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Detoxification 101I mentioned Phase I
liver enzymes and PST above. Your liver changes chemicals in your body (that
come in from food and from the environment, or that your body makes) into other
chemicals that can be disposed of. This is called biotransformation, and creates
lots of free radicals. Biotransformation is broadly broken into Phase I and
Phase II pathways. The Phase I enzymes are
mostly of the Cytochrome p450 family. These combine oxygen with the parent
molecule and oxidize it. This makes some toxins even more poisonous. This is
bioactivation. To rid itself of poisons that are produced by Phase I
bioactivation, the liver employs a Phase II system in which the oxidized
chemicals have some other substance attached to them making them soluble so they
can be excreted readily by the kidneys. This is the preferred action, but if the
load on the liver is high, or if the toxins are present in large amounts, or if
the Phase II enzyme systems are not working well, or if there are insufficient
numbers of Phase II enzymes or of their necessary substrates (sulfate,
glutathione) one of three negative possibilities may occur instead. There may be
tissue damage, such as toxic liver damage, or it may react with a cell protein
forming an antigen. The antigen may lead to a negative immunological reaction;
or, finally, the toxin may bind with DNA causing a mutation that can lead to
cancer. Individuals with
immune, CNS, and endocrine disorders often present with complex xenobiotics
(foreign chemicals) involving disturbances in the cytochrome p450 super family
of liver enzymes that parallels disturbances in peroxisomal function. The
cytochrome p450s are responsible for the biotransformation of endogenous
compounds including fatty acids, steroids, prostaglandins, leukotrienes, several
drugs like Tylenol™,
and vitamins, as well as the detoxification of exogenous compounds resulting in
substantial alterations of p450s as xenobiotics may turn off or greatly reduce
the expression of these constitutive isoenzymes. Low protein intake has been
found to increase markedly the toxicity of a number of xenobiotics. Excessive
histidine, however, increased liver cytochrome P-450, whereas excessive tyrosine
markedly decreased liver cytochrome P-450. P450 production may be inhibited or
substantially used up by H2 blockers, some antacids, SSRIs (Prozac™,
Paxil™,
Zoloft™,
etc.), and perhaps one fifth of all medications. In this manner, these drugs
have the potential to worsen, or even create, a susceptibility to many common
chemicals, and Chemical Sensitivities/Environmental Illness and related
syndromes. Prozac™
also loads the body with fluoride. The oddness of some of these symptoms may
prompt some doctors to prescribe SSRIs, thus making the situation worse! Long-term inhibition of
heme (a deep red iron containing pigment found in hemoglobin) synthesis due to
p450 insufficiency may cause anemia. This, and the resulting metabolic
reductions, may cause reductions in the body’s ability to maintain itself,
showing up as a wide variety of health problems similar to those of Wilson’s
Syndrome, as well as behavioral and cognitive problems. In other words, these
liver enzymes are inhibited, and aromatics, such as benzene-ring containing
chemicals, aldehydes, epoxides, and organic volatiles, build to toxic levels.
This is the condition of these with “PST syndrome”. As a result, some herbs,
listed later, that enhance these enzymes may be very beneficial for a time. The balance between
Phase I and Phase II is critical, and stimulation of Phase I in absence of
stimulation of Phase II reactions is dangerous. When toxins are high, we want to
enhance Phase I and Phase II together so there is a smooth passage of these
toxic products from Phase I to Phase II and out of the body. Sluggish action of
Phase II due to low sulfate/glutathione levels, or to low PST enzyme activity,
can lead to increased concentrations of toxic neurotransmitter amines, peptides,
steroids, bile acids, GAGs, and phenol amines, and to prolonged effects on the
central nervous system. Accumulation of toxic
substances depends on an individual’s quantity and quality of immune and
enzyme detoxication responses along with his age and overall health.
