 grams per day
(Slaga T, 1999).
Milk thistle has been used as a food for centuries
(Foster S, 1996), and in both human and animal studies,
seed extracts have been shown to be devoid of significant
adverse side effects (Lawrence Review, 1985, Der
Marderosian A, 1988, Foster S, 1996). Long-term clinical
trials on humans have not generated any evidence of toxicity or teratogenic effects (Bone K, 1996, Foster S, 1996).
Administration of N-acetyl-L-cysteine at 1600 mg/day
has been shown to be safe and nontoxic. The major toxicities reported were bad taste and gastrointestinal disturbances (Pendyala L, 1995). The Tolerable Upper Intake
Level (UL) for adults with vitamin C is set at 2g/day; the
adverse effects upon which the UL is based are osmotic
diarrhea and gastrointestinal disturbances (NAS, 2000).
Considerable evidence from clinical trials has revealed no
pattern of adverse effects with intakes up to 10 grams/day
over several months. The evidence of adverse effects of
vitamin C is so nebulous that no Lower Observed
Adverse Effects Level (LOAEL) can be established. The
No Observed Adverse Effects Level (NOAEL) has been
set at more than 1000 mg (Hathcock, 1997).

Contraindications and Drug Interactions

If you are allergic to any component of this product,
pregnant or nursing, have a medical condition, or are
taking a prescription medication, please consult a physician.
The ingredients in Detox Formula have been shown to
promote liver detoxification, which may affect the metabolism of prescription medicines in some people. Individuals
with active liver disease should consult with their physician before taking Detox Formula.

**These
Thesestatements
statementshave
havenot
notbeen
beenevaluated
evaluatedby
bythe
theFood
Foodand
andDrug
DrugAdministration.
Administration.This
Thisproduct
productisisnot
notintended
intendedtotodiagnose,
diagnose,treat,
treat,cure
cureororprevent
preventany
anydisease.
disease.

Directions for Use

Detox Formula is intended for individuals who desire
to provide dietary support for normal liver function.*
Take one (1) capsule with liquids with your morning and
evening meals. Take consistently for best results.

How Supplied
Pharmanex Detox Formula contains a one-month
supply of 60 capsules. Each capsule provides 125 mg
D-glucarate, 70 mg silymarin (from milk thistle extract),
125 mg N-acetyl-L-cysteine, and 150 mg vitamin C.

Storage
Store in a cool, dry place. Avoid excessive heat.
Protect from light.

Shelf Life
Expiration date and lot code numbers are stamped
on the side of the bottle.

Warnings
Keep out of reach of children. If you are pregnant or
nursing, or taking a prescription medication, consult a
physician before using this product.

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* These
statements
Foodand
andDrug
Drug
Administration.This
product
is intended
not intended
to diagnose,
treat,orcure
or prevent
any disease.
* These
statementshave
havenot
notbeen
beenevaluated
evaluated by the Food
Administration.
This product
is not
to diagnose,
treat, cure
prevent
any disease.

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* These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

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* These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

The Pharmanex 6S Quality Process

Central to the Pharmanex mission of transforming time-honored, traditional preparations into health promoting botanical products with known content and consistent activity is the Pharmanex 6S Quality Process.

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Active ingredients are isolated and studied.

Standardization

Strict standardization to at least one relevant marker molecule is required.

Proprietary processing methods to increase consistency and ensure measured dose

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Safety is assessed from available research.

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Substantiation

Documented pre-clinical and clinical studies are reviewed.

Pharmanex sponsored studies are initiated when appropriate.

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