Here is the most comprehensive explanation of the activity of alpha-lipoic acid I have ever come across. If you have ever wondered whether this amino acid is for you, you will find your answer here. This is complete with all references. It is not my work.
Diabetes Interview, April 2000
Copyright Diabetes Interview,
1-800-234-1218
Alpha-Lipoic
Acid is accessible to lipid- and water-soluble cellular compartments and able to
regenerate glutathione and vitamin E and C. Alpha-Lipoic Acid is an
important mitochondria cofactor for the production of energy from pyruvate.
Oxygen
is essential to life. It must be present in order for our cells to convert
matter to energy. Metabolism involves the chemical changes that take place in
our bodies to provide energy for vital processes and activities. The continuous
and efficient production of energy is vital to our ability to function at peak
levels in everything we do. Among the by-products of metabolism are free
radicals.
A free radical is any substance with one or more unpaired electrons. They are
the natural result of the normal metabolic process. They can also be the result
of various lifestyle and environmental influences such as smoking, drinking
alcohol, excessive exercise, pollution and over exposure to the sun. Free
radicals are very reactive substances which roam throughout the body in search
of their "missing electron". They can deform and corrode any partner they touch.
When uncontrolled free radical reactions occur, they can damage vital biological
molecules, cells, tissues and organs.
Today, the scientific community is devoting more time and research toward
understanding free radicals. The reason for this research is the increasing
realization that free radicals can have a potentially harmful effect on the
cells in our bodies and that this oxidative stress may lead to more serious
conditions. Researchers have found that antioxidant nutrients, which can
neutralize, balance and sponge up free radicals-may be effective in combating
free radical damage.
Antioxidants, whether produced in the body or obtained through diet or
supplementation, are substances which function to destroy free radicals by
coupling with the unpaired electrons. When antioxidants do this, they themselves
become free radicals. The benefit obtained, however, is that the free radical
antioxidant form is relatively unreactive and the antioxidant form can be
regenerated by interacting with other antioxidant substances.
In 1991, researchers showed for the first time the synergistic action of the
antioxidants vitamin E, vitamin C, Alpha-Lipoic Acid and glutathione. This so
called "antioxidant network" ensures comprehensive protection from free
radicals. When research suggested that this "antioxidant network" plays an
important role in the life process, the first congress on the significance of
antioxidants in preventative medicine was held in Saas Fee, Switzerland in 1992.
This congress led to the Declaration of Saas Fee which emphasized the role of
natural antioxidants such as vitamin E, vitamin C, Alpha-Lipoic Acid and
carotenoids in disease prevention. The Declaration of Saas-Fee was signed by a
large number of international experts and now has become the basis for worldwide
initiatives of prevention.
It is interesting to note that production of the free radical species of oxygen
is a normal mechanism that the body's immune system uses to harm and kill
potentially infectious microbes and viruses. To do this, immune cells are
targeted to the environment where these foreign materials are located and
perform their toxic, damaging free radical reactions in the micro environment.
For example, this is very important in the early stages of wound healing.
As long as the ratio of oxidants to antioxidants remains in balance, the
negative effects of free radicals are kept under control. When that balance is
upset by ...lifestyle or environmental factors, the antioxidants produced by the
body simply can't cope with the sudden increase of free radicals.
Supplemental antioxidants are useful aids in maintaining good health. When the
body's natural antioxidants are overwhelmed, supplementing the diet with
antioxidants such as vitamin E, vitamin C and Alpha-Lipoic Acid can help keep
free radicals in check.
Alpha-Lipoic Acid is an essential co-factor in energy metabolism in organisms
from microbes to humans. A co-factor can be simply defined as a substance
(such as a co-enzyme) that must be available in order for another substance
(such as an enzyme) to produce a specific result. It only requires a small
amount of Alpha-Lipoic Acid to fulfill this role.
Also, when present in sufficient quantities Alpha-Lipoic Acid acts as an
antioxidant. The amount of Alpha-Lipoic Acid naturally present in the body may
not be adequate to obtain the antioxidant benefits. Increasing the amount of
Alpha-Lipoic Acid through dietary supplementation can be helpful to perform this
vital function. The combination of these two attributes makes Alpha-Lipoic Acid
a unique metabolic antioxidant molecule.