Accumulation may also occur with constant exposures that allow no time for
clearing. The nutritional state needed to maintain good health is depleted by
this toxic exposure. Overload of pollutants can increasingly tax the
detoxification systems, eventually resulting in depletion of nutrients,
system/organ malfunctions, and susceptibility to illness. Among the most
insidious toxic metals are the sulfhydryl-reactive metals, which include mercury
(Hg), cadmium (Cd), lead (Pb), and arsenic (As). The pro-oxidative effects of
the metals are compounded by the fact that they inhibit antioxidative enzymes
and deplete intracellular glutathione. The metals have the potential to disrupt
the metabolism and biological activities of many proteins due to their high
affinity for free sulfhydryl groups. In addition to promoting lipid peroxidation, depleting
GSH, and inhibiting antioxidative processes, the sulfhydryl-reactive metals disrupt the structure and function of numerous
important proteins through direct binding to free sulfhydryl groups. Intact
sulfhydryl groups are critical for the biological activities of virtually all
proteins. Since all these metals are sulfhydryl reactive, the presence of more
than one is cumulative in their effects. Chemical sensitivity is
one of the major manifestations of environmentally triggered disease involving
Phase II enzymes. It is an adverse reaction(s) to ambient levels of a toxic
chemical(s) contained in air, food, and water. The nature of these adverse
reactions depends upon the tissue(s) or organ(s) involved, the chemical and
pharmcologic nature of the substance(s) involved (that is, duration of time,
concentration, and virulence of exposure), the individual susceptibility of the
exposed person (nutritional state, genetic makeup, and toxic load at the time of
exposure), and the length of time and the amount and variety of other body
stressors (total load), and the synergism at the time of the reaction(s). Chemical allergies are
a small but significant part of the overall spectrum of chemical sensitivity.
They may involve both allergic (immunologically mediated mechanisms including
all of the four types of hypersensitivity reactions) and toxic (nonimmune
mechanisms) responses. They involve the mechanisms of the IgE class of
immunoglobulins. An example of chemical allergy is the IgE-mediated toluene
diisocyanate antigen/antibody reaction that frequently manifests itself as
asthma or some other form of respiratory or vascular dysfunction. Other immune
mechanisms such as IgG, cytotoxic response, immune complexes (IgG + complement),
or T- and B-cell abnormalities are often involved in chemical sensitivity,
although these reactions are frequently secondary responses following an initial
enzyme detoxification response. Failure of enzyme detoxification appears to be
the prime mechanism in chemical sensitivity. Regardless of the mechanisms
involved, clinical manifestations of chemical sensitivity may be the same. For
example, rhinitis may occur either as an IgE response to toluene diisocyanate,
or it may be an enzyme detoxification system response to formaldehyde. Chemical sensitivities
may arise in several ways. Individuals who survive near-fatal exposures to toxic
substances often experience lowered resistance to disease as a result of the
depletion of their nutrient pool brought on by the exposure. They may then
develop chronic symptoms of ill health. If these people are later exposed to
ambient doses of toxic chemicals, they may experience additional and/or enhanced
symptoms. Numb, tingling hands and face are typical of people who are working in
contaminated buildings. “Spreading”, which can involve both new organ
systems and increased sensitivities to additional substances, may occur. For
example, an individual working in a chemical plant may be exposed to high doses
of xylene after an explosion. He immediately develops headaches and flu-like
symptoms that become chronic. Weeks later, after ongoing ambient exposures in
