Biotransformation of xenobiotics and endogenous

toxins in the liver: microsomaloxidation,

cytochromeР-450.
Role of the liver in detoxification processes.

A xenobiotics is a compound that is foreign to the body. The principal

classes of xenobiotics of medical relevance are drugs, chemical cancerogens,
and various compounds that have found their way into our environment by
one route or another (insecticides, herbicides, pesticides, food additions,
cosmetics, domestic chemical substances). Most of these compounds are
subject to metabolism (chemical alteration) in the human body, with the liver
being the main organ involved; occasionally a xenobiotics may be excreted
unchanged.

Some internal substances also have toxic properties (for example,

bilirubin, free ammonia, bioactive amines, products of amino acids decay in
the intestine). Moreover, all hormones and mediatores must be inactivated.

Reactions of detoxification take place in the liver. Big molecules like

bilirubin excreted with the bile to intestine and leaded out with feces. Small
molecules go to the blood and excreted via kidney with urine.

The metabolism of xenobiotics has 2 phases:

In phase 1, the major reaction involved is hydroxylation, catalyzed by

members of a class of enzymes referred to as monooxygenases or cytochrome
P-450 species. These enzymes can also catalyze deamination,
dehalogenation, desulfuration, epoxidation, peroxidation and reduction
reaction. Hydrolysis reactions and non-P-450-catalyzed reactions also occur
in phase 2.
 In phase 2, the hydroxylated or other compounds produced in phase 1
are converted by specific enzymes to various polar metabolites by
conjugation with glucuronic acid, sulfate, acetate, glutathione, or certain
amino acids, or by methylation.

The overall purpose of metabolism of xenobiotics is to increase their

water solubility (polarity) and thus facilitate their excretion from the body via
kidney.Very hydrophobic xenobiotics would persist in adipose tissue almost
indefinitely if they were not converted to more polar forms.

In certain cases, phase 1 metabolic reaction convert xenobiotics from

inactive to biologically active compounds. In these instances, the original
xenobioticsare referred to as prodrugs or procarcinogens. In other cases,
additional phase 1 reactions convert the active compounds to less active or
inactive forms prior to conjugation. In yet other cases, it is the conjugation
reactions themselves that convert the active product of phase 1 to less active
or inactive species, which are subsequently excreted in the urine or bile. In a
very few cases, conjugation may actually increase the biologic activity of a
xenobiotics.

Hydroxylation is the chief reaction involved in phase 1. The

responsible enzymes are calledmonooxygenases or cytochrome P-450
species. The reaction catalyzed by a monooxygenase is:

RH + O2 + NADPH + H+ → R-OH + H2O + NADP

RH above can represent a very widee variety of drugs, carcinogens,

pollutants, and certain endogenous compounds, such as steroids and a
number of other lipids. Cytochrome P-450 is considered the most versatile
biocatalyst known. The importance of this enzyme is due to the fact that
approximately 50 % of the drugs that patients ingest are metabolized by
species of cytochrome P-450. The following are important points concerning
cytochrome P-450 species:

http://www.youtube.com/watch?v=3DgxjDalZW0

1. Like hemoglobin, they are hemoproteins.

2. They are present in highest amount in the membranes of the

endoplasmic reticulum (ER) (microsomal fraction) of liver, where they can
make up approximately 20 % of the total protein. Thay are also in other
tissues. In the adrenal, they are found in mitochondria as well as in the ER;
the various hydroxylases present in that organ play an important role in
cholesterol and steroid biosynthesis.

3. There are at least 6 closely related species of cytochrome P-450

present in liver ER, each with wide and somewhat overlapping substrate
specificities, that act on a wide variety of drugs, carcinogens, and other
xenobiotics in addition to endogenous compounds such as certain steroids.

4. NADPH, not NADP, is involved in the reaction mechanism of

cytochrome P-450. The enzyme that uses NADPH to yield the reduced
cytochrome P-450 is called NADPH-cytochrome P-450 reductase.

5. Lipids are also components of the cytochrome P-450 system. The

preferred lipid is phosphatidylcholine, which is the major lipid found in
membranes of the ER.

6. Most species of cytochrome P-450 are inducible. For instance, the

administration of phenobarbital or of many other drugs causes a hypertrophy
of the smooth ER and a 3- to 4-fold increase in the amount of cytochrome P-
450 within 4-5 days. Induction of this enzyme has important clinical
implications, since it is a biochemical mechanism of drug interaction.

7. One species of cytochrome P-450 has its characteristic absorption

peak not at 450 nm but at 448 nm. It is often called cytochrome-448.This
species appears to be relatively specific for the metabolism of polycyclic
aromatic hydrocarbons (PAHs) and related molecules; for this reason it is
called aromatic hydrocarbon hydroxylase (AHH). This enzyme is important
in the metabolism of PAHs and in carcinogenesis produced by this agents.

8. Recent findings have shown that individual species of cytochrome P-

450 frequently exist in polymorphic forms, some of which exhibit low
catalytic activity. These observation are one important explanation for the
variations in drug responses noted among many patients.

http://www.youtube.com/watch?v=3DgxjDalZW0

In phase 1 reactions, xenobiotics are generally converted to more polar,

hydroxylatedderivates. In phase 2 reactions, these derivatesare conjugated
with molecules such as glucuronic acid, sulfate, or glutatione. This renders
them even more water-soluble, and they are eventually excreted in the urine
or bile.

There are at least 5 types of phase 2 reactions:

1. Glucuronidation. UDP-glucuronic acid is the glucuronyl donor, and

a variety of glucuronyltransferases, present in both the ER and cytosol, are
the catalysts. Molecules such as bilirubin, thyroxin, 2-acetylaminofluorene (a
carcinogen), aniline, benzoic acid, meprobromate (a tranquilizer), phenol,
crezol, indol and skatol, and many steroids are excreted as glucuronides. The
glucuronidemay be attached to oxygen, nitrogen, or sulfur groups of
substrates. Glucuronidation is probably the most frequent conjugation
reaction.

