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* Metabolic Detoxification
METABOLIC DETOXIFICATION
METABOLIC DETOXIFICATION
Contributor(s): Dr. Shayna Sandhaus, PhD
Table of Contents
1. Overview
2. Introduction
3. Toxin and Toxicant Exposure
4. Overview of Xenobiotic Metabolism
5. The Three Phases of Detoxification
6. Balance of Phase I and Phase II Reactions
7. Additional Aspects of the Detoxification Process
8. Nutrients
9. References
1 OVERVIEW
SUMMARY AND QUICK FACTS FOR METABOLIC DETOXIFICATION
* The body has many elegant mechanisms for eliminating potentially harmful
compounds. Metabolic detoxification refers to the pathways by which the body
processes and removes harmful compounds.
* In this protocol, learn about toxic compounds and strategies for minimizing
exposure to those toxins. Discover natural interventions that, when combined
with healthy lifestyle practices, can help the body maintain optimal function
of its detoxification pathway.
* Sulforaphane is a healthful compound found in cruciferous vegetables like
broccoli and bok choy. Supplementation with sulforaphane has been shown, in
several studies, to promote the body’s natural detoxification process.
WHAT IS METABOLIC DETOXIFICATION?
Metabolic detoxification, within the context of this protocol, is the pathway by
which the body processes unwanted chemicals for elimination. The body
metabolizes xenobiotics (foreign chemicals) and unnecessary endobiotics
(endogenously produced chemicals) so they can be excreted.
Excess hormones, environmental toxicants, and prescription drugs are all cleared
via the same enzymatic detoxification systems. Metabolic detoxification is
therefore essential for protecting the body from environmental factors and
maintaining internal homeostasis.
Natural interventions, such as B vitamins and sulforaphane, may help support
detoxification pathways by promoting the activity of essential enzymes.
Note: The body is generally very effective at detoxifying itself. Providing the
body with essential vitamins, minerals, and other nutrients is the best way to
ensure proper detoxification. Many diets and trends that claim to “detox” the
body are pushing the boundaries of scientific plausibility and may even be
harmful.
HOW DOES THE BODY DETOXIFY ITSELF?
The metabolic detoxification process is comprised of three essential steps:
* Phase I—enzymatic transformation:
* Purpose is to chemically transform compounds from lipid-soluble into more
water-soluble
* Generally carried out by cytochrome P450 (CYP) enzymes
* Phase II—enzymatic conjugation:
* Purpose is to further increase water solubility and decrease reactivity of
phase I products
* Generally carried out by UDP-glucuronlytransferases (UGTs), glutathione
S-transferases (GSTs), and sulfotransferases (SULTs)
* Phase III—transport:
* Purpose is to excrete water-soluble compounds from the cell
* Generally carried out by ATP-binding cassette (ABC) transporters
Note: Products of phase I are often more toxic than the original compounds.
Phase II reactions neutralize the products to decrease their toxicity. Several
factors, including dietary influences, smoking and consuming alcohol, advanced
age, and certain diseases may cause phase II enzymes to become overwhelmed
(leading to toxicity, such as seen in acetaminophen overdose).
HOW CAN YOU MINIMIZE EXPOSURE TO TOXINS/TOXICANTS?
* Choose cleaning products that are free of volatile organic compounds
* Choose wood, tiles, or other alternatives for flooring instead of carpet
* Use bisphenol A (BPA)-free or phthalate-free plastic containers; avoid
warming food in plastic
* Choose organic produce when possible
* Wash fruits and vegetables before consuming or remove peel
* Limit intake of processed foods
* Cook foods at lower temperatures; avoid charring
WHAT NATURAL INTERVENTIONS MAY HELP THE BODY DETOXIFY?
* Vitamins. Deficiencies in vitamins A, B2, B3, B9 (folate), C, and E are
linked with decreased phase I activity and can slow the metabolism of certain
drugs. B vitamins are also particularly important as cofactors in phase II
reactions.
* Minerals. Deficiencies in iron, calcium, copper, zinc, magnesium, and
selenium have been shown to reduce phase I enzymatic activity.
* Methionine and cysteine. The reduced glutathione for GST conjugation requires
adequate dietary sulfur-containing amino acids (methionine or cysteine) for
activity.
* Flavonoids. Several flavonoids have demonstrated mild inhibition of multiple
CYPs in animal models (which can help when phase II enzymes are overloaded);
these include genistein, diadzein, and equol from soy, and theaflavins from
black tea.
* Green tea extracts. Tannins from green tea can increase CYP activity in vivo,
but also increase phase II activity (GST and UGT).
* Sulforaphane. Sulforaphane, an isothiocyanate found in broccoli and other
cruciferous vegetables, is among the most potent natural inducers of phase II
detoxification enzymes.
* D-limonene. D-limonene has some chemopreventive activity due to its induction
of phase I and II enzymes. In rats, D-limonene has been shown to increase
total CYP activity, intestinal UGT activity, and liver GST and UGT activity.
* N-acetyl cysteine (NAC). NAC can provide sulfur for glutathione production.