the workplace and at home, this person develops asthma and sensitivity to
ambient doses of various toxic and nontoxic (e.g., perfume) substances. Of the
chemically sensitive patients seen at the EHC-Dallas, 13% relate the onset of
their sensitivity to a severe acute exposure. “If you have a strong
immune system, you don’t have environmental illness. If by heredity, you have
a weakened (imbalanced—WSL) immune system, or your immune system has been
damaged by chemicals (and vaccines—WSL), then you are apt to develop
allergies, cancer, and all kinds of terrible problems. So one of the things we
have to do is to strengthen (balance) the immune system. You are only as strong
as each cell in your body and, if all the cells lack magnesium or manganese or
some essential nutrient, you will not be well. If the immune system is damaged,
then the endocrine system and all the other systems go out of balance and
you’re in serious trouble. The immune system can be enhanced or improved by
certain nutrients”—Dr. Doris Rapp, MD, Allergy specialist. Those nutrients
are enumerated in this paper. It seems quite clear
that the chemicals act synergistically. In one 1976 study, a scientific team
used three chemicals on a group of rats. The chemicals were tested one at a time
on the rats without ill effect. When the scientists gave the rats two at a time,
a decline in health was noted. When the rats were given all three chemicals at
once, they all died within two weeks. (Alternative Medicine: The Definitive
Guide, by The Burton Goldberg Group). In addition to phenol
in foods, there is another toxic content to some foods that may play heavily in
Autism. It is malonic acid or malonate found in alfalfa sprouts, apricots, all
kinds of beans, broccoli, butternut squash peel, carrots, chaparral (dry),
chocolate, ginger root skin, grape jam (commercial), dark green zucchini, kombo
(seaweed), limes, mangos, onions (purple), oranges, papaya (Mexican), parsnips,
passion fruit, persimmons (Fuji, regular), radish (daikon), red skin of peanuts,
Tamari soy sauce, tomatoes, turnips, rutabagas, and wheat grass. This acid is
highly toxic if not excreted properly. Some of the things affected read like a
list of autistic symptoms:
Phase I liver enzymes
detoxify aromatics, such as benzene-ring containing chemicals, aldehydes,
epoxides, organic volatiles, and if you develop nausea/poor feeling from these
chemicals, you have impaired Phase I liver activity that causes these toxins to
accumulate. The reaction comes from the exposure raising the levels of these
chemicals too high due to impaired Phase I activity. It is noteworthy that of 20
cases examined, 100% showed liver detoxification profiles outside of normal. An
examination of 18 autistic children in blood analysis showed that 16 of these
children showed evidence of levels of toxic chemicals exceeding adult maximum
tolerance. If there is a vitamin B6 deficiency, aldehydes will
accumulate, and serotonin levels could be impaired, thus causing poor sleep and
other neurotransmitter disruptions. These are some of
the things to avoid: Aromatic oils; Azole antihistamine: cimetidine (Tagamet™);
Azole antifungals: fluconazole (Diflucan™—it
is fluoride based); and ketoconazole (Nizoral™),
Itraconazole (Sporanox™)
(among the reportable side effects of these three drugs are dark urine and pale
stools indicating kidney or liver problems, respectively); Azole antiparasitic
drug: metronidazole (Flagyl™);
and all porphyrics. The main risks of Flagyl™
is the impairment of Phase I, cytochrome p450, liver enzymes, especially that of
aldehyde (candida die off)
oxidation, and possible liver damage called “megamitochondria” that other
“Azole-class” drugs, that Flagyl™
is part of, have caused. Flagyl™
has also failed to work in a number of cases. The Azole antifungals work by
inhibiting the fungal cytochrome P-450 enzyme that catalyzes C-14 alpha-demethylation in the production of
ergosterols. The equivalent human
enzyme is much less sensitive to inhibition by azoles, but is affected somewhat.