Glucuronidation, the combining of glucuronic acid with toxins,

requires the enzyme UDP-glucuronyltransferase (UDPGT). Many of the
commonly prescribed drugs are detoxified through this pathway. It also helps
to detoxify aspirin, menthol, vanillin (synthetic vanilla), food additives such
as benzoates, and some hormones. Glucuronidation appears to work well,
except for those with Gilbert's syndrome--a relatively common syndrome
characterized by a chronically elevated serum bilirubin level (1.2-3.0 mg/dl).
Previously considered rare, this disorder is now known to affect as much as
5% of the general population. The condition is usually without serious
symptoms, although some patients do complain about loss of appetite,
malaise, and fatigue (typical symptoms of impaired liver function). The main
way this condition is recognized is by a slight yellowish tinge to the skin and
white of the eye due to inadequate metabolism of bilirubin, a breakdown
product of hemoglobin. The activity of UDPGT is increased by foods rich in
the monoterpene limonene (citris peel, dill weed oil, and caraway oil).
Methionine, administered as SAM, has been shown to be quite beneficial in
treating Gilbert's syndrome.

2. Sulfation. Some alcohols, arylamines, and phenols are sulfated. The

sulfate donor in these and other biologic sulfation reactions is adenosine 3´-
phosphate-5´-phosphosulfate (PAPS); this compound is called active sulfate.
 Sulfation is the conjugation of toxins with sulfur-containing
compounds. The sulfation system is important for detoxifying several drugs,
food additives, and, especially, toxins from intestinal bacteria and the
environment. In addition to environmental toxins, sulfationis also used to
detoxify some normal body chemicals and is the main pathway for the
elimination of steroid and thyroid hormones. Since sulfation is also the
primary route for the elimination of neurotransmitters, dysfunction in this
system may contribute to the development of some nervous system disorders.

Many factors influence the activity of sulfate conjugation. For example,

a diet low in methionine and cysteine has been shown to reduce sulfation.
Sulfationis also reduced by excessive levels of molybdenum or vitamin B6
(over about 100 mg/day). In some cases, sulfationcan be increased by
supplemental sulfate, extra amounts of sulfur-containing foods in the diet,
and the amino acids taurine and glutathione.

Sulfoxidation is the process by which the sulfur-containing molecules

in drugs and foods are metabolized. It is also the process by which the body
eliminates the sulfite food additives used to preserve many foods and drugs.
Various sulfites are widely used in potato salad (as a preservative), salad bars
(to keep the vegetables looking fresh), dried fruits (sulfites keep dried
apricots orange), and some drugs. Normally, the enzyme sulfite oxidase
metabolizes sulfites to safer sulfates, which are then excreted in the urine.
Those with a poorly functioning sulfoxidation system, however, have an
increased ratio of sulfite to sulfate in their urine. The strong odor in the urine
after eating asparagus is an interesting phenomenon because, while it is
unheard of in China, 100% of the French have been estimated to experience
such an odor (about 50% of adults in the U.S. notice this effect). This
example is an excellent example of genetic variability in liver detoxification
function. Those with a poorly functioning sulfoxidation detoxification
pathway are more sensitive to sulfur-containing drugs and foods containing
sulfur or sulfite additives. This is especially important for asthmatics, which
can react to these additives with life-threatening attacks. Molybdenum helps
asthmatics with an elevated ratio of sulfites to sulfates in their urine because
sulfite oxidase is dependent upon this trace mineral.

3. Conjugation with Glutathione. Glutathione (γ-

glutamylcysteinylglycine) is a tripeptide consisting of glutamic acid,
cysteine, and glycine. Glutathione is commonly abbreviated to GSH; the SH
indicates the sulfhydryl group of its cysteine and is the business part of the
molecule. A number of potentially toxic electrophilic xenobiotics (such as
certain carcinogens) are conjugated to the nucleophilic GSH. The enzymes
catalyzing these reactions are called glutathione S-transferases and are
present in high amounts in liver cytosol and in lower amounts in other
tissues. glutathione conjugates are subjected to further metabolism before
excretion. The glutamyl and glycinyl groups belonging to glutathione are
removed by specific enzymes, and an acetyl group (donated by acetyl-CoA)
is added to the amino group of the remaining cystenyl moiety. The resulting
compound is a mercapturic acid, a conjugate of L-acetylcysteine, which is
then excreted in the urine.

Glutathione is also an important antioxidant. This combination of

detoxification and free radical protection, results in glutathione being one of
the most important anticarcinogens and antioxidants in our cells, which
means that a deficiency is cause of serious liver dysfunction and damage.
Exposure to high levels of toxins depletes glutathione faster than it can be
produced or absorbed from the diet. This results in increased susceptibility to
toxin-induced diseases, such as cancer, especially if phase I detoxification
system is highly active. Disease states due to glutathione deficiency are not
uncommon.

A deficiency can be induced either by diseases that increase the need

for glutathione, deficiencies of the nutrients needed for synthesis, or diseases
that inhibit its formation. Smoking increases the rate of utilization of
glutathione, both in the detoxification of nicotine and in the neutralization of
free radicals produced by the toxins in the smoke. Glutathione is available
through two routes: diet and synthesis. Dietary glutathione (found in fresh
fruits and vegetables, cooked fish, and meat) is absorbed well by the
intestines and does not appear to be affected by the digestive processes.
Dietary glutathione in foods appears to be efficiently absorbed into the blood.
However, the same may not be true for glutathione supplements.

In healthy individuals, a daily dosage of 500 mg of vitamin C may be

sufficient to elevate and maintain good tissue glutathione levels. In one
double-blind study, the average red blood cell glutathione concentration rose
nearly 50% with 500 mg/day of vitamin C. Increasing the dosage to 2,000 mg
only raised red blood cell (RBC) glutathione levels by another 5%. Vitamin
C raises glutathione by increasing its rate of synthesis. In addition, to vitamin
C, other compounds which can help increase glutathione synthesis include N-
acetylcysteine (NAC), glycine, and methionine. In an effort to increase
antioxidant status in individuals with impaired glutathione synthesis, a
variety of antioxidants have been used. Of these agents, only microhydrin,
vitamin C and NAC have been able to offer some possible benefit.

