The Role of Antioxidants in the Free Radical Concept of Disease

What is the Free Radical Concept of Disease?

The “free radical pathology concept of disease” holds that most disease is ultimately a result of oxidative damage to the cell by highly reactive, inter cellular metabolic end products known as “free radicals”. It states that, so long as the body is healthy and is provided balanced nutrition, these normal, potentially toxic, metabolically generated free radicals will be almost completely neutralized, inactivated, or detoxified by the body’s “anti-oxidant defense system”. However, if the body becomes excessively stressed the number of free radicals produced may increase and finally exceed the ability of the body’s adaptive antioxidant defense mechanism to neutralize these toxic free radicals. Furthermore, if the healthy body is not provided dietary antioxidants or antioxidant precursors, its antioxidant defense system will become weakened and will no longer be able to neutralize what would other wise be a normal free radical load. In either case we have an imbalance develop where the free radicals out number the antioxidants. This imbalance results in injury to the cell in the form of an oxidation of the cell wall, the mitochondria and the DNA. Such oxidative injury is the beginning of cellular pathology and organ disease. Said another way, as the number of free radicals begins to exceed the body’s capacity to keep them under control, the molecular structure of the cell becomes progressively damaged with clinical disease being the eventual outcome. The “Free Radical Pathology Concept of Disease” and its mirror image the “Antioxidant Adaptation Hypothesis” is supported by a stack of scientific and clinical evidence. Together these two concepts offer a rational biochemical explanation for the mechanism of immunity and pathology on a molecular, cellular, and clinical level. The development of clinical pathological processes including aging, inflammation, degenerative disease, allergy and environmental hypersensitivity, cancer, immune deficiency and auto immune disease can all be explained within the context of these two complementary concepts. As more and more research is done the free radical concept of disease is very likely to become the unifying view for the mechanism of disease and aging. It could very possibly become the new paradigm for considering all animal and human pathology.

The free radical pathology concept of disease proposes that various forms of stress such as bacteria, viruses, physical trauma, toxic chemicals, environmental pollutants, and even emotional stress are all capable of generating oxidative damage to cells, tissues, and organs by way of free radical activity. Furthermore, it proposes that the susceptibility of a specific tissue to damage from free radical oxidation is determined by the net balance between factors acting on tissue to promote oxidation and those that exert anti-oxidant actions. It has been suggested that an organisms health status is determined by the degree of “oxidative stress” imposed on its antioxidant defense system by risk factors such as exposure to environmental chemicals, drugs, infection etc.

The free radical pathology concept reflects a paradigm shift which is now occurring and which will eventually lead to a more unified view of the mechanisms which underlie biologic aging, inflammation, degeneration, allergies, cancer, environmental chemical sensitivities, immune suppression and auto-immune disease. It is possible that the antioxidant defense system may be the backbone of our body’s interlinking defenses. The processes of inflammation , immunity, and detoxification all have mechanisms which function through pathways that generate free radicals. The unifying position of free radical pathology is that oxidative stress (free radicals), however generated, always leads to disease unless neutralized by an antioxidant defense mechanism.

What is Meant by the Terms “Free Radical” and “Oxidative Stress”?

The ability to utilize molecular oxygen in metabolism allows air breathing organisms considerably greater efficiency in converting foods to energy, when compared to their anaerobic counterparts. This increased efficiency is unfortunately accompanied by Important biologic drawbacks, namely the potential toxicity of the oxygen molecule.

A free radical is defined as a reactive atom, group of atoms or a molecule with an unpaired electron in its outer orbit. A free radical is, therefore, considered to be in a very reactive state because it is searching for another atom or molecule with which to combine (oxidize) and obtain the extra stabilizing electron. Free radicals are “oxidants” because they oxidize the other molecules they combine with by stealing or sharing their electrons. The free radical which does the oxidizing becomes “reduced” to a more stable state during this process. Free radials have the ability to attack vital cell components and damage cell membranes, inactivate enzymes, and damage genetic material. The mitochondria is the major site of free radical production. Although free radicals are essential for life in oxygen breathing organisms, if the free radicals become too abundant or are not adequately controlled, they oxidize the cell membrane, the mitochondria, and the DNA, causing serious damage to the cell. All cellular components are susceptible to free radical attack but the cell membrane systems are the major targets because their high lipid content is very susceptible to oxidative damage. Once generated, free radicals tend to multiply by taking part in chain reactions with other less active molecules. Consequently, the toxicity of a single free radical may be greatly enhanced by producing a chain reaction which results in many more free radicals. Such toxicity is known as “oxygen toxicity”. “Oxidative stress” is measured by the degree to which free radicals use up the body’s antioxidant reserve.

There are 5 main categories of free radicals: 1) The Superoxide anion radical 2) The Hydrogen Peroxide radical 3) Hydroxyl radical 4) Peroxyl radical 5) Singlet oxygen.