This inhibition may become clinically significant when given with another
compound that is metabolized by that enzyme. Specific drug interactions have
been reported with rifampin, coumadin, phenytoin, cyclosporine, theophylline,
oral hypoglycemics, terfenadine, cisapride, and astemizole. Cimetidine
antihistamine and Fluconazole antifungal have caused such damage, so one has to
be careful when Phase I liver enzymes already are impaired, for the risk is then
higher. Vanillin (synthetic vanilla) greatly inhibits dopamine sulfation (Phase
II) allowing a toxic buildup. Another possible source of excess dopamine with
reduced norepinephrine is the presence of clostridia overgrowth. Many popular herbs
inhibit Phase I enzymes, and they should not be used by anyone suspected of
having impaired Phase I function: black cohosh, blue cohosh, chaparral, boneset,
buchu, comfrey, cyani, elecampane, fever few, Gotu Kola, grapefruit seed extract
(Citricidal™),
grapeseed extract or Pycnogenol™,
and barberry (these and other anthocyanidins also provide phenolic compounds),
Irish moss (red seaweed), juniper, Kava Kava, mistletoe, mullein, nettle,
periwinkle (Vinpocetine™),
pokeweed, Quercetin, Reishi mushroom, Rosemary, Seneca, Shitake mushroom, Una de
Gata (cat’s claw), and Valerian are ones that I know of. Using these herbs will
lead to a buildup of Phase I toxins, for example, benzene-aromatic rings
such as found in gasoline vapors; 1,4-dichlorobenzene such as found in
mothballs and room deodorizers; xylene such as found in deodorants, room
fresheners, gasoline, and paint vapors (do you get a headache?); dioxin such
as found in herbicides, auto exhaust, and wood treatment; styrene such as
found in Styrofoam cups and on carpet backing (fumes); ketones (fat waste
products); aldehydes (formaldehyde, furfural), a major source of which is
aspartame, a phenolic compound (Nutrasweet™
type sweeteners); various perfumes (most are made with petroleum
chemicals, phenyl-acetylaldehydes, not with flower scents), and candida
yeast infection. These children must be kept away from these substances
some of which are found in aerosols and room fresheners that have been shown to
contribute to headache and depression in adults, and to ear infection and
diarrhea in children. Additionally, these inhibit release of steriods,
estrogens, body alcohols, prostaglandins, retinoic acid (vitamin A), fatty
acids, and glycine. In 1979, Dr. Robert
Gardner, a very allergic person, hypothesized that his allergies were caused by
sensitivity to some aromatic compounds found naturally in all plants. He
acquired some of these pure aromatic compounds, made dilutions, started
sublingual tests and monitored changes in pulse rates upon applications. There
were reactions to various extracts, and neutralizing doses were found for each
compound. He found that neutralizing doses of these compounds would neutralize
allergic reactions to specific foods. Dr. Joseph J. McGovern, an allergist in
Oakland, was the first clinician to investigate Dr. Gardner’s findings. He has
shown that these natural, food borne aromatics induce behavioral disturbances in
children, including hyperkinesis. Progressive
neutralization of these compounds has led to vast improvements in the majority
of patients. Neutralizing these compounds results in disappearance of arthritic
pains, decreased abdominal bloating, improved bowel function, decrease of
recurrent canker sores, and less anxiety. School performance improves
noticeably, and this has been noted in most children treated. The treatment has
been particularly successful with infants and children, with excellent results
in autism, mental retardation, hyperactivity, dyslexia, insomnia, enuresis,
respiratory allergies, headaches, abdominal pains, and asthma. Results with
adults have been as exciting with remissions achieved in many chronic problems
including migraine, fatigue, depression, asthma, arthritis, colitis,
hypertension, menstrual disorders, dermatological problems, chronic
constipation, and arrhythmias. A phenolic compound may
cause a variety of different symptoms in various individuals. When a suspected
phenolic is given to a person, exactly the same allergic symptom occurs over and
over. Some people begin crying for no apparent reason, become depressed, or have
any of their usual symptoms. When a neutralizing dose is given to stop the
reaction, they start smiling, laughing, joking, and their allergic symptoms
disappear. Instead of desensitizing to several foods containing the same
phenolic compound, you would desensitize the one chemical that is in all of the
foods. Since these chemicals are often repeated throughout nature,
desensitization to a few main chemicals could reduce most of the symptoms caused
by foods, pollens, and environmental chemicals. Regarding ketones,
these accumulate, leading to ketoacidosis (ketosis) leading to a loss of
calcium, magnesium, and potassium into the urine. This could relate to liver
insufficiency due to a vitamin A deficiency—common among autistics. The early
signs are nausea and a faster rate of breathing. Increased thirst, excessive
urination, abdominal pain or vomiting, listlessness, and eventually sleepiness
can follow this. If not recognized and dealt with, this acidosis will lead to
coma. The build up of ketones in the blood for a few days, or even a few hours,
can be life threatening. If you are not feeling well, or you are showing
excessive amounts of sugar in the blood, you must test for ketones (Use Acetest™
tablets or Ketostix™
dipsticks.). The use of L-carnitine as a therapeutic supplement (1000 to 3000 mg
daily) can enhance the metabolism of fats, and prevent ketones, triglycerides,
and cholesterol from building up in the blood. Those using high fat diets to
produce a ketosis to control seizures must supplement magnesium, potassium, and
calcium, and consider using carnitine to ensure adequate energy production.