Over the past 5-10 years, the use of NAC and glutathione products as
antioxidants has become increasingly popular among nutritionally oriented
physicians and the public. While supplementing the diet with high doses of
NAC may be beneficial in cases of extreme oxidative stress (e.g. AIDS,
cancer patients going through chemotherapy, or drug overdose), it may be an
unwise practice in healthy individuals.

4. Acetylation. These reactions is represented by X + Acetyl-CoA →

Acetyl-X + CoA, where X represents a xenobiotic. These reactions are
catalyzed by acetyltransferases present in the cytosol of various tissues,
particularly liver. The different aromatic amines, aromatic amino acids, such
drug as isoniazid, used in the treatment of tuberculosis, and sulfanylamides
are subjects to acetylation. Polymorphic types of acetyltransferases exist,
resulting in individuals who are classified as slow or fast acetylators, and
influence the rate of clearance of drugs such as isoniazid from blood. Slow
acetylators are more subject to certain toxic effects of isoniazid because the
drug persists longer in these individuals.

Conjugation of toxins with acetyl-CoA is the primary method by which

the body eliminates sulfa drugs. This system appears to be especially
sensitive to genetic variation, with those having a poor acetylation system
being far more susceptible to sulfa drugs and other antibiotics. While not
much is known about how to directly improve the activity of this system, it is
known that acetylation is dependent on thiamine, pantothenic acid, and
vitamin C.

5. Methylation. A few xenobiotics (amines, phenol, tio-substances,

inorganic compounds of sulphur, selen, mercury, arsenic) are subject to
methylation by methyltransferases, employing S-adenosylmethionine as
methyl donor. Alsocatecholamines and nicotinic acid amid (active form of
vitamin PP) are inactivated due to methylation.
 Very important way of detoxification is ureogenes (urea synthesis).
Free ammonia, which formed due to metabolism of amino acids, amides and
amines, removed from organism in shape of urea.

Methylation involves conjugating methyl groups to toxins. Most of the

methyl groups used for detoxification come from S-adenosylmethionine
(SAM). SAM is synthesized from the amino acid methionine, a process
which requires the nutrients choline, vitamin B12, and folic acid. SAM is able
to inactivate estrogens (through methylation), supporting the use of
methionine in conditions of estrogen excess, such as PMS. Its effects in
preventing estrogen-induced cholestasis (stagnation of bile in the gall
bladder) have been demonstrated in pregnant women and those on oral
contraceptives. In addition to its role in promoting estrogen excretion,
methionine has been shown to increase the membrane fluidity that is
typically decreased by estrogens, thereby restoring several factors that
promote bile flow. Methionine also promotes the flow of lipids to and from
the liver in humans. Methionine is a major source of numerous sulfur-
containing compounds, including the amino acids cysteine and taurine.

Are there things that support liver detoxification?

Nutritional factors

Antioxidant vitamins like vitamin C, beta-carotene, and vitamin E are

obviously quite important in protecting the liver from damage as well as
helping in the detoxification mechanisms, but even simple nutrients like B-
vitamins, calcium, and trace minerals are critical in the elimination of heavy
metals and other toxic compounds from the body. The lipotropic agents,
choline, betaine, methionine, vitamin B6, folic acid, and vitamin B12, are
useful as they promote the flow of fat and bile to and from the liver.
Lipotropic formulas have been used for a wide variety of conditions by
nutrition-oriented physicians including a number of liver disorders such as
hepatitis, cirrhosis, and chemical-induced liver disease. Lipotropic formulas
appear to increase the levels of SAM and glutathione. Methionine, choline,
and betainehave been shown to increase the levels of SAM.

Botanical medicines

There is a long list of plants which exert beneficial effects on liver

function. However, the most impressive research has been done on silymarin,
the flavonoids extracted from silybummarianum (milk thistle). These
compounds exert a substantial effect on protecting the liver from damage as
well as enhancing detoxification processes. Silymarin prevents damage to the
liver through several mechanisms: by acting as an antioxidant, by increasing
the synthesis of glutathione and by increasing the rate of liver tissue
regeneration. Silymarin is many times more potent in antioxidant activity
than vitamin E and vitamin C. The protective effect of silymarin against liver
damage has been demonstrated in numerous experimental studies.
Silymarinhas been shown to protect the liver from the damage produced by
such liver-toxic chemicals as carbon tetrachloride, amanita toxin,
galactosamine, and praseodymium nitrate.

One of the key mechanisms by which silymarin enhances

detoxification is by preventing the depletion of glutathione. Silymarin not
only prevents the depletion of glutathione induced by alcohol and other toxic
chemicals, but has been shown to increase the level of glutathione of the liver
by up to 35%, even in normals. Inhuman studies, silymarinhas been shown to
have positive effects in treating liver diseases of various kinds, including
cirrhosis, chronic hepatitis, fatty infiltration of the liver, and inflammation of
the bile duct. The standard dosage for silymarin is 70-210 mg three
times/day.

Amino acid conjugation

Several amino acids (glyucine, taurine, glutamine, arginine, and

ornithine) are used to combine with and neutralize toxins. Of these, glycine is
the most commonly utilized in phase II amino acid detoxification. Patients
suffering from hepatitis, alcoholic liver disorders, carcinomas, chronic
arthritis, hypothyroidism, toxemia of pregnancy, and excessive chemical
exposure are commonly found to have a poorly functioning amino acid
conjugation system. For example, using the benzoate clearance test (a
measure of the rate at which the body detoxifies benzoate by conjugating it
with glycine to form hippuric acid, which is excreted by the kidneys), the rate
of clearance in those with liver disease is 50% of that in healthy adults.

Even in apparently normal adults, a wide variation exists in the activity

of the glycine conjugation pathway. This is due no only to genetic variation,
but also to the availability of glycine in the liver. Glycine, and the other
amino acids used for conjugation, become deficient on a low-protein diet and
when chronic exposure to toxins results in depletion.

Dietary Changes

Adding certain supplements to your diet can stimulate detoxification.

