Free Radicals, Types, Sources and Damaging Reactions

Free radicals are a chemical species that possess an

unpaired electron in the outer shell of the molecule.

Structure of free radicals

Fig. 1: The structure of free radicals

(Reiter & Jo Robenson 1995)

The chemistry of free radical generation

Free radicals can be generated both in-vivo and I
n-vitro by one of the following mechanisms:
1. Homolytic cleavage of a covalent bond, in
which a normal molecule fragments in two, each
fragment retaining one of the paired electrons. Homolytic
cleavage occurs less commonly in biological systems,
as it requires high-energy input from ultra-violet light,
heat or ionising radiation.
2. Loss of a single electron from a normal molecule.
3. Addition of an electron to a normal molecule.
A fundamental fact about free radicals is that the unpaired electrons in their outer shells do not affect the charge on
the resultant molecule. Free radicals can be negatively charged, positively charged or electrically neutral
(Cheeseman and Slater, 1993). This is because charge is concerned with the number of negatively charged
electrons in relation to the positively charged protons whereas free radicals are related only to the spatial
arrangement of the outer electron. The unpaired electron may have been gained on top of a neutral molecule
making it negative; alternatively, it may have resulted from the loss of an electron from the same molecule
resulting in a positive charge. Likewise, if the original molecule were not neutral to begin with the addition or
removal of an unpaired electron would result in a neutral charge.
Properties:
The magnetic properties of free radicals provide a powerful tool for their detection and study.Molecules with even numbers of paired
electrons are diamagnetic; i.e., they are slightly repelled by a magnet. Free radicals, however, are paramagnetic (attracted by a
magnet) because of the spin of the odd electron, the spins of the remaining paired electrons effectively canceling each other. The
magnetic property of a substance most commonly studied is its magnetic susceptibility, effectively its behaviour in an
inhomogeneous magnetic field, and the extent of paramagnetism of the substance is described.

Medical significance:
This study investigates evidence of oxidative stress during bicarbonate hemodialysis by measuring total glutathione and lipid peroxidation
products in plasma, and characterizes the free radicals produced by neutrophils from healthy volunteers when incubated in vitro with
increasing concentrations of bicarbonate. Blood samples were taken from nine hemodialysis patientsbefore and after two hemodialysis
sessions. Plasma hydroperoxides and total glutathione were measured. A significant increase was found in total glutathione (1.04 +/- 0.4
versus 2.11 +/- 0.9 microM, P < 0.001) and hydroperoxides by ferrous oxidation in xylenol orange version 2 method (4.6 +/- 0.53 versus 6.4
+/- 0.63 microM, P < 0.001) after hemodialysis, which indicated increased oxidative injury during hemodialysis. Normal neutrophils,
activated by contact adhesion, produced a dose-dependent increase in free radical production (measured by luminol-
enhancedchemiluminescence) when incubated with increasing concentrations of bicarbonate (up to 35 mM). Bicarbonate had the same
effect on the chemiluminescence of a cell-free hypoxanthine/acetaldehyde system generating superoxide, but not on a glucose
oxidase/myeloperoxidase system generating hydrogen peroxide and hypochlorous acid. These findings areconsistent with (1) the
hypothesis that superoxide generated during hemodialysis reacts with bicarbonate to form the toxic carbonate and formate radicals and
(2) our previous observation that some patients undergoing bicarbonate (but not lactate) dialysis have increased plasma concentrations of
formate after hemodialysis. It is suggested that the increased plasma total glutathione and hydroperoxide concentrations are a result
of lipid peroxidation by these species. These reactive radicals caninitiate lipid peroxidation and contribute to the
cardiovascular complications of hemodialysis patients.
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Antioxidant is the descriptive term given to a group of organic substances that generally function within the body to promote
health through their counteraction against the potentially destructive effect of oxygen in human tissues, as carried out by agents
known as free radicals. The best known anti-oxidants are vitamin C (ascorbic acid), vitamin E, selenium (a mineral), and the
carotenoids, the class of the pigmentation substances that color many fruits and vegetables. An example of a carotenoid is
betacarotene, the substance that produces the color in carrots.