Remember that carnitine also burns essential fatty acids. So, when supplementing
carnitine, ensure adequate Omega-6 and Omega-3 fatty acids are provided. When
carnitine is used, one must ensure that adequate calories are taken in also. A
failure to do so can produce seizures. Vegetarians are apt to be lacking in
carnitine due to a diet low in lysine, and the absence of meat. When Phase I is under
high stress, additional antioxidants are needed to help the Phase I system act
smoothly, and to ensure there is no oxidative damage occurring in the liver,
impairing its function. The best antioxidants to help the liver with no toxicity
to the liver or Peripheral Mononuclear Blood Cells (immune cells) and no adverse
effect on Phase I are Ambrotose® and Phyt•Aloe® by Mannatech™,
and Green Tea Extract (however, the high content of both aluminum and fluoride
in tea is cause for great concern as aluminum greatly potentiates fluoride’s
effects on G-protein activation, the on/off switches involved in cell
communication and of absolute necessity in thyroid hormone function and
regulation). Other helps recommended by natural healers are the hormone
pregnenolone (25 mg), phosphatidylcholine, Milk Thistle, and Turmeric. Pregnenolone enhances
Phase one liver function by conserving the cytochrome P450 enzymes. Its use
could be considered when the EPA/DHA levels are excessively high in relation to
GLA, but I think it more basic to look to support the thyroid that is likely
sluggish. More than two decades of clinical trials indicate that
phosphatidylcholine (PC) protects the liver against damage from alcoholism,
pharmaceuticals, pollutant substances, viruses, and other toxic influences, most
of which operate by damaging cell membranes. The human liver is confronted with
tens of thousands of exogenous substances. The metabolism of these xenobiotics
can result in the liver’s detoxicative enzymes producing reactive metabolites
that attack the liver tissue. Dietary supplementation with PC (a minimum 800 mg
daily, with meals) significantly speeds recovery of the liver. PC is fully
compatible with pharmaceuticals, and with other nutrients. PC is also highly
bioavailable (about 90% of the administered amount is absorbed over 24 hours),
and PC is an excellent emulsifier that enhances the bioavailability of nutrients
with which it is co-administered. PC’s diverse benefits and proven safety
indicate that it is a premier liver nutrient (Alt Med Rev 1996;1(4):258-274).