Fiber, vitamin C and other antioxidants, chlorophyll, and glutathione (as the
amino acid L-cysteine) will all help. Herbs such as garlic, red clover,
echinacea, or cayenne may also induce some detoxification. Saunas, sweats,
and niacin therapy have been used to cleanse the body.
 Simply increasing liquids and decreasing fats will shift the balance
strongly toward improved elimination and less toxin buildup. Changes might
include increased consumption of filtered water, herb teas, fruits, and
vegetables, as well as reducing fats, especially fried food, meat and milk
products. In general, moving from an acid-generating diet to a more alkaline
one will aid the process of detoxification. Acid-forming foods, such as meats,
milk products, breads and baked goods, and especially the refined sugar and
carbohydrate products, will increase body acidity and lead to more mucus
production and congestion, whereas the more alkaline vegetarian foods
enhance cleansing and clarity in the body.

A deeper level of detoxification diet is made up exclusively of fresh

fruits and vegetables, either raw and cooked, and whole grains, both cooked
and sprouted. This diet keeps fiber and water intake high and helps colon
detoxification. Most people can handle this well and make the shift from their
regular diet with a few days transition. Some people do well on a brown rice
fast (a more macrobiotic plan), usually for a week or two, eating three to four
bowls of rice daily along with liquids such as teas."

Role of liver in excretion.

Bile is an important vehicle for bile acid and cholesterol excretion, but
it also removes many drugs, toxins, bile pigments, and various inorganic
substances such as copper, zinc, and mercury.

Evaluating of liver’s functions.

Different methods are used for evaluating of liver’s functions. Base for
some of them is role of liver in proetin metabolism (e.g. thymol’s test), for
another – role of liver in detoxification (indican’s test) or in excretion
(checking of bilirubin level in blood). In all cases physician must make a
conclusion about disorder of liver’s functions after complex investigation,
because, as mentioned above, all metabolic ways are present in liver.

The liver filter can remove a wide range of microorganisms such

as bacteria, fungi, viruses and parasites from the blood stream, which is
highly desirable, as we certainly do not want these dangerous things building
up in the blood stream and invading the deeper parts of the body. Infections
with parasites often come from the contaminated water supplies found in
large cities, and indeed other dangerous organisms may find their way into
your gut and blood stream from these sources. This can cause chronic
infections and poor health, so it is important to protect your liver from
overload with these microorganisms. The safest thing to do is boil your water
for at least 5 minutes, or drink only bottled water that has been filtered and
sterilized. High loads of unhealthy microorganisms can also come from
eating foods that are prepared in conditions of poor hygiene by persons who
are carrying bacteria, viruses or parasites on their skin. Foods, especially
meats that are not fresh or are preserved, also contain a higher bacterial load,
which will overwork the liver filter if they are eaten regularly.

Recently, it has become very fashionable for people to detoxify

their bodies by various means, such as fasting or cleansing the bowels with
fiber mixtures. Fasting can by its extreme nature, only be a temporary method
of cleansing the body of waste products, and for many people causes an
excessively rapid release of toxins which can cause unpleasant, acute
symptoms. The liver filter, like any filter, needs to be cleansed regularly, and
it is much easier and safer to do it everyday. This is easily and pleasantly
achieved by adopting a daily eating pattern that maintains the liver filter in a
healthy clean state. By following the methods and guidelines on this site, you
will be able to keep the liver filter healthy and clean. Although it is important
to keep the intestines moving regularly and to sweep their walls with high
fiber and living foods, it is important to remember that the bowels are really a
channel of elimination and not a cleansing organ per se. In other words the
bowels cannot cleanse, filter or remove toxic wastes from the blood stream.

The liver is the most important organ in detoxification, as it is the

body's premier cleansing organ. All the blood in the body passes through the
liver, which removes toxins, impurities, and debris from the bloodstream.

The liver stores fat-soluble substances; these can include chemicals,

which can be stored in the liver for years. Using enzymes, the liver
transforms these chemicals into water-soluble substances that can be excreted
though the kidneys or the gastrointestinal tract.

Hormones are metabolized by the liver. Estrogen produced by the body

and from hormone replacement therapies is broken down. If estrogen is not
adequately processed, excess estrogen can result in endometriosis; high blood
pressure; PMS; and breast, uterine, and vaginal cancer.

The liver also manufactures bile to digest fats; chemically changes

many foods into vitamins and enzymes; converts carbohydrates and proteins
into glucose for brain fuel and glycogen for muscular energy; and stores
nutrients to be secreted as needed by the body to build and maintain cells.

If the liver cannot perform these jobs well, you may exhibit a number
of symptoms. These include gas; constipation; a feeling of fullness; loss of
appetite; nausea after fatty meals; an oily taste in the mouth; revulsion to
fatty foods; frequent headaches not related to stress; weak ligaments, tendons,
and muscles; skin problems; and emotional excesses.
 What Can Affect the Liver?

Briefly put, living. What you eat, where you live, and what you do all
can affect the liver's performance. If you consume a lot of processed foods,
the additives can eventually affect the liver. If you live in an area that is
highly polluted, exposure to chemicals in the air and water affects the liver.
All of this can hurt the liver's performance.

An impaired liver does not process food or detoxify substances as

rapidly or as completely as a healthy liver. If the liver is not producing
enough bile, it cannot adequately digest fats. If the liver is detoxifying more
slowly than it should, it can result in more toxic substances circulating in the
body.

If toxins continue to accumulate, the liver may not be able to work fast
enough to clean the blood. It is like being on a treadmill that is going a little
too fast: try as you might, you cannot go forward, but instead are swept back
into greater toxicity. Instead of being converted into something useful or
being eliminated, toxins remain unchanged. They are eventually stored in
fatty body tissue and in the cells of the brain and central nervous system. The
stored toxins may be slowly released to recirculate in the blood, contributing
to many chronic illnesses.

A toxin is basically any substance that creates irritating and/or harmful

effects in the body; stressing and undermining one's biochemical health and
organ function. Toxins can come from by products of normal cell metabolism
or from the outside environment e.g. pollution, drugs, pesticides, dyes,
chemicals, microbes, heavy metals, tobacco smoke and so on.