It is effective at reducing oxidative stress, particularly due to heavy metal
toxicity.
* Milk thistle. The milk thistle derivative silymarin promotes detoxification
by several complementary mechanisms. It can act as an antioxidant to lower
the liver oxidative stress associated with toxin metabolism, which conserves
cellular glutathione levels.
* Artichoke. Artichoke and other plants and vegetables can stimulate bile flow,
which is essential for toxin excretion.
* A variety of natural products have been shown in vitro or cell culture to
directly increase activity of phase II enzymes; these include
epigallocatechin gallate (EGCG), resveratrol, curcumin and its metabolite
tetrahydrocurcumin, alpha lipoic acid, alpha tocopherol, lycopene, gingko
biloba, allyl sulfides from garlic, among others.
* Other natural interventions that may be helpful for detoxification include
calcium-D-glucarate, chlorophyllin, probiotics, and derivatives of quercetin.
2 INTRODUCTION
Detoxification ("detox") has broad connotations ranging from the spiritual to
the scientific, and has been used to describe practices and protocols that
embrace both complementary (fasting, colonic cleaning) and conventional
(chelation or antitoxin therapy) schools of medical thought—as well as some that
push the boundaries of scientific plausibility (such as ionic foot
detoxification).
In the context of human biochemistry (and this protocol), detoxification can be
described with much more precision; here it refers to a specific metabolic
pathway, active throughout the human body, that processes unwanted chemicals for
elimination. This pathway (which will be referred to as metabolic
detoxification) involves a series of enzymatic reactions that neutralize and
solubilize toxins, and transport them to secretory organs (like the liver or
kidneys), so that they can be excreted from the body. This type of
detoxification is sometimes called xenobiotic metabolism, because it is the
primary mechanism for ridding the body of xenobiotics (foreign chemicals);
however, detoxification reactions are frequently used to prepare unneeded
endobiotics (endogenously-produced chemicals) for excretion from the body.
Excess hormones, vitamins, inflammatory molecules, and signaling compounds,
amongst others, are typically eliminated from the body by the same enzymatic
detoxification systems that protect the body from environmental toxins, or clear
prescription drugs from circulation. Metabolic detoxification reactions,
therefore, are not only important for protection from the environment, but
central to homeostatic balance in the body.
This protocol describes nutritional approaches for general optimization of
metabolic detoxification; it is designed to provide a foundation for proper
function of this critical system. Specific health concerns may require
supplementary detoxification "intervention" protocols (such as "Heavy Metal
Detoxification" or "Alcohol: Reducing the Risks").
3 TOXIN AND TOXICANT EXPOSURE
Toxins are poisonous compounds produced by living organisms; sometimes the term
"biotoxin" is used to emphasize the biological origin of these compounds.
Man-made chemical compounds with toxic potential are more properly called
toxicants. Toxins and toxicants can exert their detrimental effects on health in
a number of ways. Some broadly act as mutagens or carcinogens (causing DNA
damage or mutations, which can lead to cancer), others can disrupt specific
metabolic pathways (which can lead to dysfunction of particular biological
systems such as the nervous system, liver, or kidneys).
The diet is a major source of toxin exposure. Toxins can find their way into the
diet by several routes, notably contamination by microorganisms, man-made
toxicants (including pesticides, residues from food processing, prescription
drugs and industrial wastes), or less frequently, contamination by toxins from
other "non-food" plant sources.1,2 Some of the toxic heavy metals (lead,
mercury, cadmium, chromium), while not "man-made," have been
released/redistributed into the environment at potentially dangerous levels by
man, and can find their way into the diet as well. Microbial toxins, secreted by
bacteria and fungi, can be ingested along with contaminated or improperly
prepared food.
Even the method of food preparation has the potential for converting
naturally-occurring food constituents into toxins.3 For instance, high
temperatures can convert nitrogen-containing compounds in meats and cereal
products into the potent mutagens benzopyrene and acrylamide, respectively.
Smoked fish and cheeses contain precursors to toxins called N-nitroso compounds
(NOCs), which become mutagenic when metabolized by colonic bacteria.