Antioxidants get their name because they combat oxidation. They are substances that protect other chemicals of the body from
damaging oxidation reactions by reacting with free radicals and other reactive oxygen species within the body, hence hindering the
process of oxidation. During this reaction the antioxidant sacrifices itself by becoming oxidized. However, antioxidant supply is not
unlimited as one antioxidant molecule can only react with a single free radical. Therefore, there is a constant need to replenish
antioxidant resources, whether endogenously or through supplementation.

Human diet is subdivided into two general classifications for the purpose of basic nutritional assessment. The first classification is

macronutrients, the term that refers to all of the food products that contain carbohydrate, protein, and/or fat. The second

classification is micronutrients, the term that defines all of the vitamins and most of the minerals that are absorbed into the body

through food digestion. Phytochemicals are the trace substances found in plants and plant food products that are absorbed into the

body as a part of either macronutrients or micronutrients; many phytochemicals also possess antioxidant properties.

An understanding of the function of antioxidants begins with the process of oxidation within the body. Oxidation occurs in a number

of biological processes that are beneficial to the body. The essential role of oxygen within the aerobic energy system, and the

oxidation of various harmful bacteria that invade the body are two examples of oxygen and its positive relation to human cell

function.
Oxidation has a negative impact on the health of cells in certain conditions. While the oxygen molecule, described by the chemical

equation O2, is often present in the body, it is not always as a stable, electrically neutral substance, but as the chemical structure

known as free radicals, in which either atoms or molecules have one or more unpaired electron. When the cells have used oxygen,

free radicals are often created as a byproduct of that process.

Atoms or molecules in which all electrons within the structure are paired tend to be stable; free radicals are unstable and are

therefore highly reactive with other molecules. The free radicals seek out atoms or molecules from which they may "steal" an

electron to create electrochemical balance within the radical; this results in instability in the unbalanced molecule, which will in

turn seek to address its newly unstable state. This process will lead to a chain reaction of electron theft, which produces damage to

both the membrane of cells and the contents of cells. Heart disease, increased incidence of stroke, diabetes, cancer, macular

degeneration (a disease affecting the function of the macula, a small but vital area of the retina within the eye), and the

acceleration of the general aging process have all been scientifically linked to the actions of free radicals within the body.

The micro-effects of oxidation within the body are similar to commonly observed oxidation in the world at large, such as the

formation of rust (iron oxide) when bare steel is exposed to the elements.

Antioxidants do not attack these free radicals so much as they are scavengers of them. Antioxidants possess the ability to "donate"

electrons, typically from a present hydrogen atom with the antioxidant structure, to electrically neutralize the free radical. Different

types of antioxidants perform specialized types of scavenging and free radical-neutralizing work within the body.

Vitamin A is a fat-soluble vitamin, meaning that it may be stored within the body, either in the adipose (fat storage) tissue or in the

liver. Common sources of vitamin A and other betacarotenoids are carrots, squash, and broccoli, as well as all other brightly colored

fruits. Vitamin E is also fat soluble; it operates to specifically protect the free fatty acids in the bloodstream and the cell structures

from oxidation; the presence of these fatty acids places an important role in the overall healthy function of cells. Vitamin E is

present in many types of nuts, seeds, vegetable oils, and many types of whole grains.

The antioxidant role performed by vitamin C within the body is one of the many important functions of this chemical; vitamin C is

essential to the manufacture of collagen, the protein that is the primary building material in bones and connective tissue. Vitamin C

is water soluble, and it acts as a scavenger against waterborne free radicals before these agents can act against fat-soluble

compounds, an event that creates the damaging chain reactions associated with cellular damage.

The chemical reaction between vitamin C and the encountered free radical results in the donation of a hydrogen atom to the

oxidizing radical. The presence of enzymes creates a recycling effect on the vitamin C, permitting it to scavenge other radicals. The

rate at which vitamin C can scavenge free radicals is increased by a factor of approximately ten times if the scavenging process

occurs in the presence of phosphates. Vitamin E has been to shown to work as an excellent co-antioxidant with vitamin C. Vitamin

C is present in all varieties of citrus fruits, as well as broccoli, strawberries, and tomatoes.
Selenium is plentiful in fish, red meats, and grains. It most commonly acts as an antioxidant in conjunction with glutathione

peroxidase, a nonessential amino acid (an amino acid produced by the body), to protect white blood cells from the adverse effects

of free radicals.