Alpha-Lipoic
Acid is a small molecule that is soluble in both water and fat. This is
significant because water soluble antioxidant nutrients (vitamin C for example)
are found within the cell and fat soluble antioxidants (vitamin E for example)
are found on the cell membrane. Because Alpha-Lipoic Acid works both inside the
cell and at the membrane level, you get dual protection. At the membrane level
you get protection before free radicals enter the cell. Any free radicals that
makes it past the first line of protection are combated right in the cell
itself.
Alpha-Lipoic Acid may exist in its original oxidized form or its reduced form
(as dihydrolipoic acid.) Most antioxidant substances can be oxidized and reduced
and usually can only act as antioxidants when they are in their reduced form.
Alpha-Lipoic Acid is unique in that both its oxidized and reduced forms possess
antioxidant properties. In its oxidized form, the surface atoms at the end of
the molecule form a ring structure known as the dithiolane ring. It is because
of a minute particle of disulfide in this ring that Alpha-Lipoic Acid is able to
perform its attributed functions as an enzyme catalyst and as an antioxidant.
The dithiolane ring is broken when the molecule is reduced, either by enzymes or
free radicals. The result is dihydrolipoic acid, which itself is an even more
potent antioxidant.
Alpha-Lipoic
Acid appears to function in two ways in the body. First, it functions as a
co-enzyme in the metabolic process. Second, at levels which may be achieved
through supplementation, it also works as an antioxidant.
Alpha-Lipoic
Acid serves as a co-factor for a number of vital enzymes responsible for the
conversion of glucose, fatty acids and other energy sources into chemical energy
(ATP). Small amounts of Alpha-Lipoic Acid are bound chemically (co-enzyme) at
the active site of enzyme complexes. Alpha-Lipoic Acid works by becoming reduced
and facilitates biological reactions from which energy is harnessed.
Alpha-Lipoic
Acid also affects the biochemistry of the body when it is in its free form, that
is, not bound to enzymes. The fact that Alpha-Lipoic Acid is predisposed to
donating an electron to unpaired molecules makes it an ideal antioxidant when
confronted by free radicals. Alpha-Lipoic Acid is able to inhibit free radical
reactions from such diverse sources as those generated from the body's own
metabolism or from various environmental sources.
There
are four criteria that must be met before any substance can be considered a
potent and successful antioxidant. First, it must be readily absorbable. Second,
it must be easily transported across cell membranes. Third, there must be
pathways in the cell whereby the substance is reduced from the oxidized form to
the antioxidant potent reduced form. Fourth, it must be shown to interact
favorably with a variety of more oxidative species.
Since Alpha-Lipoic Acid is a relatively small molecule, it is readily absorbed
and transported across cell membranes and, therefore, satisfies the first two
criteria. In this way, Alpha-Lipoic Acid differs from glutathione which is the
other major (sulfur containing) antioxidant in the body. Since glutathione
cannot be transported across the intestinal tract, glutathione levels cannot be
increased by dietary means to augment the antioxidant defense from this
substance. In contrast, Alpha-Lipoic Acid which is readily absorbed and has, in
fact, been found to increase glutathione levels as the result of its ability to
regenerate glutathione back to its potent antioxidant form.
As to
the third criteria, Alpha-Lipoic Acid is readily reduced in cells and tissues.
Once inside the cells, Alpha-Lipoic Acid is reduced or broken down to
dihydrolipoic acid (DHLA). Most importantly, both Alpha-Lipoic Acid and
dihydrolipoic acid (the reduced form of Alpha-Lipoic Acid) are antioxidant
compounds that react with a number of oxidative species. While both Alpha-Lipoic
Acid and dihydrolipoic acid perform antioxidant functions, dihydrolipoic acid,
the reduced form of Alpha-Lipoic Acid, is the more potent form in performing
antioxidant functions. Dihydrolipoic acid acts directly to destroy certain
oxygen species such as superoxide radicals, hydroperoxy radicals, and hydroxyl
radicals
Alpha-Lipoic
Acid acts with other antioxidants in two significant ways. First, through the
enhancement of the antioxidant network resulting from increased activity among
the antioxidants within the cell. And second, through the regeneration of
other antioxidants by bringing them back to their reduced antioxidant-potent
form.