Outside of the diet, respiratory exposure to volatile organic compounds (VOCs)
is a common risk which has been associated with several adverse health effects,
including kidney damage, immunological problems, hormonal imbalances, blood
disorders, and increased rates of asthma and bronchitis.4
One of the greatest sources of non-dietary toxicant exposure is the air in the
home.5 Building materials (such as floor and wall coverings, particle board,
adhesives, and paints) can "off-gas" releasing several toxicants that can be
detected in humans.6 For example, a toxic benzene derivative commonly used in
disinfectants and deodorizers was detected in 98% of adults in the Environmental
Protection Agency's (EPA) "TEAM" study.7 In another EPA study, three additional
toxic solvents were present in 100% of human tissue samples tested across the
country.8
Newly built or remodeled buildings can have substantial amounts of chemical
"off-gassing," giving rise to what has been called "sick building syndrome."9
Carpet is an especially big offender, potentially releasing several neurotoxins;
in testing of over 400 carpet samples, neurotoxins were present in more than 90%
of the samples, quantitatively sufficient in some samples to cause death in
mice.10 Ironically, shortly after the TEAM report, 71 ill employees evacuated
the new EPA headquarters in Washington DC complaining claiming health problems,
which were eventually attributed to the 27,000 sq. feet of new carpet.11
Carpets also trap environmental toxins; the "Non-Occupational Pesticide Exposure
Study" (NOPES) found an average of 12 pesticide residues per carpet sampled, and
determined that this route of exposure likely provides infants and toddlers with
nearly all of their non-dietary exposure to the notorious pesticides DDT,
aldrin, atrazine, and carbaryl.12
AVOIDING TOXIN/TOXICANT EXPOSURE
While it is not possible to completely eliminate toxin/toxicant exposure from
all sources, there are ways to minimize it:
* Limit the introduction of VOCs in the home by using VOC-free cleaning
products, low-VOC paints, and choosing throw rugs instead of new carpeting13;
* Store food in bisphenol A (BPA)-free or phthalate-free containers, and avoid
reheating foods in plastic containers;
* Look for organic produce, which is grown without pesticides, and will contain
less residue than conventionally-produced fruits and vegetables (although be
aware that organic produce isn't necessarily "pesticide free")14;
* Washing fruits or vegetables can decrease some pesticide residue, although it
is not effective against all pesticide types,15 and commercial fruit and
vegetable wash solutions may not be any more effective than water alone.16
Peeling skins off of produce may help to further lower pesticide levels;
* Limit intake of processed foods. Even ones that are free of synthetic
preservatives may contain detectable amounts of toxic compounds that were
introduced (by chemical transformation) during processing. For example,
numerous toxins are produced by the high temperatures used to manufacture
some processed food ingredients.17
* Although the risk of acute toxicity from undercooking meat (food poisoning)
is likely a greater risk than toxin exposure from overcooking it, there are
ways to reduce toxin production during meat preparation: avoid direct
exposure of meat to open flame or hot metal surfaces; cook meat at or below
250°F via stewing, braising, crockpot cooking (slow food preparation methods
that utilize liquid); turn meat often during cooking, avoid prolonged cooking
time at high temperatures, and refrain from consuming charred portions.18
4 OVERVIEW OF XENOBIOTIC METABOLISM
The driving force in the evolution of sophisticated metabolic detoxification
systems was actually fairly straight forward and dependent on the ability of
water to act as a "solvent" to dissolve substances.
Since cellular membranes are primarily lipid based and impermeable to most water
soluble (scientifically: "polar") substances, the transport of water-soluble
compounds into a cell requires specialized transport proteins. By placing the
appropriate transport proteins on the cell membrane, a cell will only allow
desirable water-soluble molecules to enter, and will prevent entry of
water-soluble toxins. This same paradigm also applies when the cell needs to
excrete unwanted water-soluble compounds (like cellular wastes); they exit the
cell by a similar mechanism.
In contrast to water-soluble compounds, the lipid cell membrane presents little
barrier to lipid-soluble compounds, which can freely pass through it.
Potentially damaging lipid-soluble toxins can therefore gain free access to
cellular interiors, and are much more difficult to remove.
The metabolic detoxification systems address this problem by converting
lipid-soluble toxins into inactive water-soluble metabolites. The
"solubilization" of a toxin is accomplished by enzymes which attach (conjugate)
additional water-soluble molecules to the lipid-soluble toxin at specific
attachment points. If the toxin does not contain any of these attachment points,
they are first added by a separate set of enzymes which chemically transform the
toxin to include these molecular "handles." Following the solubilization
reactions, the chemically-modified toxin is transported out of the cell and
excreted.
These three steps or phases of removing undesirable or harmful lipid-soluble
compounds are performed by three sets of cellular proteins or enzymes, called
the phase I (transformation) and phase II (conjugation) enzymes, and the phase
III (transport) proteins.
Phase I, II, and III metabolisms have different biochemical requirements and
respond to different metabolic signals, but must work in unison for proper
removal of unwanted xenobiotics (such as toxins or drugs) or endobiotics (such
as excess hormones). Enzymes of the phase I, II, and III pathways have several
characteristics that make them well suited for their important roles.19 Unlike
most other enzymes, detoxification enzymes; can react with many different
compounds broadening the number of toxins a single enzyme can metabolize; are
more concentrated in areas of the body that are most directly exposed to the
environment (like the liver, intestines, or lungs); are inducible, meaning that
their synthesis can be increased in response to toxin exposure.
The liver is the primary detoxification organ; it filters blood coming directly
from the intestines and prepares toxins for excretion from the body. Significant
amounts of detoxification also occur in the intestine, kidney, lungs, and brain,
with phase I, II, and III reactions occurring throughout the rest of the body to
a lesser degree.
5 THE THREE PHASES OF DETOXIFICATION
PHASE I DETOXIFICATION: ENZYMATIC TRANSFORMATION
Under most circumstances, phase I enzymes begin the detoxification process by
chemically transforming lipid soluble compounds into water soluble compounds in
preparation for phase II detoxification. The bulk of the phase I transformation
reactions are performed by a family of enzymes called the cytochrome P450s
(CYPs).