The antioxidants that are contained within various phytochemicals have also been the subject of specialized research in recent

years. The best known of these substances are the flavanoids, a group of polyphenols (compounds with a hydrocarbon-based

structure), found in soy, red wine, raw grapes, and cranberries. Lycopene, the chemical that is responsible for the red pigmentation

of tomatoes and watermelon, is a powerful carotenoid. Lignan, a chemical found in flax, barley, and oatmeal, has also been

identified as a water-soluble antioxidant.

Lutein is the antioxidant linked to the onset of macular degeneration; research suggests that a lutein deficiency is an underlying

cause of the degenerative condition.

The body is capable of producing its own anti-oxidant defenses through its manufacture of two different enzymes, glutathione

peroxidase, and superoxide dismutase (SOD). Enzymes are proteins manufactured by the body, primarily in the liver. Enzymes

function as catalysts for a specific chemical reaction or series of reactions. When it comes into contact with a free radical oxygen

molecule, SOD is the fastest reacting antioxidant available, in that it can neutralize more free radicals more quickly than any other

substance within the body.

Significant publicity has been generated worldwide as to whether the consumption of antioxidants through dietary supplements, in

larger quantities than are otherwise available through regular diet, will have a proportionately greater and beneficial effect on

health. Numerous antioxidant products are marketed on the basis of claims that the products will either eliminate or reduce the

risks associated with various types of cardiovascular disease, cancer, and a multitude of conditions that occur as a result of aging.

Scientific research has proved inconclusive as to whether this type of supplementation in fact achieves an antioxidant result.

Studies that were specifically directed about the relationship between supplement consumption and the effect on the low density

lipoproteins (LDLs) present in the blood vessels were conducted between 2003 and 2005 in the United States. LDL molecules were

known to be particularly vulnerable to oxidation by free radicals, tending to cause the LDL molecules to proliferate on arterial walls,

leading to the formation of plaque and creating stenosis, an unhealthy narrowing of the blood vessel that renders the individual

more vulnerable to arteriosclerosis and stroke. The research in this area has proved to be inconclusive. Further studies where the

test subjects were provided with large doses of vitamin A, vitamin C, and vitamin E as supplements failed to establish any evidence

of increased disease prevention.

It is well established in the diet and nutritional sciences that the best manner in which to ingest nutrients of any kind and to have

the nutrients effectively absorbed into the body is through food, and not supplements. The reduction of LDL and other unhealthy

cholesterols in the bloodstream is most effectively addressed by examining the components of the foods consumed, as opposed to

eating poor foods and then addressing a perceived cholesterol or LDL concern. Most nations of the world have published food

guidelines that are similar in their scope to those advanced by the United States Department of Agriculture (the "Food Pyramid")
and the American Heart Association. In general terms, the guidelines state that, as an alternative to antioxidant supplements, a

healthy adult, eating six or more servings of grain products (bread, pastas, etc.), five servings of fruit or vegetables, between two

to four servings of low fat dairy products, and a maximum of 6 oz (200 g) of lean meat or fish, will ingest 100% of the

recommended daily allowances of the vitamins and minerals with antioxidant properties.

Molecular structure:
An understanding of the function of antioxidants begins with the process of oxidation within the body. Oxidation occurs in a number of biological processes that are
beneficial to the body. The essential role of oxygen within the aerobic energy system, and the oxidation of various harmful bacteria that invade the body are two
examples of oxygen and its positive relation to human cell function.
Oxidation has a negative impact on the health of cells in certain conditions. While the oxygen molecule, described by the chemical equation O2, is often present in
the body, it is not always as a stable, electrically neutral substance, but as the chemical structure known as free radicals, in which either atoms or molecules have one
or more unpaired electron. When the cells have used oxygen, free radicals are often created as a byproduct of that process.
Atoms or molecules in which all electrons within the structure are paired tend to be stable; free radicals are unstable and are therefore highly reactive with other
molecules. The free radicals seek out atoms or molecules from which they may "steal" an electron to create electrochemical balance within the radical; this results in
instability in the unbalanced molecule, which will in turn seek to address its newly unstable state. This process will lead to a chain reaction of electron theft, which
produces damage to both the membrane of cells and the contents of cells. Heart disease, increased incidence of stroke, diabetes, cancer, macular degeneration (a
disease affecting the function of the macula, a small but vital area of the retina within the eye), and the acceleration of the general aging process have all been
scientifically linked to the actions of free radicals within the body.