What is Meant by the Terms “Antioxidant” and “Antioxidant Defense System”?

Antioxidants are specific vitamins, minerals, enzymes, amino acids and peptides which are either produced by the body or are obtained through the diet. They combine with the free radicals by giving up or sharing an electron in order to neutralize the free radical’s reactive state and prevent it from injuring the cell. Antioxidants are also known as “free radical quenchers “or “free radical scavengers”‘ When a free radical combines with an antioxidant, the free radical is reduced and the antioxidant is oxidized. In other words, the antioxidant sacrifices itself and is oxidized in place of the cell membrane. To control the dreaded free radical oxidant molecules a very elaborate system of natural antioxidant protection mechanisms has developed that can protect threatened biological tissues. During a pathological attack from free radicals these antioxidant defenses can ultimately become exhausted. When protective antioxidant factors cannot be maintained or replenished, living systems will deteriorate into disease. The mammalian antioxidant defense system attempts to balance the free radical production through a variety of mechanisms. It utilizes nonenzymatlc, dietary derived antioxidants acting in conjunction with nutritional modulated antioxidant enzyme. to detoxify free radicals. The antioxidant defense system is able to respond to free radical challenges, based on the availability of nutritional cofactors and other antioxidant elements. The adaptability of the antioxidant defense system is remarkable. Upon oxidative challenge by free radicals, the system can rapidly increase the required antioxidant components (both enzyme and non-enzyme), and then mobilize these antioxidants to “hot spots” of oxidative attack. For example, increased rates of synthesis of antioxidant enzymes such as Super Oxide Dismutase (SOD ) and Glutathione Peroxidase (GP) become quite noticeable following the onset of oxidative attack, thereby providing greater resistance to oxidative stress by selected tissues. A laboratory test that can measure the antioxidant status of the body is now available.

The antioxidant defense system’s reserves are maintained by 1) endogenous production and 2) by dietary means. Much of our dietary supply of anti-oxidants is removed from foods by processing practices geared to convenience, taste, and profit rather than health. Having lost antioxidants from foods, we must return them to our diet by replacing processed foods with whole foods rich in essential nutrients or taking concentrates of these essential nutrients. We must also avoid foods that are conducive to the production of free radicals such as refined sugar, heated or rancid fat and food contaminated by pesticides. We must do our best to avoid airborne pollutants such as cigarette smoke, smog, and excessive ozone all of which use up our antioxidant defense reserves. In addition we must learn methods to reduce emotional stress.

Antioxidant enzymes include: 1st line of antioxidant defense; endogenously produced

  • Super oxide dismutase (SOD) – inter cellular; converts superoxide to hydrogen peroxide; Zn, Cu, and Mn are cofactors
  • Catalase – inter cellular; converts hydrogen peroxide to water; Zn, Cu, and Mn are essential for activation
  • Glutathione peroxidase-inter cellular; converts hydrogen peroxide to water; Se is an essential cofactor for activation

Antioxidant Nutrients include: 2nd line of antioxidant defense; nutritionally obtained

  • Vitamins C, E, A, Beta-carotene
    • vitamins C & E are necessary for the body to endogenously produce SOD
  • Vitamins BI, B2, B6, BI 2 , Choline are cofactors necessary for biosynthesis of endogenous antioxidant enzymes
  • Glutathione – a triple peptide
  • Minerals – Se, Zn, Cu, Mn, Mg, Fe,
    • Selenium stimulates the endogenous production of Glutathione Peroxidase

Free Radicals are Both Beneficial and Toxic to the Body

When under proper control of the antioxidant defense system these free radicals do good deeds that are essential for life. For example, the white blood cells shoot out free radicals, like missiles, to destroy intruders, while the vascular endothelium, puts out the superoxide radical to help regulate the contraction of the smooth muscles of the blood vessels, thereby maintaining proper blood flow. Free radicals are important for normal cellular oxygen utilization because they are required for severing the hemoglobin-oxygen bond. Our bodies have been designed to operate with just enough free radicals to keep us in good health, however, when that balance is upset the trouble begins. It is a strange irony that these reactive oxygen molecule (free radicals) have 2 contrasting sides to their nature. On one hand they are essential to supporting those processes necessary for life while, on the other hand, they ultimately act as toxins which destroy all life through oxidation of the cell. This cellular oxidation has been described as “oxygen toxicity” and is equivalent to the rusting out process that takes place in our automobiles.

What are the Predisposing Conditions Leading to Free Radical Production?