The body's major natural antioxidant substances that defend us against free
radicals are substances such as vitamin E, and vitamin C, which are essential in
the diet. Another important antioxidant is glulathione. Vitamin E is the most
lipid soluble (fat soluble) antioxidant preventing cell membrane damage. Vitamin
C and glutathione work in the cytoplasms, the aqueous or water-soluble parts of
cells. As mentioned previously, one of the unique characteristics of Alpha-Lipoic
Acid is that it has both water and fat soluble characteristics. Thus, Alpha-Lipoic
Acid is a molecule which connects the activity of antioxidants in the cell
membrane with antioxidants in the cytoplasm, strengthening the antioxidant
network. Hence, the intake of vitamin E and vitamin C should be coupled with
Alpha-Lipoic Acid supplementation in order to ensure complete cell protection
since vitamin E, vitamin C, and Alpha-Lipoic Acid work synergistically.
Alpha-Lipoic Acid plays an important role in antioxidant and vitamin recycling.
This process can be viewed as a sort of chain reaction. Antioxidants are most
powerful in their reduced form. When antioxidants come into contact with free
radicals, they lose their free radical scavenger fighting abilities and return
to their oxidized form.
The reduced form of molecules always has an extra electron. The reduced form of
Alpha-Lipoic Acid, dihydrolipoic acid, is able to donate this electron to the
oxidized or antioxidant-inactive form of glutathione and vitamin C. The oxidized
form of glutathione is called glutathione disulfide. The oxidized form of
vitamin C is called dehydroascorbate. When Alpha-Lipoic Acid donates the
electron to either of these molecules, it serves to regenerate them back to
their reduced, potent antioxidant forms known as glutathione and ascorbate
(vitamin C) respectively. The reduced form of vitamin C (ascorbate), regenerates
vitamin E from its oxidized form (chromanoxyl radical to its reduced form (tocopherol)
by means of a similar process of electron donation.
This must be viewed as a cycle. After donating the electron, the dihydroliopic
acid returns to its oxidized form, Alpha-Lipoic Acid. Each time a molecule in
its reduced form donates an electron, it returns to its oxidized form. Each time
a molecule in its oxidized form receives or accepts an electron it returns to
its reduced form. This is known as the "redox cycle".
As stated earlier, one of the unique characteristics of Alpha-Lipoic Acid is
that it possess antioxidant qualities in both its oxidized and reduced forms.
This enables the molecule to perpetuate the regeneration cycle. Thus, Alpha-Lipoic
Acid is able to supply reducing potential to maintain all of the major
antioxidant substances in their biologically active and potent forms.
The reduced form of the antioxidant works in a similar way in combating free
radicals. For example, vitamin E donates an electron to peroxide, a free
radical, thus balancing out the unpaired electron in the peroxide molecule to
create hydrogen peroxide, a relatively harmless molecule. Now that vitamin E has
given up the extra electron it loses its free radical scavenging properties and
is in its oxidized state. The presence of Alpha-Lipoic Acid initiates the chain
of regeneration as described above, ultimately leading to the reduction of
vitamin E whereby it regains its antioxidant potencies
An
artificially induced deficiency that leads to severe debilitation is the classic
test to determine whether or not a substance is a vitamin. Since Alpha-Lipoic
Acid is produced naturally in the body, it does not meet the requirements of
this test and cannot be classified as a vitamin in the classical sense.
Alpha-Lipoic Acid exhibits "vitamin like" effects as shown by its
function in an antioxidant network which leads to a general increase in the
antioxidant defense mechanism. Vitamin E and vitamin C are well known members of
the vitamin family that possess antioxidant functions. Symptoms of vitamin E and
vitamin C deficiency may be prevented by Alpha-Lipoic Acid supplementation. It
was found in 1959 that Alpha-Lipoic Acid prevented symptoms of vitamin E and
vitamin C deficiency in animals that were on vitamin C or vitamin E deficient
diets. These results were reconfirmed in similar observations in1994.