Toxicity occurs when we take in more then we can utilize and

eliminate. Toxic chemicals can be a real problem, since after years of
exposure to these substances the body’s ability to eliminate them can slow
down. They can get recirculated into the bloodstream or stored in the liver,
body fat or other parts of the body. These types of buildups and problems
throughout the body can contribute to the development of serious illnesses.
Many chemicals are so widespread that we are unaware of them. But they
have worked their way into our bodies faster than they can be eliminated, and
are causing allergies and addictions in record numbers. The body's built in
detoxification apparatus include the respiratory, gastrointestinal, urinary, skin
and lymphatic systems.

Symptoms of Toxicity
Cancer and cardiovascular disease are two of the main toxicity-related
diseases. Arthritis, allergies, obesity, and many skin problems are others. In
addition, a wide range of symptoms, such as headaches, fatigue, pains,
coughs, gastrointestinal problems and problems from immune weakness can
all be related to toxicity.

Common indications of toxicity include frequent, unexplained

headaches, back or joint pain, tight or stiff neck, arthritis, chronic respiratory
or sinus problems, asthma, abnormal body odor, bad breath, coated tongue,
food allergies, poor digestion, chronic constipation with intestinal bloating or
gas, brittle nails and hair, psoriasis, adult acne, unexplained weight gain over
10 pounds, unusually poor memory, chronic insomnia, anxiety, depression,
irritability, chronic fatigue, and environmental sensitivities, especially to
odors.

Detoxification is the process of clearing toxins from the body or

neutralizing them. Energy balancing and detoxification herbal baths prompt
the body to eliminate toxins from specific areas of the body. As these toxins
are released from the areas where they have been stored, they move into the
blood, lymph and other body fluids out of the body through the urinary,
gastrointestinal, lymphatic and respiratory systems and the skin. The period
of detoxification can be a few days, a few weeks or a months depending on
the extent, location and type of the toxins in the body. As a person is
detoxifying they may experience uncomfortable symptoms including
depression, mood changes, nausea, diarrhea , foggy head, fatigue, lack of
energy, bad breathe, foul urine odour, foul perspiration odour, body odour,
sores, rashes, acne, cold or flu like symptoms, headaches or any other
symptom. This period where symptoms may seem to worsen is sometimes
called a healing crisis, but is actually just the body's reacting to the presence
of the toxins in the bloodstream and the movement of the toxins out of the
body. .

How does the body get rid of toxins?

"The liver is one of the most important organs in the body when it
comes to detoxifying or getting rid of foreign substances or toxins. The liver
plays a key role in most metabolic processes, especially detoxification. The
liver neutralizes a wide range of toxic chemicals, both those produced
internally and those coming from the environment. The normal metabolic
processes produce a wide range of chemicals and hormones for which the
liver has evolved efficient neutralizing mechanisms. However, the level and
type of internally produced toxins increases greatly when metabolic
processes go awry, typically as a result of nutritional deficiencies. These non-
end-product metabolites have become a significant problem in this age of
conventionally grown foods and poor diets.

Many of the toxic chemicals the liver must detoxify come from the
environment: the content of the bowels and the food, water, and air. The
polycyclic hydrocarbons (DDT, dioxin, 2,4,5-T, 2,3-D, PCB, and PCP),
which are components of various herbicides and pesticides, are an example of
chemicals that are now found in virtually all fat tissues measured. Even those
eating unprocessed organic foods need an effective detoxification system
because all foods contain naturally occurring toxic constituents.

The liver plays several roles in detoxification: it filters the blood to

remove large toxins, synthesizes and secretes bile full of cholesterol and
other fat-soluble toxins, and enzymatically disassembles unwanted
chemicals. This enzymatic process usually occurs in two steps referred to as
phase I and phase II. Phase I either directly neutralizes a toxin, or modifies
the toxic chemical to form activated intermediates which are then neutralized
by one of more of the several phase II enzyme systems.

Proper functioning of the liver's detoxification systems is especially

important for the prevention of cancer. Up to 90% of all cancers are thought
to be due to the effects of environmental carcinogens, such as those in
cigarette smoke, food, water, and air, combined with deficiencies of the
nutrients the body needs for proper functioning of the detoxification and
immune systems. The level of exposure to environmental carcinogens varies
widely, as does the efficiency of the detoxification enzymes, particularly
phase II. High levels of exposure to carcinogens coupled with slow
detoxification enzymes significantly increases susceptibility to cancer.

How does the liver remove toxins from the body?

One of the liver's primary functions is filtering the blood. Almost 2

quarts of blood pass through the liver every minute for detoxification.
Filtration of toxins is absolutely critical as the blood from the intestines
contains high levels of bacteria, bacterial endotoxins, antigen-antibody
complexes, and various other toxic substances. When working properly, the
liver clears 99% of the bacteria and other toxins during the first pass.
However, when the liver is damaged, such as in alcoholics, the passage of
toxins increases by over a factor of 10.

Bile Excretion

The liver's second detoxification process involves the synthesis and

secretion of bile. Each day the liver manufactures approximately 1 quart of
bile, which serves as a carrier in which many toxic substances are dumped
into the intestines. In the intestines, the bile and its toxic load are absorbed by
fiber and excreted. However, a diet low in fiber results in inadequate binding
and reabsorption of the toxins. This problem is magnified when bacteria in
the intestine modify these toxins to more damaging forms.

What happens when excretion of bile is inhibited?

When the excretion of bile is inhibited (i.e. cholestasis), toxins stay in

the liver longer. Cholestasis has several causes, including obstruction of the
bile ducts and impairment of bile flow within the liver. The most common
cause of obstruction of the bile ducts is the presence of gallstones. Currently,
it is conservatively estimated that 20 million people in the U.S. have
gallstones. Nearly 20% of the female and 8% of the male population over the
age of 40 are found to have gallstones on biopsy and approximately 500,000
gall bladders are removed because of stones each year in the U.S. The
prevalence of gallstones in this country has been linked to the high-fat, low-
fiber diet consumed by the majority of Americans.