CYP enzymes are relatively non-specific, each has the potential to recognize and
modify countless different toxins; after all, a mere 57 human CYPs must be able
to detoxify any potential toxin that enters the body.20 However, the cost of
this versatility is speed; CYPs metabolize toxins very slowly compared to other
enzymes. For instance, compare the predominant CYP3A4, which metabolizes 1‒20
molecules per second,21 to superoxide dismutase (SOD), which metabolizes over a
million molecules per second. Major sites of detoxification overcome the slower
speed by producing large amounts of CYPs; CYPs may represent up to 5% of total
liver proteins, and similar large concentrations can be found in the intestines.
CYPs are amongst the most well studied and best characterized detoxification
proteins due to their role in the metabolism of prescription drugs, and to their
role in metabolizing endogenous biochemicals (for example, aromatase, which
transforms testosterone to estradiol, is a CYP).22
Several other enzymes contribute to the phase I process as well, notably the
flavin monooxygenases (FMOs; responsible for the detoxification of nicotine from
cigarette smoke); alcohol and aldehyde dehydrogenases (which metabolize drinking
alcohol); and monoamine oxidases (MAO's; which break down serotonin, dopamine,
and epinephrine in neurons and are targets of several older antidepressant
drugs).23
PHASE II DETOXIFICATION: ENZYMATIC CONJUGATION
Following phase I transformation, the original lipid-soluble toxin has been
converted into a more water-soluble form. However, this reactive intermediate is
still unsuitable for immediate elimination from the cell for a couple of
reasons: 1) phase I reactions are not sufficient to make the toxin water-soluble
enough to complete the entire excretion pathway; and 2) in many cases, products
from the phase I reactions have been rendered more reactive then the original
toxins, which makes them potentially more destructive than they once were. Both
of these shortcomings are addressed by the activities of the phase II enzymes,
which modify phase I products to both increase their solubility and reduce their
toxicity. The activation of the phase II enzymes is responsible for the
anti-mutagenic and anti-carcinogenic properties of the metabolic detoxification
systems; it is widely accepted that phase II enzymes protect against chemical
carcinogenesis, especially during the initiation phase of cancers.24
At the genetic level, the production of most phase II enzymes is controlled by a
protein called nuclear factor erythroid-derived 2 (Nrf2), a master regulator of
antioxidant response.25 Under normal cellular conditions, Nrf2 resides in the
cytoplasm (the liquid inside cells within which the cells components are
contained) of the cell in an inactive state.26 However, the presence of
oxidative stress (triggered by metabolism of toxins by CYPs) activates Nrf2,
allowing it to travel to the cell nucleus.27 In the cell nucleus, Nrf2 turns on
the genes of many antioxidant proteins, including the phase II enzymes.28 In
this way, Nrf2 "senses" oxidative stress or the presence of toxins in the cell,
and allows the cell to mount an appropriate response. Nrf2 regulates the
activity of genes involved in the synthesis and activation of important
detoxification molecules including glutathione and superoxide dismutase (SOD).
It also plays an important role in initiating heavy metal detoxification, and
the recycling of CoQ10, a potent antioxidant.29-31
Certain dietary constituents (including sulforaphane from broccoli and
xanthohumol from hops) may also directly activate Nrf2 and stimulate antioxidant
enzyme activity; this may partially explain their beneficial effects on
detoxification.32
There are several families of phase II enzymes that differ significantly in
their activities and biochemistry. In several cases, phase II enzymes exhibit
redundancy—a particular xenobiotic or endobiotic can be detoxified by more than
one phase II enzyme.
UDP-glucuronosyltransferases. UDP-glucuronosyltransferases (UGTs) catalyze
glucuronidation reactions, the attachment of glucuronic acid to toxins to render
them less reactive and more water-soluble. There are several different UGTs that
are distributed throughout the body, with the liver being the major location. In
humans, many xenobiotics, environmental toxicants, and 40‒70% of clinical drugs
are metabolized by UGTs.33 The plasticizer bisphenol A34 and benzopyrene (from
cooked meats)35 are two notable examples of UGT substrates (a substrate is a
molecule upon which an enzyme acts). Intestinal UGTs may affect oral
bioavailability of several drugs and dietary supplements, and may be responsible
for chemoprevention in this tissue.36
Glutathione S-transferases. Glutathione S-transferases (GSTs) catalyze the
transfer of glutathione (a significant cellular antioxidant) to phase I
products. GSTs play a major role in the metabolism of several endobiotics,
including steroids, thyroid hormone, fat-soluble vitamins, bile acids, bilirubin
and prostaglandins.37 GSTs can also function as antioxidant enzymes, detoxifying
free radicals38 and oxidized lipids or DNA.39 GSTs are soluble enzymes that are
ubiquitous in nature and in humans, forming about 4% of the soluble protein in
the human liver and present in several other tissues (including brain, heart,
lung, intestines, kidney, pancreas, lens, skeletal muscle, prostate, spleen and
testes).40,41 Products of GST conjugation can be excreted via bile, or can
travel to the kidneys where they are further processed and eliminated in urine.