Alpha-Lipoic
Acid will be mainly found in food stuffs which have been derived from sources
where active energy production is occurring. These are usually high in
mitochondria. Mitochondria are round or rod-shaped structures found just outside
the cell nucleus. They produce energy for the cell and have abundant fats,
protein and enzymes. Since one of the more important functions of Alpha-Lipoic
Acid involves the production of energy which takes place in the mitochondria of
cells, cells or tissues that are mitochondria-rich would be expected to have
higher sources of Alpha-Lipoic Acid. Alpha-Lipoic Acid is present in the leaves
of plants containing mitochondria and non-photosynthetic plant tissues, such as
potatoes. A survey of plant tissues rich in Alpha-Lipoic Acid is currently
underway.
Another source which is very high in mitochondria is red meat. This is
probably the richest source of naturally-occurring Alpha-Lipoic Acid.
Bearing that in mind, dietary supplementation of Alpha-Lipoic Acid may be
especially important for vegetarians and those cutting down on red meat
consumption.
Under normal conditions, our bodies contain small amounts of Alpha-Lipoic Acid.
However, these may not be sufficient levels to provide optimal protection from
free radicals. It may be difficult to consume adequate levels of Alpha-Lipoic
Acid in the normal diet to prevent free radical damage. Therefore,
supplementation of Alpha-Lipoic Acid may be necessary to ensure sufficient
levels in order to obtain the antioxidant benefits of this nutrient.
As with any antioxidant, the optimum levels of Alpha-Lipoic Acid would be
expected to vary from individual to individual and with levels of exposure to
sun, physical activity, diet and lifestyle, exposure to stress and polluted
environments. Factors that increase oxidative stress would be expected to
increase the need for antioxidant protection. Therefore, it is very difficult to
set an exact daily amount of Alpha-Lipoic Acid.
Numerous
studies have shown that daily intake of 50 mg of Alpha-Lipoic Acid produced no
specific side effects. Evidence of low toxicity was observed in four different
human studies where the daily intake of Alpha-Lipoic Acid was between 100 and
600mg for three weeks up to six months. In very high doses given consistently to
humans in excess of 500mg per day or more, slight blood glucose lowering effects
have been observed. Some allergic skin reactions have also been reported in a
few subjects at these high dosages. These side effects have been reported for
individual cases. Other research has documented that there is no evidence of
mutagenicity, teratogenicity, or carcinogenicity.
It was
observed in 1937 that certain bacteria required a component of potato extract
for growth. The so-called "potato growth factor" was, in fact, Alpha-Lipoic
Acid. In 1947, it was reported that yeast extracts contained an unidentified
compound that allowed Streptococcus feacalis to oxidize the carbohydrate
pyruvate to acetate. Additional studies with yeast extracts in 1952 led
researchers to conclude that the compound they were studying was not a simple
fatty acid. Armed with this background information, in 1957, the compound was
formally isolated and characterized as Alpha-Lipoic Acid.
The in-vitro antioxidant function of Alpha-Lipoic Acid was investigated in 1939.
Following this, intensive research over the next five years showed that the
antioxidant functions of Alpha-Lipoic Acid were able to protect cells from free
radicals. Research continues to be conducted throughout the world on this unique
metabolic antioxidant nutrient focusing on its metabolic and antiantioxidant
characteristics and the interactive effects and benefits of Alpha-Lipoic Acid
and other nutrients.
ALPHA-LIPOIC ACID
Perhaps the most
established neuro-protective antioxidant is alpha-lipoic acid (also see
above under section Alpha-lipoic acid (thioctic acid) has the ability to cross
the blood-brain barrier, so that it can exert its antioxidant benefits in the
central and peripheral nervous system (101;125;126). Numerous clinical studies
document the ability of alpha-lipoic acid to promote normal peripheral nerve
function in people with diabetes (127-129). Other nutrients that have been shown
to maintain nerve function in people with diabetes are chromium (130) and
vitamin E (77).