Impairment of bile flow within the liver can be caused by a variety of

agents and conditions. These conditions are often associated with alterations
of liver function in laboratory tests (serum bilirubin, alkaline phosphatase,
SGOT, LDH, GGTP, etc.) signifying cellular damage. However, relying on
these tests alone to evaluate liver function is not adequate, since, in the initial
or subclinical stages of many problems with liver function, laboratory values
remain normal. Among the symptoms people with enzymatic damage
complain of are:

Fatigue;general malaise; digestive disturbances; allergies and

chemicalsensitivities; premenstrual syndrome; constipation

Perhaps the most common cause of cholestasis and impaired liver

function is alcohol ingestion. In some especially sensitive individuals, as little
as 1 ounce of alcohol can produce damage to the liver, which results in fat
being deposited within the liver. All active alcoholics demonstrate fatty
infiltration of the liver. Methionine, taken as SAM, has been shown to be
quite beneficial in treating two common causes of stagnation of bile in the
liver--estrogen excess (due to either oral contraceptive use or pregnancy) and
Gilbert's syndrome.

Oranges and tangerines (as well as the seeds of caraway and dill)
contain limonene, a phytochemical that has been found to prevent and even
treat cancer in animal models. Limonene's protective effects are probably due
to the fact that it is a strong inducer of both phase I and phase II
detoxification enzymes that neutralize carcinogens.

Are there things that inhibit detoxification?

Grapefruit juice decreases the rate of elimination of drugs from the

blood and has been found to substantially alter their clinical activity and
toxicity.

Curcumin, the compound that gives turmeric its yellow color, is

interesting because it inhibits phase I while stimulating phase II. This effect
can be very useful in preventing certain types of cancer. Curcumin has been
found to inhibit carcinogens, such as benzopyrene (found in charcoal-broiled
meat), from inducing cancer in several animal models. It appears that the
curcumin exerts its anti-carcinogenic activity by lowering the activation of
carcinogens while increasing the detoxification of those that are activated.
Curcuminhas also been shown to directly inhibit the growth of cancer cells.

As most of the cancer-inducing chemicals in cigarette smoke are only

carcinogenic during the period between activation by phase I and final
detoxification by phase II, curcumin in the turmeric can help prevent the
cancer-causing effects of tobacco. Those exposed to smoke, aromatic
hydrocarbons, and other environmental carcinogens will probably benefit
from the frequent use of curry or turmeric.

The activity of phase I detoxification enzymes decreases in old age.

Aging also decreases blood flow through the liver, further aggravating the
problem. Lack of the physical activity necessary for good circulation,
combined with the poor nutrition commonly seen in the elderly, add up to a
significant impairment of detoxification capacity, which is typically found in
aging individuals. This helps to explain why toxic reactions to drugs are seen
so commonly in the elderly.

HepaticFailure

Liver failure, or hepatic failure, is severe deterioration of liver

function resulting from extensive damage of liver cells. The syndrome
respresents a severe clinical condition and is associated with high
mortality; therefore, a great challenge to intensive care management.

Causes
Hepatic failure, on one hand, may be caused by viral hepatitis
(particularly B/C), drugs and intoxications. In these cases, hepatic
failure is diagnosed in the absence of chronic liver disease (fulminant
liver failure). On the other hand, hepatic failure often occurs at the
terminal stage of chronic hepatic illness, e.g. liver cirrhosis (acute-on-
chronic liver failure).

Symptoms
Signs and symptoms of hepatic failure often include jaundice, a yellow
discoloration of the skin and vitreous body (white area) due to
abnormally high levels of bilirubin in the bloodstream. In addition,
hepatic encephalopathy occurs as brain function deteriorates due to
toxic substances in the blood. It is characterized by changes in logical
thinking; changes in personality and behavior; drowsiness; confusion;
disorientation; impaired and/or loss of consciousness; coma. Hepatic
failure is further associated with complications such as hypoglycemia,
cerebral edema, metabolic acidosis, coagulopathy and renal failure.

Pathobiochemistry
Corresponding to the manifold liver functions, hepatic failure disrupts
most of the body's functions. Major organs and systems such as the
kidneys, the central nervous system, the cardiovascular system, and the
clotting system are severely affected. Various substances, which are
normally detoxified by the liver, accumulate in blood; subsequently,
patients with hepatic failure suffer from intoxication because the body
fails to remove poisonous substances from the blood. Patients with
hepatic failure usually have high concentrations of the following in
their bloodstream: bilirubin, bile acids, certain amino acids, phenolic
 substances, ammonia.

Jaundice is a cause for concern and there are many misconceptions

associated with it. DrVikramAnanthakrishnan (M.S., F.R.C.S) answers some
frequently asked questions about this common ailment and about the liver.

Jaundice can be broadly classified as infective and obstructive jaundice.

A virus called Hepatitis A, is a common cause of infective jaundice. This

virus is transmitted through water and food. Children are often affected.

The other viruses such as Hepatitis B and Hepatitis C viruses are transmitted
through blood. Viruses responsible for these infections spread through the body
secretions like saliva, sweat, semen, vaginal fluids of infected persons. Close
contact and sexual intercourse are important factors in spread. Homosexuals
contract these infections more easily. Blood, blood products, contaminated needles
and tattooing, are also important sources through which infection spreads. These
viruses are more resistant to the various methods of sterilisation than the AIDS
virus. They are a major cause for concern as they spread rapidly. There are more
people infected by Hepatitis B virus in the world than the AIDS virus.

Hepatitis B and Hepatitis C infections can lead to chronic liver diseases,

cirrhosis and eventually liver cancer & liver failure.

The other viruses associated with jaundice are Hepatitis D and E. Hepatitis E
infection can be acquired from contaminated water.

Diseases like Leptospirosis can also cause jaundice.

Stones or growths, blocking the pathway of bile, cause a type of jaundice

called obstructive jaundice. Occasionally, drugs can also cause jaundice.
 How is Leptospirosis transmitted and how is it treated?

This is an infection caused by water or food contaminated with rats’ urine.

Patients develop fever and later jaundice and eventually (renal) kidney failure. If
left unrecognised leptospirosis can be fatal. The infection is treated with antibiotics
like penicillin and doxycycline.

Amongst the different types of infective jaundice, which is worse?

Hepatitis C is the most dangerous type of jaundice. Like Hepatitis B it also

leads to chronic liver disease.

Which form of jaundice requires surgery?

