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Feature
Article: Anti-Oxidants, Oxidative Stress,
and Cellular Aging
Examples: Vitamin E and Vitamin C
by Elishalom
Yechiel, Ph.D.
Many
consumers are aware of anti-oxidants primarily as unexplained features
of products they know they should prefer. They've been told they
should drink green tea rather than black tea (and green tea has become
a common ingredient in topical formulations) because green tea is
high in anti-oxidants; high levels of anti-oxidants in orange juice
are one of many good reasons to enjoy it; a skin care product which
contains anti-oxidants is bound to be good. Although the belief that
anti-oxidants are desirable is widespread, understanding of the nature
of anti-oxidants, even at the minimal level of recognizing just what
they are "anti-", is rare. To objectively evaluate the
benefits of anti-oxidants, it is essential to obtain a good understanding
of the subject so that decisions about product selection and ingredient
preference can be made from a realistic standpoint and a broad perspective. Highlighted
words within this article link to a glossary entry
for that term.
Why are anti-oxidants interesting?
Anti-oxidants have
gained enormous popularity in the past several decades, and
are used as additives in almost all foods and skincare products.
Since oxidation is
one of the processes by which materials degrade, anti-oxidants
were first widely used as preservatives: sliced apples and
potatoes turn brown because of oxidation; dipping the slices
in lemon juice, which contains the anti-oxidant Vitamin C,
delays the oxidation process.
When peroxidation began
to be emphasized as a critical factor in the aging and cancer
processes, the term "anti-oxidant" become almost
synonymous with the term "anti-aging".
This connection to anti-aging studies raised the status of
anti-oxidants so that, rather than being considered mere
preservatives, anti-oxidant ingredients were assumed to have
value in saving and prolonging life.
Anti-oxidants
have beneficial attributes in a wide spectrum, making it
possible for them to interfere with the processes of cancer,
heart disease, and aging. However, there is also a growing
body of rumors, backed by fragmentary scientific-appearing
studies which overstate antioxidants’ healing powers
and claim they can cure or prevent an unreasonable multitude
of other health problems.
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Vitamin
C, Vitamin E, and Glutathaione are three of the most important
and relevant anti-oxidants to bio-systems. The synergistic
mechanism of cooporation between these three anti-oxidants
will be elaborated later in this document.
|
Vitamin
C is a water-soluble anti-oxidant with a rapid turnover.
It
is virtually non-toxic and it can be consumed in
large quantities.
Though
it is water-soluble, it can interact with the active
site of Vitamin E. as will be later explained.
|
Vitamin
E is an oil-soluble anti-oxidant with protective activity
against phospholipid peroxidation. It is situated in the
lipidic bilayer of cell membranes, but its active site
is accesible to Vitamin C recycling activity. More information
about the recycling mechanism is available later in this
document.
Vitamin
C itself must be recycled after it recycles Vitamin E.
Glutathaione can recycle Vitamin C. Glutathaione also participates
in central biochemical cascades in a bio-system.
|
What are anti-oxidants "anti-"?
Who is the oxidant enemy
which anti-oxidants fight? There is more than one enemy. Indeed,
the chemistry of life generates oxidants; energy generating cycles
and metabolic pathways also generate free
radicals and non-free
radicals including superoxides,
peroxides, and many other oxidants.
What are Oxidative Stress and Reactive Oxygen Species
(ROS)?
|
Oxidative
stress is a term describing the burden imposed
on a bio-system by free radical (molecules with un-paired
electrons) and non-free radical molecules, collectively called Reactive
Oxygen Species (ROS). Anti-oxidants fight oxidative
stress.
While superoxide
( *O2- )
and hydroxyl peroxide (*OH)
are examples of free radical ROS-type molecules, hydrogen peroxide
(H2O2)
and singlet oxygen (1O2)
are non-free radical ROS-type molecules.
Free radicals
differ from each other in their reactivity.
Hydroxyl peroxide is a very reactive free radical and possibly
one of the most damaging one. However, hydroxyl radicals can
be generated from less reactive free radical molecules such as
superoxide and non-free radical molecules such as hydrogen peroxide.
Low reactivity free radicals can actually act as antioxidant
buffers, which are analogous to electrical transformers. Just
as electrical transformers are lowering voltage to make electricity
less reactive and less dangerous, so do antioxidants modulate
free radicals in quenching very reactive free radicals and becoming
stable, low reactivity free radicals themselves in the process.