Richard A. Passwater,
Ph.D., In Lipoic Acid: The Metabolic Antioxidant, states, "Both
insulin-dependent and non-insulin-dependent diabetics will be excited to learn
that lipoic acid has been used for nearly 30 years in Europe to treat diabetic
neuropathy, help regulate blood sugar and prevent diabetic retinopathy and
cardiopathy," Passwater says. "Lipoic acid not only protects the nervous system,
but also may be involved In regenerating nerves. It is also being studied in the
treatment of Parkinson's disease and Alzheimer's disease."
Although we make some
lipoic acid in our bodies, it is usually not enough, so we rely on food -
potatoes, red meat, etc.- to supply what we need for optimal health. Alpha-lipoic
acid supplements are now available In health food stores to insure a sufficient
intake of the nutrient.
Passwater adds that lipoic
acid's antioxidant function is of major importance, since antioxidant nutrients
help protect the body against the damage that can cause heart disease, cancer,
aging and about 80 other diseases. This damage is caused by free radicals, those
undesirable byproducts of metabolism.
Interaction with vitamins C & E
As mentioned above, another function of lipoic acid is that it both interacts
with its antioxidant partners vitamin E and vitamin C and also helps to conserve
them. When the body is deficient in lipoic acid, the other antioxidants do not
properly network together.
"Lipoic acid has also been
used for decades to protect the liver and to detoxify the body of heavy metal
pollutants, such as excessive iron and copper and toxic metals such as cadmium,
lead and mercury," Passwater continues. One of the most exciting recent
developments is that lipoic acid appears to help slow the progression of
HIV-infection to clinical AIDS."
It appears that alpha-lipoic
acid, alone or together with vitamin E, is an effective treatment for radiation
exposure, lessening indices of oxidative damage and normalizing organ function,
according to Lester Packer, Ph.D., et al. in Free Radical Biology and
Medicine 1995. This therapy has been effective In treating children living
in areas affected by the Chernobyl accident in the former Soviet Unlon.
Neither animal nor human
studies, so far, have shown serious side effects with the use of alpha-lipoic
acid, Packer says. However, it is not recommended for pregnant women without
proper supervision. Since it may interfere with vitamin B-1 utilization, a
thiamine supplement may be warranted if lipoic acid is given to
thiamine-deficient individuals, such as alcoholics.
Protection from cat
Writing in a previous
issue of Free Radical Biology and Medicine, I. Maitra, et al., reported that,
when lab animals were treated with buthionine sulfoximine (BSO), all developed
cataracts. But supplementation with lipoic acid protected 60 percent of the BSO-treated
animals from cataract formation.
Maitra and colleagues added
that concentrations of glutathione, vitamin C and vitamin E, which decrease
after BSO administration, were restored to levels similar to the controls.
Lipoic acid also restored the protein complexes glutathione peroxidase and
catalase, as well as ascorbate free radical reductase activities, in the lens of
the animals.
Hans-J. Tritschler, Ph.D.,
a well-known researcher of lipoic acid, says that the substance is a very
important cofactor for glucose metabolism. And, since it is both fat- and
water-soluble, it is the missing link between vitamin E and vitamin C
metabolism.
"Since there isn't an overwhelming amount of alpha-lipoic acid In our bodies, an expert panel has recommended 50 mg/day as a preventive measure against diseases caused by free-radical attacks,'' Tritschler says.
Please note the following if you are a diabetic who takes alpha-lipoic acid:
Other Properties of Alpha Lipoic Acid
As an adjunct to the article in the January 2000 issue of Diabetes Interview relating to alpha lipoic acid, I suggest you do an additional literature search on this subject as there are other important properties of alpha lipoic acid that were not mentioned.
For example, it inhibits glycosylation of proteins and therefore can reduce the incidence of many long-term diabetic complication. It also increases insulin sensitivity, even in slim, Type I diabetics who are not insulin resistant. It should also be pointed out that while large doses are necessary to achieve many of the effects, the water-soluble version is effective in much lower doses. Inhibiting glycosylation of proteins usually reduces levels of HbA1c in people who take this product and means they can no longer use HbA1c results as an indication of average blood sugar.
Diabetes Interview, April 2000
Copyright Diabetes Interview,
1-800-234-1218