1. Foods contaminated with insecticides or fats that have gone rancid
2. Deficient diets that do not supply adequate antioxidants and or their precursors
3. Air pollution, including cigarette smoke, smog, car exhaust fumes, industrial solvents, excessive ozone
4. Certain drugs, and anesthetics; especially cancer therapies
5. Radiation and ultraviolet light from the sun
6. Water polluted with pesticides and other contaminants
7. Trauma to joints and other tissues. Excessive exercise.
8. Emotional stress
9. Viruses, bacteria, fungi, parasites

A Metaphor for Understanding Antioxidant Adaptation and Free Radical Pathology

Please consider the following metaphor. Free radicals are like sparks coming off a metabolic fire, and antioxidants act like the fire place screen which prevents free radical sparks from igniting the surrounding molecules which would in turn produce more free radical sparks and consequently a chain reaction similar to a forest fire burning out of control. This metabolic forest fire burning out of control damages our cells and tissues and leads to disease and premature aging. The inner fire of animal life results from burning (oxidizing) food which acts as the fuel for the fire. The brightness of the fire is the rate at which our body produces energy our metabolic rate. The free radicals ,like sparks, are an unavoidable consequence of combustion and represent inherent inefficiencies (2-5%) in the burning process. The higher the metabolic rate, the brighter the body’s fire bums, and the greater the number of free radicals produced. As free radical escape through the antioxidant defense screen they are free to start other fires in unintended places that are not supportive of healthy biological activity. The antioxidants provide spark control.

How Does the Body Maintain its Antioxidant Reserves?

When the above mentioned predisposing conditions for free radical production are present it is necessary for the body to supply an additional quantity of antioxidants in order to stop the excess number of free radicals from damaging the cell. Our body can increase its antioxidant defenses In 2 ways. First, we can consume more antioxidant by eating foods rich in antioxidants and by taking antioxidant supplements. Or two, our body can produce more antioxidant enzymes, providing the proper cofactors are present in adequate quantities in the diet. For the most part the availability of antioxidant compounds, precursors, and cofactors for the antioxidant defense system is determined by the diet. Factors which impair the adsorption and utilization of these special nutrients can threaten the organism with oxidative degeneration. The antioxidants concentrates to consider consuming are the enzymes Superoxide Dismutase, Catalase, Coenzyme QiO, the vitamins C, E, A and betacarotene, B3, 86, the minerals selenium, suIfur, zinc, manganese, magnesium, copper, and iron , and the polypeptide glutathione. It has been suggested that an organism’s health status is determined by the degree of oxidative stress imposed on its antioxidant defense system by events such as exposure to environmental pollutants, drugs, infection etc. One might predict that in the face of continual oxidative stress, unless the body’s storage depot of antioxidants can be replenished rapidly there would occur a decrease in antioxidant defenses In the least essential tissues and organs. It is hypothesized that the development of adaptive resistance to oxidative stress in one organ can deplete or reduce antioxidant reserves elsewhere in the body.

The function of Glutathione Peroxidase (GP) is to detoxify peroxides. Normally the GP of the intestinal mucosa can detoxify small amounts of lipid peroxides ingested as part of the normal diet. However, consumption of high levels of lipid peroxides, i.e. rancid pet food, can rapidly overwhelm the detoxifying abilities of intestinal GP, thereby allowing toxic quantities of peroxides to enter the circulation and pose a threat to other organs, particularly the liver and the aorta. The ability of animals to respond to oxidative stress by increasing the activity of glutathione peroxidase is one of the main features of the antioxidant defense system.

Inflammation, Degeneration, Immune Deficiencies, Autoimmune States, Cancer and Environmental Hypersensitivies are All Conditions Resulting from Unchecked Free Radical Damage
Free radicals exist in biological systems from both formation within the body and from external sources. Their role in health and disease is not yet completely understood but they are believed to either cause or accelerate a variety of chronic diseases i.e. cataracts. Parkinson’s, arthritis, diabetes, and macular degeneration have all been linked to free radical damage.

Inflammatory, immunogenic and carcinogenic states are all examples of syndromes which appear to be derived from unchecked oxygen toxicity (free radicals). Antioxidants block prostaglandins and consequently reduce inflammation. The role of antioxidants as anti-inflammatory agents and as immune stimulants is noted through out the literature. Nutrient antioxidants that have anti-inflammatory effects are also some of the most important for essential cell functions in the immune response. Selenium, Dimethylglycine, Vitamin A, C, E and Beta Carotene are all both anti inflammatory and immune stimulatory. Some of the hypersensitivity reactions in environmentally hypersensitive people appear to result directly from the free radical mediated chain reaction and the release of inflammatory substances.

An thorough literature review on cancer indicates that the majority of carcinogens operate through the free radical mechanisms. Many researchers now see cancer susceptibility as a direct result of exhaustion of the antioxidant defense system. The depletion of antioxidants allow free radicals to damage the DNA of the cell leading to cancer production.. Research on cancer and antioxidants has led to the conclusion that natural antioxidants are also natural anti cancer agents.