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The
Relative Reactivity of Reactive Oxygen Species
| SYMBOL |
NAME
|
MOLECULAR
SPECIES
CATEGORY
|
| *OH |
Hydroxyl
radical
|
Extremely
reactive |
1O2
|
Singlet
oxygen
|
Extremely
reactive |
ONOO-
|
Peroxynitrite
anion
|
Extremely
reactive
|
| *O2- |
Superoxide |
Intermediately
reactive |
| H2O2 |
Hydrogen
peroxide |
Moderately
reactive |
| NO* |
Nitric
oxide radical |
Moderately
reactive |
| C* |
Ascorbate
free radical
(oxidized Vitamin C) |
Low
reactivity |
E*
|
Tocopheroxyl
free radical
(oxidized Vitamin E) |
Low
reactivity |
|
An introduction to chemical pathways: How are very reactive
free radicals generated and how are free radicals perpetuated?
| |
Bio-systems
commonly include the reactive molecules (ROS) which work
via different mechanisms but which can also interact with
each other or change from one to the other. These are categorized
by their relative reactivity. Not all reactive molecules
are oxygen-based, and the term "oxidation" can apply to
atoms other than oxygen; when an atom of oxygen or anything
else
loses an electron, it is oxidized. Iron and copper in the
reduced forms of Fe++ and Cu+ respectively play a major
role in mediating and perpetuating the free radical chain
reaction.
The problem
with free radicals is not just in their reactivity but
also in their action as catalysts. After a free radical
attacks another molecule, it is not inactivated but can
rather generate another free radical so that the process
is amplified
and perpetuated. |
|
CHEMICAL
PATHWAY
|
EXPLANATION
|
*O2- + H2O2 --> O2 + *OH +
OH-
*O2 + NO* --> ONOO-
|
Intermediately
and moderately reactive molecular species such as superoxides
and hydrogen peroxide are not very dangerous to bio-systems.
However, interactions between low reactivity molecular species
can produce highly reactive and dangerous molecular species. |
| Transition
Iron Ions
Fe++ + H2O2 --> Fe+++ + *OH +
OH-
Fe+++ + *O2-- --> Fe++ +
O2
*O2- +
Fe+++ --> O2 + Fe++
Transition
Copper Ions
Cu+ + H2O2 --> Cu++ + *OH +
OH-
Cu++ + H2O2 --> Cu+ + *O2- +
2H+
|
Transition
metal ions mediate production of extremely strong oxidants
from more moderate oxidants’ species. |
|
The
way to put a stop to this is either by having it interact with a molecule
that will not allow the generation of a new free radical, or by attenuating
the effect by generating less reactive new free radicals. This is where
anti-oxidants enter into the picture.
How do anti-oxidants fight free radicals?
To help reduce oxidative
stress, antioxidants have a critical role in minimizing the perpetuation
of free radicals or in reducing their reactivity.
Free
radicals such as Vitamin C, Vitamin E, and glutathione play a major
role in free radical control. Glutathione is a natural thiol commonly
involved
in coupling with undesirable molecules (via a sulphydryl group),
eliminating them via renal excretion.
To better understand how anti-oxidants work, we have to understand the
major mechanisms of free radical turnover.
Free radicals can be initiated, propagated, and terminated.
When there
is an external source generating free radicals, it is an initiation
reaction. Initiation reactions result in a net increase in
the number of free radicals. Initiation reactions can generate free
radicals from
stable molecules by
irradiation or by interaction with existing free radicals. For example:
X2 + hv --> 2X*
Propagation
reactions involve free radicals' reactions
in which the total number of free radicals is not increased. However,
in the process more reactive
free radical species may evolve. For example:
*O2- + H2O2 --> O2 + *OH + OH-
Termination reactions are reactions between free radicals
in which two free radicals combine to form a stable molecule. For example:
2X* --> X2
Propagation is very often the reaction of choice for the
containment of free radicals rather than termination. Free radical
containment by propagation is achieved by transfer of the free radical
into a host molecule
where the free radical is stabilized and its reactivity is thus modulated.
What are some examples of anti-oxidants' mechanism of action?
Two of the most effective
anti-oxidants are Vitamin E and Vitamin C. Vitamin E protects lipids
from peroxidation. In the process, Vitamin E can
be oxidized
to tocopheryl quinone or into tocopheroxyl free radical. It
is reduced in both cases by ascorbate (Vitamin C), which is oxidized
in the process
into either dehydroascorbate or ascorbate free radical.
Vitamin
C Recycles Vitamin E
Dehydroascorbate and ascorbate free radicals can be regenerated by the
enzyme semidehydroascorbate reductase. In the process, NADH is oxidized
to NAD; the NAD/NADH cycle is a critical factor in many biochemical
cascades and key to aerobic and anaerobic energy generation pathways.