Properties:
A dietary antioxidant is a substance (commonly found in foods) that significantly decreases the harmful effects of "reactive species", such as reactive oxygen and
nitrogen molecules, that disrupt normal physiological function on a cellular level in humans.
Examples include the antioxidant nutrients vitamin C, vitamin E, selenium, and the carotenoids. A multitude of other nutrients, including minerals such as copper,
manganese, and zinc, flavonoids (such as grape seed extract and phenols found in green tea), and coenzyme Q10, also possess antioxidant properties.
The primary function of vitamin C (ascorbic acid) is the production of collagen, which forms the basis for connective tissue in bones, teeth, and cartilage. It also
plays an important role in wound healing, immunity, and the nervous system, and acts as a water-soluble antioxidant.
Because vitamin C is water soluble, its antioxidant functions take place in aqueous body compartments. It also helps protect low-density lipoproteincholesterol
(LDL-C) against free radical damage. As an antioxidant, it helps protect against cancer, cardiovascular disease, and certain effects of aging.
Vitamin E is the name given to a group of eight fat-soluble compounds. Unlike other vitamins, which are involved in metabolic reactions, it appears that the primary
role of vitamin E is to act as an antioxidant. Vitamin E is incorporated into the lipid portion of cell membranes and other molecules, protecting these structures from
oxidative damage and preventing the propagation of lipid peroxidation. Vitamin E appears to have protective effects against cancer, heart disease, and complications
of diabetes.

As an antioxidant, vitamin E plays a protective role in many organs and systems. Vitamin E is necessary for maintaining a healthy immune system, and it protects
the thymus and circulating white blood cells from oxidative damage. Also, it may work synergistically with vitamin C in enhancing immune function. Recent
research evidence indicates that the combined use of high doses of vitamin C and vitamin E helps prevent Alzheimer’s disease. In the eyes, vitamin E is needed for
the development of the retina and protects against cataracts and macular degeneration.

Vitamin E deficiency is rare, and occurs mostly in people with chronic liver disease and fat malabsorption syndromes, such as celiac disease andcystic fibrosis. It can
lead to nerve damage, lethargy, apathy, inability to concentrate, staggering gait, low thyroid hormone levels, decreased immune response, and anemia. Marginal
vitamin E deficiency may be much more common and has been linked to an increased risk of cardiovascular disease and cancer.

The only specific effect of carotenoids in humans is to act as a source of vitamin A in the diet, but they also have important antioxidant actions. The latter are based
on the caretenoids' ability to quench singlet oxygen and trap peroxyl radicals, thereby preventing lipid peroxidation.

As a result, carotenoids protect against the development of cancer, cardiovascular disease, and ocular disorders. Carotenoids also affect cell growth regulation and
gene expression. Diets low in carotenoids may lead to increased risk of cancer and heart disease. Lycopene is the most potent antioxidant for quenching single
oxygen and scavenging free radicals.

Antioxidant nutrients are often thought of as enhancing immune function. Vitamin C, in particular, is generally perceived as useful in the prevention and treatment of
the common cold. Some evidence does support a role of vitamin C, vitamin E, and carotenoids in enhancing immunity.
Vitamin C has been found to affect the human immune response, with increased antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis,
and delayed dermal sensitivity. Studies have involved pharmacologic doses of vitamin C (200 mg/day to 6 grams/day in addition to dietary intake); therefore, the
effect does not appear to apply to nutritional intake of vitamin C from food alone.

Medical significance:
Antioxidant: Any substance that reduces oxidative damage (damage due to oxygen) such as that caused by free radicals. Free radicals are highly
reactive chemicals that attack molecules by capturing electrons and thus modifying chemical structures.

Well-known antioxidants include a number of enzymes and other substances such asvitamin C, vitamin E and beta carotene (which is converted
to vitamin A) that are capable of counteracting the damaging effects of oxidation. Antioxidants are also commonly added to food products like
vegetable oils and prepared foods to prevent or delay their deterioration from the action of air.

Antioxidants may possibly reduce the risks of cancer and age-related macular degeneration (AMD). Antioxidants clearly slow the progression of AMD.