Sulfotransferases. Sulfotransferases (SULTs) attach sulfates from a sulfur donor
to endo- or xenobiotic acceptor molecules. This reaction is important both in
detoxification reactions, as well as normal biosynthesis (the addition of
sulfate to chondroitin and heparin, for example, is catalyzed by specific
SULTs).42 SULTs play a major role in drug and xenobiotic detoxification, and the
metabolism of several endogenous molecules (including steroids, thyroid and
adrenal hormones, serotonin, retinol, ascorbate and vitamin D).43 SULTs in the
placenta, uterus, and prostate are thought to play a role in the regulation of
androgen levels.44 In contrast to other phase II enzymes, SULTs can convert a
number of procarcinogens (such as heterocyclic amines from cooked meats) into
highly reactive intermediates which may act as chemical carcinogens and
mutagens.45
While the UGTs, GSTs, and SULTs catalyze the bulk of human detoxification
reactions, several other phase II enzymes contribute to the process to a lesser,
but still important extent, including:
* Methyltransferase enzymes. Methyltransferase enzymes catalyze methylation
reactions using S-adenosyl-L-methionine (SAMe) as a substrate. Catechol
O-methyltransferase (COMT) is a major pathway for eliminating excess
catecholamine neurotransmitters (such as adrenaline or dopamine). Methylation
reactions are one of the few phase II reactions that decrease water
solubility46;
* Arylamine N-acetyltransferases (NATs). NATs detoxify carcinogenic aromatic
amines and heterocyclic amines47;
* Amino acid conjugating enzymes. Acyl-CoA synthetase and acyl-CoA amino acid
N-acyltransferases attach amino acids (most commonly glycine or glutamine) to
xenobiotics. The food preservative benzoic acid is one example of a toxin
metabolized by amino acid conjugation.48
PHASE III DETOXIFICATION: TRANSPORT
Phase III transporters are present in many tissues, including the liver,
intestines, kidneys, and brain, where they can provide a barrier against
xenobiotic entry, or a mechanism for actively moving xenobiotics and endobiotics
in and out of cells.49 Since water-soluble compounds require specific
transporters to move in and out of cells, phase III transporters are necessary
to excrete the newly formed phase II products out of the cell. Phase III
transporters belong to a family of proteins called the ABC transporters (for
ATP-binding cassette),50 because they require chemical energy, in the form of
ATP, to actively pump toxins through the cell membrane and out of the cell.51
They are sometimes called the multidrug resistance proteins (MRPs), because
drug-resistant cancer cells use them as protection against chemotherapy drugs.52
In the liver, phase III transporters move glutathione, sulfate, and glucuronide
conjugates out of cells into the bile for elimination. In the kidney and
intestine, phase III transporters can remove xenobiotics from the blood for
excretion from the body.53
6 BALANCE OF PHASE I AND PHASE II REACTIONS
The products of phase I metabolism are potentially more toxic than the original
molecules, which does not present a problem if the phase II enzymes are
functioning at a rate to rapidly neutralize the phase I products as they are
formed. This, however, is not always the case. Factors which increase the ratio
of phase I to phase II activity can upset this delicate balance, producing
harmful metabolites faster than they can be detoxified, and increasing the risk
of cellular damage. Some of the factors include: diet (some foods and
supplements increase phase I enzyme activity), smoking and alcohol consumption
(both induce phase I), age (which can decrease phase II UGT, GST, and SULT
activity), sex (premenopausal women show 30‒40% more phase I CYP3A4 activity
than men or postmenopausal women), disease, and genetics.54
An illustrative (and unfortunately common) example of the consequences of phase
I/phase II imbalance is toxicity caused by overdose of the analgesic
acetaminophen (paracetamol)—the active ingredient in Tylenol. Acetaminophen
toxicity is the most common cause of liver failure in the United States.55 With
a normal therapeutic dose of acetaminophen, the drug is predominantly detoxified
by the phase II UGT and SULT enzymes. A small amount of the drug is detoxified
by a third mechanism: it is first transformed into the toxic metabolite NAPQI
(N-acetyl-p-benzoquinoneimine) by phase I CYP enzymes; and this intermediate is
detoxified by conjugation with glutathione using the phase II enzyme GST.
During acetaminophen overdose, the UGT and SULT enzymes become quickly
overwhelmed. Proportionally more of the drug undergoes the third detoxification
mechanism (transformation to NAPQI and conjugation by GST). Eventually, activity
of the phase II GST enzyme slows as glutathione stores become depleted,56 and
NAPQI is produced faster than it can be detoxified. Rising levels of NAPQI in
the liver cause widespread damage, including lipid peroxidation, inactivation of
cellular proteins, and disruption of DNA metabolism.57 Treatment for
acetaminophen overdose involves the timely replenishment of glutathione stores
through administration of the precursor amino acids for glutathione synthesis
(most commonly N-acetyl cysteine).58
7 ADDITIONAL ASPECTS OF THE DETOXIFICATION PROCESS
Several other mechanisms work in concert with the phase I, II, and III enzyme
systems to improve their efficiency or extend their functionality. While not
officially characterized as part of xenobiotic metabolism, they are nonetheless
important for reducing or mitigating toxin exposure.