Another enzyme, dehydroascorbate reductase,
also recovers ascorbate; in the
process, reduced glutathione
(GSH) is
oxidized into glutathione
(GSSG).
Glutathione Recycles Vitamin C
Examples of enzymatically catalyzed ROS terminators
The
enzyme superoxide dismutase catalyzes the condensation of two superoxide
molecules into the less reactive hydrogen peroxide (H2O2)
and oxygen (O2). The enzyme catalase further helps the
transformation of hydrogen peroxide into water (H2O) and
oxygen (O2).
If anti-oxidants fight free radicals,
are free radicals always bad? Are anti-oxidants always good?
Free radicals and peroxides
are not just “bad” and are not just
the result of unfortunate side effects of the metabolic process; they
are bioactive molecules which the body generates by design to
be used
in some
metabolic processes and in defense mechanisms. The following table
compares between the good and bad aspects of these special molecules.
POSITIVE
AND NEGATIVE ASPECTS OF FREE RADICALS AND PEROXIDES
POSITIVE
|
NEGATIVE
|
| ROS are
synthesized and used by the body’s defense
system to kill bacteria.
ROS
are used by the body for detoxification and also play a role
in immune system activity.
Nitric oxide, a common
free radical, is now recognized to play an important role in
control of vasodilation and in neurotransmission.
H2O2 is
used by the enzyme thyroperoxidase as a substrate in the production
of tyroxin in
the thyroid gland and is generated there.
Thyroperoxidase catalyzes iodine attachment to thryoglobulin.
H2O2 is
generated in peroxisomes to aid in the degradation of fatty
acids and other molecules, and
H2O2 is used for detoxification
reactions involving the liver cytochrome P-450 system.
|
Excessive
production of ROS leads to oxidative stress and disease.
Hydrogen peroxide, nitric oxide,
and superoxide can be transformed into the dangerous hydoxyl
radical.
Peroxynitrite anion can
cause damage to DNA, generate lipid peroxide, death of nerve
cells and related degenerative diseases.
Cumulative oxidative stress
can result in cancer, heart disease, and accelerated aging.
|
Conclusion
Reactive Oxygen Species
and anti-oxidants are major players in bio-systems. Because of
their high reactivity, the unclear and
narrow borders between their “good” and
their “bad” effects, and the limited understanding of
their roles in living systems, much caution is recommended. Elimination
of too many free radicals can be as damaging as the presence of
too
many free radicals. Until more is known,
it is best to stick to anti-oxidants which are well known and be
very cautious when exploring new anti-oxidants. There are other methods
of addressing the problems addressed by anti-oxidants. For example,
the role of free iron in perpetuating free radicals is well established.
Iron is so far recognized as critical in the perpetuation of highly
toxic free radicals. Iron-mediated damage can be controlled by
specific,
non-toxic iron chelators or more general heavy metal
chelators;
this will be
discussed in a future article.
GLOSSARY
TERM
|
EXPLANATION |
| anti-oxidant |
a reducing
agent; a buffer molecule protecting
biologically important molecules from peroxidation, taking the
"hit" of oxidants. |
| oxidation |
removing an
electron; increasing positivity of a molecule. |
| peroxidation |
the oxidative damage
imposed by a peroxide on another molecules. Peroxides are sometimes
called oxidants but are actually a reactive group within the
more general oxidant group. |
| anti-aging |
protection from
damaging molecules which are thought to increase the pace of aging. |
| free
radical |
an un-paired electron. |
| non-free radical |
a reactive
oxidant molecule which is not a free radical. |
| superoxide |
a subspecies
of free radical molecules |
| oxidative
stress |
increase in
oxidants is counteracted by the body by an increase in anti-oxidative
activity. Concentrating resources to battle oxidants can be very
stressfull to a bio-system. |
| Reactive
Oxygen Species (ROS) |
very reactive
molecules which are oxidating in nature, including free radicals
and non free radical molecules. |
| reactivity |
reactivity
is a measure of how likely a molecule is to attack another molecule.
Some highly reactive molecules are surprisingly not very damaging
to many molecules in a bio-system because they like to attack each
other or simple molecules with not much bearing on the bio-system. |
| O |
chemical symbol for
oxygen |
| H |
chemical symbol for hydrogen |
| N |
chemical symbol for nitrogen |
| Fe |
chemical symbol for iron |
| Cu |
chemical symbol for copper |
| bioactive |
a molecule
that is active in a bio-system and which has activity significant
to a bio-system. Even a synthetic molecule can be bioactive. |
|
In
this issue:
Welcome
to the Journal of Topical Formulations
Feature
Article: Anti-Oxidants, Oxidative
Stress, and Cellular Aging
The Formulator's Bookshelf
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