Sometimes stones & growths block the pathway of bile drainage from the
liver (where it is made) to the small intestine (where it acts on the food to digest
and break down fats). This can also cause jaundice. Stones in the bile pathway
usually originate in the gall bladder. This often requires removal of the gall bladder
along with the stones in the biliary pathway. Growths may require major surgery
for their removal. In case they are very advanced, a bypass operation may need to
be done to relieve the jaundice.

What are the tests (investigations) done for jaundice?

These can be broadly classified as blood tests, scans and endoscopy.

Blood tests are done to assess the overall function of the liver. These tests
are collectively called Liver Function Tests.

These tests will show if there is on going destruction of the liver. Blood tests
will help identify the type of jaundice.

They will show whether the synthetic function of the liver is good. The
various clotting tests can be done to see if the liver is producing adequate proteins
for clotting purposes.
 Ultrasound scan is done to see if there are any gross architectural
abnormalities in the liver. What cannot be captured by ultrasound can be done by
CT scan and the MRI. M.R.I has now become the gold standard in looking for
abnormalities in the liver and the surrounding organs when there is obstructive
jaundice.

Endoscopy may be performed to look at the oesophagus (food pipe),

stomach and the first few inches of the small intestine. A special variety of
endoscope may also be used wherein a dye can be injected into the bile ducts and
the pancreatic ducts and pictures can be taken. This gives complete visualisation of
the pathway that bile takes to drain into the small intestine. It also studies the ducts
of the pancreas. It is called E.R.C.P. (endoscopic retrograde
cholangiopancreaticogram).

What is the diet recommended for jaundice patients?

Foods that are rich in glucose are recommended in jaundice. These help the
liver cells to regenerate and also provide the required nourishment for the body.
Fats are to be taken in reduced quantities. Deep fried foods & alcohol are to be
avoided.

What is the treatment for Jaundice?

The treatment for jaundice depends upon the type of jaundice. For viral
hepatitis, causing jaundice, there is no definitive treatment. Only supportive
measures are given. The virus is slowly eliminated from the body with the help of
the immune system.

In case it is jaundice caused by blockage to the pathway of bile, surgery may

be needed.

What is the role of immunisation in Jaundice?

 Hepatitis B is one of the common causes of jaundice that can have serious
consequences. Immunising a person can prevent this viral infection and its
consequences. The vaccine is easily available and is usually given in three doses
either at monthly intervals or two doses are given at monthly intervals and the third
six months after the first dose. Immunisation with the vaccine now begins from the
infant period itself. A single booster dose is required once every five years to
maintain the protection.

What is the role of Herbs in treating Jaundice?

The common herb used is Keezhanelli. Its role in treatment is not fully
proven.

Liver Disease

What are the functions of the liver?

The liver has a variety of functions. Its two main functions are synthesising
and detoxifying.

Synthesising:

It helps to break down and store various nutrients like carbohydrates,

proteins and fat.

Whenever there is excess glucose in the blood, it converts it to fat and stores
it.

If the blood glucose levels are low it breaks down fat and protein into
glucose.

It stores vitamins A, D, K , B12, Folate.

Liver is responsible for a variety of protein syntheses. It helps in the

synthesis of substances for clotting of blood, as well as albumin (the most
important protein).
 Detoxyfying

It breaks down drugs, alcohol and poisons absorbed from the intestines.

It is said that, “Liver failure is power failure.”

What is the relation between alcohol and Liver disease?

The liver takes up alcohol from the blood stream. (One of the main functions
of the liver is to clean up the blood of various poisons and the intestines from
invading organisms.) The liver breaks down alcohol (metabolises) and thus bears
the brunt of this poison. Intake of 3 units of alcohol or more in men and 2 or more
units in women for more than five years causes disease.

What is cirrhosis of the liver?

Cirrhosis of the liver is the end result of various insults on the liver. The
insults could be poisons or viruses. It is a process wherein the normal liver tissue is
replaced by non-functioning fibrous tissue. This alters the blood flow within the
liver causing other pathways to open thus resulting in various complications.

What are the complications of cirrhosis liver?

Complications are:

Fluid retention causing large and distended abdomen.

This retention of fluids with a reduction in the synthesis of proteins can lead
on to swelling of the legs (Oedema).

There can be Anaemia (low Haemoglobin) and susceptibility to infections.

The blood flow through the liver could be blocked causing alternate
pathways to open up. This leads to dilatation of veins especially in the lower end of
the food pipe (oesophagus). These veins can rupture causing massive bleeding. The
liver can fail in its function of removing various poisons in the body causing
altered behaviour patterns and eventually coma and death.

Biochemistry of Liver Function

In the past, the liver has been referred to as the center of courage, passion,
temper, and love and even as the center of the soul. it was once believed to produce
"yellow bile" necessary for good health. Today, the liver is a complex organ
responsible for many major metabolic functions in the body. More than 100 tests
measuring these diverse functions have existed in the clinical laboratory at one
time. However, many were abandoned in favor of those that have proven to be
most clinically useful.

The liver performs several hundred functions each day. These function can
be classified into the following:

1.Excretory Function

2. Synthetic Function

3. Detoxification Function

1. Excretory Function

One of the more important liver functions, and one that is disturbed in a
large number of hepatic disorders, is the excretion of bile.

The excretion of bile:

Bile comprises bile salts, bile acids, bile pigments (primarily bilirubin),
cholesterol, and other substances extracted from the blood. Total bile production
averages about 3 L per day, although only 1 L is excreted.
 Bile acids: The primary bile acids are cholic acid and chenodcoxycholic
acid. They are formed in the liver from cholesterol. The bile acids are conjugated
with the amino acids glycine or taurine, forming bile salts. Bile salts (conjugated
bile acids) are excreted into the bile canaliculi by means of a carriermediated active
transport system. During fasting and between meals, a major portion of the bile
acid pool is concentrated up to 10-fold in the gallbladder. Bile acids reach the
intestine when the gallbladder contracts after each meal. Approximately 500-600
mL of bile enter the duodenum each day.