BILE SECRETION
Bile secretion is a critical digestive process for the absorption of dietary
fats and fat-soluble nutrients, but also functions as the major mechanism for
moving conjugated toxins out of the liver and into the intestines, where they
can be eliminated.
ANTIOXIDATION
Antioxidation is a necessary protective measure against the harsh phase I
oxidation reactions, which frequently produce free-radical byproducts. The
production of antioxidant enzymes, many of which are under the same genetic
regulation (by Nrf2) as the phase II enzymes, is important for minimizing this
free-radical damage.
HEAVY METAL TOXICITY
Heavy metal toxicity can lead to oxidative damage by direct generation of free
radical species and depletion of antioxidant reserves.59 Mercury, arsenic, and
lead, for example, effectively inactivate the glutathione molecule so it is
unavailable as an antioxidant or as a substrate for xenobiotic detoxification60;
lead can also reduce the activity of the enzymes of that recycle glutathione.61
One method for heavy metal removal is their chelation by the cellular proteins
metallothioneins (MTs), which have a high capacity to bind various reactive
metal ions, such as zinc, cadmium, mercury, copper, lead, nickel, cobalt, iron,
gold, and silver.62 One molecule of MT can bind 7–9 zinc or cadmium ions (or any
combination of these two), up to 12 copper ions, and up to 18 mercury ions.63
Cellular stress (particularly oxidative stress), turns up MT production, which,
like the phase II enzymes, is stimulated by the activity of Nrf2.64
PREVENTION OF ABSORPTION
Prevention of absorption through trapping of potential toxins (such as surface
adhesion to another molecule in the gut, like activated charcoal or kaolin
clay)65 is an effective means of mitigating exposure; this mechanism has the
requirement of some dietary adsorbent to be taken while the toxin is in transit
in the GI tract. Uptake of potential toxins and their detoxification by
beneficial colonic microflora could have a similar effect.
WHAT YOU NEED TO KNOW ABOUT METABOLIC DETOXIFICATION
* Detoxification is the metabolic process of removing unwanted lipid-soluble
compounds from the body.
* These "unwanted" compounds can be foreign (such as an environmental
toxicants) or endogenous (toxins; such as excess hormone) in nature.
* Detoxification reactions occur throughout the body, with the liver being the
predominant detoxifying organ.
* Detoxification reactions follow three steps or "phases" that have the
ultimate goal of converting the toxin into an inert, water-soluble form for
excretion:
Phase I reactions transform the toxin into a chemical form that can be
metabolized by the phase II enzymes. Phase I reactions are performed primarily
by the cytochrome P450 enzymes.
Phase II reactions conjugate (attach) the toxin to other water-soluble
substances to increase its solubility. Each of the different types of phase II
enzymes catalyzes a different type of conjugation reaction.
* UDP-glucuronosyltransferases (UGTs) catalyze the glucuronidation of most
clinical drugs, and several environmental toxins
* Glutathione-S-transferases (GSTs) conjugate toxins with the antioxidant
glutathione; they can also directly detoxify free radicals
* Sulfotransferases (SULTs) catalyze sulfonation reactions; they may also be
important for controlling sex hormone levels
Other types of phase II reactions that are used less frequently include
methylation and amino acid conjugation reactions.
Phase III detoxification involves the transport of the transformed, conjugated
toxin into or out of cells. Different phase III transport proteins work in
concert to shuttle toxins from different parts of the body into bile or urine
for excretion.
Following detoxification reactions, the toxins are removed from the body by
excretion:
A) Products of liver detoxification often leave the body by being secreted into
the intestines in bile, but can sometimes be transported into the bloodstream
for processing by the kidneys.
B) The cells that line the intestines can detoxify toxins as they are absorbed,
and release them back into the intestinal lumen.
C) The kidneys can filter and further process toxins from circulation, excreting
them from the body as urine.
8 NUTRIENTS
Given the sheer number of diverse enzymes and transport proteins involved in
metabolic detoxification and its related pathways, it is no surprise that
detoxification depends on, and is sensitive to, a large number of dietary
factors.
Macronutrient and micronutrient intake influences phase I and II systems.
Protein deficiency decreases CYP metabolism, while high protein diets increase
it.66 The opposite effects are observed for carbohydrates; the effects of lipids
on CYP metabolism are unclear. Efficient phase I reactions require sufficiency
in several micronutrients; deficiencies in vitamins A, B2 and B3, folate, C, E,
iron, calcium, copper, zinc, magnesium, selenium have all been shown to decrease
the activities of one or more phase I enzymes, or slow the transformation of
specific drugs.67
The diverse set of phase II enzymes require an equally diverse set of essential
nutrients, especially B vitamins, as cofactors.