Even when milk thistle failed, PC was successful in improving the liver. Long-term intakes of
certain of the antiepileptic drugs, especially phenytoin, pose a high risk of
liver damage. Hisanaga and collaborators (1980) in Japan followed 38 subjects
who had received phenytoin and other antiepileptic drugs for an average of five
years. A subgroup with the highest degree of damage (assessed by SGGT enzyme
elevation), after being given PC orally for six months, experienced remarkable
benefits. Milk thistle assists
the glutathione-S-transferase (GST), a Phase II enzyme that adds a glutathione
group to Phase I products, activity by increasing glutathione production up to
35%, but it does not directly stimulate the enzyme. Silymarin also causes liver
regeneration, but milk thistle is dangerous for one with impaired sulfation
(PST) for it also enhances cytochrome p450 (Phase I) activity. The glutathione
it supplies is best supplied by other herbs and foods. Rosemary and sage are
sometimes recommended because they contain an antioxidant and inhibit the
bioactivation of certain toxins that combine with DNA, but Rosemary inhibits
Phase I activity and Sage is toxic to liver and immune cells. Turmeric enhances
Phase I activity, but is toxic to the liver and immune cells (An Invitro
Screening Study of 196 Natural Products for Toxicity and Efficacy by Dr. Darryl
M. See, MD, JANA, Winter 1999). These four herbs should not be used except under
direction of a competent herbologist. These may not have a deleterious effect in
the short run, but to stimulate Phase I activity for long periods (unless
testing proves it needs stimulation) will be detrimental for it will clear many
necessary body substances at a higher than normal rate and produce deficiencies
in fatty acids, estrogen, steroids, body alcohols, Prostaglandins, retinol, and
glycine, and it reduces the effectiveness of many drugs. It would also overload
a deficient Phase II system (PST). Similarly to inhibit this pathway will build
these substances to unnatural and unwanted levels. Good herbalists would not
recommend one of these herbs for long periods, but would suggest Dandelion,
Ambrotose®, and Phyt•Aloe® to enhance glutathione, and Globe Artichoke which
is choleretic (increases the flow of bile) and assists in removal of metabolites
from the liver. These would work well with a combination of antioxidants and
Phase I/Phase II stimulants such as Schizandra. Glutathione-S-transferase
T1 (GST T1), the enzyme that forms glutathione, displays a genetic polymorphism.
Due to this polymorphism about 25% of the individuals of the Caucasian
population lack this activity (“non-conjugators”), while 75% show it
(“conjugators”) (Hallier, E., et al., 1993). Using our newly developed HPLC-fluorescence detection assay (Muller, M., et al., 2001) we have profiled
the kinetics of enzyme inhibition in erythrocyte lysates of two individuals
previously identified as “normal conjugator” (medium enzyme activity) and
“super-conjugator” (very high enzyme activity). For the normal conjugator we
have determined a 2.77 mM thimerosal concentration to inhibit 50% of the GST T1
activity. In the case of the super-conjugator a 2.3 mM thimerosal concentration
causes a 50% inhibition of the enzyme activity. A study published in “Lancet” reports that St. Jude researchers determined that children who received the antiseizure medicines phenytoin (Dilantin™), phenobarbital, and carbamazepine (Tegretol™), which potently increase the amount of drug-metabolizing enzymes in the liver, have lower chances of event-free survival than those who did not receive such medicines. The Phase I liver enzymes are responsible for clearing many clinically-used medications from the body, so that the use of these antiseizure medicines, by enhancing Phase I, is comparable to lowering the doses of the antileukemic chemotherapy and many drugs. These Phase I enzymes also deplete the substances listed two paragraphs above. Additionally, Dilantin™ depletes the body of biotin, folic acid, vitamins B1, B12, D, and K, and the mineral calcium, and Tegretol™ depletes biotin, folic acid, and vitamin D. It also decreases alpha-ketoglutarate thereby increasing toxic ammonia levels—“Drug-induced Nutrient Depletion Handbook” by Pharmacists Pelton, LaValle, Hawkins, and Krinsky. Conversely, several human pharmacokinetic studies have shown that vaccination may deserve full consideration as a cause of inhibited hepatic drug metabolism. Influenza vaccination impaired theophylline elimination with a 122% increase of its half-life, and it inhibits aminopyrine metabolism markedly. Some medicines can give falsely low thyroid blood test results, especially Tegretol™ (carbamazepine).
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