Bile salts help in the digestion and absorption of lipids. When the conjugated
bile acids (salts) come into contact with bacteria in the terminal ileum and colon,
dehydration to secondary bile acids (deoxycholic and lithocolic) occurs, and these
secondary bile acids are subsequently absorbed. The absorbed bile acids enter the
portal circulation and return to the liver, where they are reconjugated and
reexcreted. The enterohepatic circulation of bile occurs 2-5 times daily.

Bilirubin is the principal pigment in bile. It is formed by the breakdown of

hemoglobin when red blood cells are phagocytized by the reticuloendothelial
system. The reticuloendothelial system is mainly in the spleen, liver, and bone
marrow. About 80% of the bilirubin formed daily comes from the degradation of
hemoglobin. The remainder comes from destruction of hemecontaining proteins
(myoglobin, cytochromes, catalase) and catabolism of heme. When hemoglobin is
destroyed, the protein portion -globin- is reused by the body. The iron enters the
body's iron stores and is also reused.

The porphyrin ring is changed to biliverdin, which is easily reduced to

bilirubin. Bilirubin is transported to the liver in the bloodstream bound to albumin.
This bilirubin is referred to as unconjugated bilirubin or indirect bilirubin.

At the liver, unconjugated bilirubin is separated from the albumin and taken
up by the hepatic cells. Two nonalbumin proteins, isolated from liver cell
cytoplasm and designated Y and Z, account for the intracellular binding and
transport of bilirubin. Conjugation of bilirubin occurs in the hepatocytes. An
enzyme, uridyldiphosphateglucuronyltransferase (UDPGT), transfers glucuronic
acid molecules to bilirubin, converting bilirubin into a diglucuronide ester. This
product, bilirubin diglucuronide, is referred to as conjugated bilirubin or direct
bilirubin. Conjugated bilirubin is water soluble. It is secreted from the hepatic cell
into the bile canaliculi and then into larger bile ducts and eventually into the
intestine. In the colon, the bile pigments are acted on by enzymes of the intestinal
bacteria. The first product of this reaction is mesobilirubin, which is reduced to
form mesobilirubinogen. This produces urobilinogen which is a colorless product.
The oxidation of urobilinogen produces the red-brown pigment urobilin, which is
excreted in the stool.

A small portion of the urobilinogen is reabsorbed into the portal circulation

and returned to the liver, where it is again excreted with the bile into the intestine.
This is calledenterohepatic circulation of bile pigments. However, a small quantity
of urobilinogen remains in the blood. This urobilinogen, which is colorless, is
ultimately filtered by the kidney and excreted in the urine.

A total of 200-300 mg of bilirubin is produced daily in the healthy adult. A

normally functioning liver is required to eliminate this amount of bilirubin from
the body. This excretory function requires that bilirubin be in the conjugated form;
that is, the water-soluble diglucuronide. Almost all the bilirubin formed is
eliminated in the feces, and a small amount of the colorless product urobilinogen is
excreted in the urine.

Reference Value of Bilirubins:

• Total bilirubin 0.2 - 1.0 mg/dL

• Direct (Conjugated) 0.0 - 0.2 mg/dL

• Indirect (Unconjugated) 0.2 - 0.8 mg/dL

2. Synthetic Function
 The liver is the main site of synthesis of:

Proteins:

The liver plays an important role in production of albumin and the majority
of the α and β-globulins. All the blood-clotting factors (except VIII) are
synthesized in the liver. Deamination of glutamate in the liver is the primary
source of ammonia, which is converted to urea.

Carbohydrates:

The synthesis and metabolism of carbohydrates is centered in the liver.

Glucose is converted to glycogen (Glycogenesis), a portion of which is stored in
the liver and later reconverted to glucose (Glycogenolysis) as necessary. An
additional important liver function is gluconeogenesis from amino acids.

Lipids:

Fat is formed from carbohydrates in the liver (Lipogenesis) when nutrition is

adequate and the demand for glucose is being met from dietary sources. The liver
also plays a key role in the metabolism of fat. It is the major site for the

- removal of chylomicron remnants

- the conversion of acetyl- CoA to fatty acids, triglycerides, and cholesterol.

- metabolism of cholesterol into bile acids

- Synthesis of Very-low-density lipoproteins

- Synthesis of high-density lipoproteins

- Synthesis of phospholipids.

The formation of ketone bodies occurs in the liver. When the demand for
gluconeogenesis depletes oxaloacetate and acetyl-CoA cannot be converted rapidly
enough to citrate, acetyl-CoA accumulates and a ,decyclase in the liver liberates
ketone bodies into the blood .

The liver is the storage site for all fat-soluble vitamins (A, D, E, and K) and
several water-soluble vitamins, such as B12. Another vitamin-related function is
the conversion of carotene into vitamin A.

The liver is the source of somatomedin (an insulin-like factor that mediates
the activity of growth hormone) and angiotensinogen, and is a major site of
metabolic clearance of many other hormones. As the source of transferrin,
ceruloplasmin, and metallothionein, the liver plays a key role in the transport,
storage, and metabolism of iron, copper, and other metals .

Many enzymes are synthesized by liver cells. Those enzymes that have been
found useful in the diagnosis of hepatobiliary disorders include aspartate amino
transferase (AST, or serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine amino transferase (ALT, or serum glutamic pyruvic transaminase [SGPT]),
alkaline phosphatase (ALP) and 5'-nucleotidase (5NT), and γ-glutamyltransferase
(GGT).

3. Detoxification Function

Because the liver is interposed between the splanchnic circulation and the
systemic blood, it serves to protect the body from potentially injurious substances
absorbed from the intestinal tract and toxic by-products of metabolism.

The most important mechanisms of detoxification includ oxidation,

reduction, hydrolysis, hydroxylation, carboxylation, and demethylation.
Detoxification mechanisms convert many toxic or insoluble compounds into less
toxic or more water-soluble compounds and, therefore, excretable by the kidney.
For example, ammonia, a toxic substance arising in the large intestine through
bacterial action on amino acids, is carried to the liver by the portal vein and
converted by hepatocytes into the innocuous compound urea.
 Conjugation with compounds, such as glycine, glucuronic acid, sulfuric acid,
glutamine, acetate, cysteine, and glutathione, occurs mainly in the cytosol. This
mechanism is the mode of bilirubin and bile acid excretion.