The reduced glutathione for GST conjugation depends on adequate dietary
sulfur-containing amino acids (methionine or cysteine), vitamin B6 for the
conversion of methionine to cysteine, as well vitamins B2 and B3 for the
activity of glutathione reductase, which recycles oxidized glutathione.
The methylation reactions use SAMe as a substrate; which, in turn, is
synthesized through folate- and vitamin B12-dependent enzymatic reactions.
The conjugation reactions of the NAT's and amino acid acyltransferases use the
cofactor acetyl-coenzyme A (acetyl-CoA), which is synthesized from vitamin B5,
using enzymes that themselves depend on multiple B vitamins.
Several phase II reactions require the energy molecule ATP in some fashion. For
example, the chemical cofactors for the phase II methylation, sulfonation,
glucuronidation, and glutathione conjugation reactions are all made using ATP;
these ATP mediated reactions are magnesium-dependent.
Flavonoids have been extensively studied in vitro and in animal models for their
ability to lower the activity of CYPs, and increase phase II enzyme activities
(except for SULTs, which they tend to inhibit).68 The inhibition of CYP activity
by naringenin (the principle flavonoid in grapefruit) has been well documented
in humans69; hence the recommendation to avoid grapefruit when taking
prescription drugs. Other flavonoids that have demonstrated mild inhibition of
multiple CYPs in animal models include genistein, diadzein, and equol from
soy,70,71 and theaflavins from black tea.72
Green tea extracts and the quercetin derivatives isoquercetin and rutin are an
exception to most other flavonoids; green tea tannins can increase CYP activity
in vivo,73 but also increase phase II activity (GST and UGT). Similarly, the
quercetin derivatives were demonstrated to increase intestinal and liver CYPs in
rats; quercetin had no effect on CYPs in this experiment.74
Nrf2 activators. 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),75 resveratrol,76
curcumin77 and its metabolite tetrahydrocurcumin, which has greater phase II
activity,78 cinnamaldehyde,79 caffeic acid phenyethyl ester, alpha lipoic
acid,80 alpha tocopherol,81 lycopene,82 apple polyphenols (chlorogenic acid and
phloridzin),83 gingko biloba,84 chalcone,85 capsaicin,86 hydroxytyrosol from
olives,87 allyl sulfides from garlic,88 chlorophyllin,89 and xanthohumols from
hops.90 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 signalling.91
Isothiocyanates derived from glucosinolates are reactive sulfur compounds with
potent chemopreventive properties; the prototypical member is sulforaphane, a
constituent of broccoli that is the subject of several human cancer trials.
Isothiocyanates such as sulforaphane and indoles such as indole-3-carbinol (I3C)
are among the most potent natural inducers of phase II detoxification enzymes.92
Sulforaphane and a derivative of I3C both directly activate Nrf2,93 which
increases the production of several protective enzymes, including GSTs, UGTs,
glutamate-cysteine ligase (which synthesizes glutathione), and NQO1.94 I3C
derivatives are also strong inducers of many phase I and II enzymes, and thus
are among the most well studied phytochemicals for detoxification, as well as
cancer prevention.95-99
Compounds from the Japanese horseradish Wasabi japonica,100,101 and benzyl
isothiocyanate (BITC)102 from cruciferous vegetables similarly stimulate phase
II enzyme activity via Nrf2 activation. Both sulforaphane and HITC also lower
CYP activity.103
Sulfur constituents from garlic are inhibitors of various CYPs,104 andinduce GST
and NQO1 activity in gastrointestinal tissues in rats.105 By activating Nrf2,
components in garlic were able to reverse the depletion of antioxidant enzymes
caused by a toxic metal compound in the livers of laboratory rats.106
D-limonene (from citrus oil) has been investigated for anticancer activity in
uncontrolled human trials and animal studies with some success107; part of this
chemopreventive activity is due to the induction of phase I and phase II
enzymes. In rats, D-limonene has been shown to increase total CYP activity,108
intestinal UGT activity109 and liver GST and UGT activity.110,111
Calcium D-glucarate is present in many fruits and vegetables, and can be
produced in small amounts in humans.112 When activated in the gut, it functions
as an inhibitor of beta-glucuronidase, an enzyme produced by colonic bacteria
and intestinal cells. In the intestines, beta-glucuronidase removes
(deconjugates) glucuronic acid from neutralized toxins—essentially reversing the
reaction catalyzed by UGTs. Deconjugation reverts the toxin to its previous
dangerous form, and allows it to be reabsorbed. Elevated beta-glucuronidase
activity has been associated with increased cancer risk.113
Chlorophyllin is a chlorophyll derivative114 that inhibits CYP activity,115 and
stimulates GST activity in cell culture and rodent models.116 The unique
chemical structures of chlorophyllin and chlorophyll enable them to bind and
"trap" toxins in the gut preventing their absorption. In animal models,
chlorophyllin and chlorophyll lower the bioavailability and accelerate the
excretion of several environmental carcinogens.117-119 Toxin trapping may partly
explain the results of a human trial of residents of Qidong, China, an area with
a high incidence of liver cancer due to exposure to aflatoxin (a toxin produced
by species of the fungus Aspergillus). Among the 180 people who took 100 mg of
chlorophyllin three times daily, urinary levels of DNA-aflatoxin conjugates (a
marker for DNA mutation) went down 55% compared to untreated people.120
Probiotics. Certain strains of probiotic bacteria may minimize toxin exposure by
trapping and metabolizing xenobiotics or heavy metals.121 Examples include the
detoxification of aflatoxin and patulin (two toxins produced by Aspergillus, a
type of mold),122 the metabolism of heterocyclic amines and
dimethylhydrazine,123 and the binding of lead and cadmium.124 Additionally, the
production of the short chain fatty acid butyrate by lactic acid bacteria (from
the fermentation of dietary fiber) has been shown to stimulate GST production in
intestinal cell culture; this may also contribute to some of the
anticarcinogenic properties of dietary fiber.125
N-acetyl cysteine can provide an alternative source of sulfur for glutathione
production. It is a free radical scavenger on its own, effective at reducing
oxidative stress, particularly due to heavy metal toxicity.126 Because it can
directly replenish glutathione stores, NAC is more effective than methionine at
preventing liver damage,127 and is the current treatment for acetaminophen
toxicity. It is an effective treatment for acute liver failure due to
non-acetaminophen drug toxicity as well.128
Milk thistle (Silybum marianum), the most well-researched plant in the treatment
of liver disease,129 contains a mixture of several related polyphenolic
compounds called silymarin. Silymarin promotes detoxification by several
complementary mechanisms. The antioxidant capacity of silymarin can lower the
liver oxidative stress associated with toxin metabolism, particularly lipid
peroxidation,130 which has the effect of conserving cellular glutathione
levels.131 Like NAC, silymarin can protect against acetaminophen toxicity
(possibly by the similar mechanism of preserving glutathione levels). Silymarin,
however, may be a more effective antidote than NAC for acetaminophen toxicity if
the treatment is delayed (in an animal model, it was effective when administered
up to 24 hours after overdose).132
Phase III transporters, while important for removing toxins from healthy cells,
can also decrease the effectiveness of pharmaceutical therapies by increasing
their clearance. This can be especially problematic with chemotherapy drugs, to
which phase III transporters enable cancer cells to become resistant. Therefore,
stimulation of phase III activity may not always be desirable.
Dietary factors can have differing effects on phase III transporters. For
example, apple polyphenols133 and sulforaphane (at levels equivalent to about
two servings of broccoli)134 both stimulate the activity of the phase III
proteins. In contrast, the curcumin metabolite tetrahydrocurcumin decreases the
activity of the phase III transporters in human cervical carcinoma and breast
cancer cell lines.135 Resveratrol decreases phase III protein synthesis which
prevented acute myeloid leukemia cells from becoming resistant to the
chemotherapy drug doxorubicin in cell culture.136 Silibinin, the chief
constituent of milk thistle,137 is also a phase III inhibitor, both in vitro and
in vivo.138
Bile flow. As a major carrier of toxins from the body, proper bile flow is a
critical final step in the metabolic detoxification process. Impairment of bile
flow (cholestasis), resulting from dysfunction within the liver or blockage of
the bile duct, can result in the buildup of liver toxins and liver injury.
Cholestasis can also be the result of the detoxification process itself; there
is increasing evidence that the detoxification and excretion of clinical drugs
into the bile can produce cholestatic liver disease.139 Artichoke has been used
for centuries in folk medicine as a liver protectant and to stimulate bile flow
(choleresis), and is the best-studied herbal choleretic agent.
Artichoke contains several antioxidants that can protect against oxidative liver
damage, as well as caffeoylquinic acids, which have been shown to stimulate bile
flow in animal models.140 Caffeoylquinic acids may also be responsible for the
choleretic properties of yarrow,141,142 fennel,143 and dandelion.144
Andrographis, garlic, cumin, ginger, ajowan (carom seed), and curry and mustard
leaf have also been shown to stimulate bile flow or bile acid production in
rodent models.145-148
DISCLAIMER AND SAFETY INFORMATION
This information (and any accompanying material) is not intended to replace the
attention or advice of a physician or other qualified health care professional.
Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle
change intended to prevent or treat a specific disease or condition should first
consult with and seek clearance from a physician or other qualified health care
professional. Pregnant women in particular should seek the advice of a physician
before using any protocol listed on this website. The protocols described on
this website are for adults only, unless otherwise specified. Product labels may
contain important safety information and the most recent product information
provided by the product manufacturers should be carefully reviewed prior to use
to verify the dose, administration, and contraindications. National, state, and
local laws may vary regarding the use and application of many of the therapies
discussed. The reader assumes the risk of any injuries. The authors and
publishers, their affiliates and assigns are not liable for any injury and/or
damage to persons arising from this protocol and expressly disclaim
responsibility for any adverse effects resulting from the use of the information
contained herein.
The protocols raise many issues that are subject to change as new data emerge.
None of our suggested protocol regimens can guarantee health benefits. Life
Extension has not performed independent verification of the data contained in
the referenced materials, and expressly disclaims responsibility for any error
in the literature.
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