Anitioxidants and Aging

Aging may very well be a result of the break down of the antioxidant defense mechanism and therefore the use of antioxidants may significantly extend an individuals life.. Free radical damage is a very important part of the aging process. A growing body of evidence suggests that free radicals make us age Research is also beginning to show how the oxidative damage can be prevented and reversed. Strong associations between free radical damage and chronic diseases such as heart disease and cancer have been made. In the early 1970’s it was shown that dietary measures designed to reduce endogenous free radical levels in mice tended to increase their average life expectancy by 20-30%.

The following is the pathophysiological explanation of free radical aging:
With time our antioxidant defenses become progressively less adaptive. The number of free radicals assaulting the body eventually exceeds the bodies ability to neutralize them with antioxidants. As a result the following changes occur.

1. Free radicals oxidize and change collagen, elastin and chromosomes
2. Free radicals break down mucopolysacharides and glycoaminoglycans (GAGS)
3. Free radicals oxidize the cell membrane, mitochondria, and DNA
4. Free radicals cause fibrosis of the arteries and capillaries

Six Stages of Pathology in the Free Radical Concept of Disease

The antioxidant defense system utilizes non enzymatic, nutrient obtained antioxidants, acting in conjunction with nutrient influenced antioxidant enzymes, to detoxify free radicals The antioxidant defense system is able to react adaptively in response to oxidative challenges, subject to the availability of nutrient-obtained antioxidants and antioxidant cofactors.

The antioxidant defense system is composed of complex and simple compounds ranging from antioxidant enzymes, vitamins, minerals, peptide and amino acid, The body obtains its antioxidants, by endogenous synthesis and or through gastro-intestinal absorption of antioxidants and cofactors. When the oxidative stress starts to overwhelm the available antioxidant defenses, it shifts the body away from Its state of equilibrium. Then a variety of adaptive changes occur, which if not successful, eventually give way to clinical disease. Inflammatory, immune deranged and carcinogenic states are representative examples of clinical situations which appear to result from unchecked oxygen toxicity. Below is a summary of a six stage progression beginning with a well balanced antioxidant free radical relationship, followed by the introduction of increased oxidative stress’, followed by antioxidant adaptation, followed by exhaustion of the antioxidant defense system, followed by overt disease, followed by allergies, immune suppression , autoimmune disease, and cancer.

Stage I
Individual is in good health and responds well to oxidative stress.
Healthy individual is exposed to xenobiotics (foreign chemicals) in the environment. Even though these xenobiotics are diverse structurally, and their effects upon biological systems vary. they have in common the fact that their destructive effects are mediated by oxidative stress.

Stage 2
We are now one step lower in our overall health status as a result of the effects of accumulative oxidative stress from the environmental pollutants (i.e. smog, leaky gas stoves, chemicals in the work place, and pesticides), as well as from emotional stress. In stage 2 the body is more susceptible to pathogens, drug side effects, and to food allergens.

Stage 3
At this point the organism is beginning to lose the battle, and clinical symptoms of disease are beginning to show. Depletion of antioxidant reserves so compromises the antioxidant defenses that they can no longer adequately adapt. Major metabolic functions begin to suffer. Signs of illness are a reflection of inflammatory damage which appears first in the more susceptible organs. Free radicals produce increasingly more cell destruction by attacking the cell membranes which results in lipid peroxidation and consequently, the liberation of mediators of inflammation such as arachidonic acid, histamines, and serotonin. Allergic reactions to foods and autoimmune disease can follow as secondary consequences to ongoing oxidative stress. The body makes a great effort to strengthen the antioxidant defenses at the target organ at the cost of wiping out the antioxidant reserves left to protect the rest of the body and consequently damage may begin to show up at distant sites.

Stage 4
Generalized systemic breakdown and exhaustion characterize this stage in the development of a disease process. With the antioxidant defenses badly damaged by oxidant attack and br a nutritional antioxidant deficiency, a vicious cycle is created. “The point is reached at which the rate of deterioration of the system continually exceeds the rate of recovery.”

Stage 5
Once systemic oxidative damage becomes established degenerative disease may follow. Each new oxidant attack produces inflammatory episodes, with deranged arachidonic acid catabolism producing a variety of lipid derived prostaglandins. A great many of these prostaglandins are not only pro-inflammatory but are also immune suppressive. Peroxidized membrane lipids can alter cellular membrane activity and eventually destroy membrane continuity. Antigens derived from oxidized cellular molecules can produce auto immune responses. Degenerative organ specific symptoms may result.

Step 6
Carcinogenesis: Many researches have come to view cancer susceptibility as a direct consequence of exhaustion of the antioxidant defense. As a consequence of antioxidant exhaustion cells can become increasingly susceptible to oxidative attack on its genetic material which could, in turn, lead to inheritable chromosomal alterations.

The known protective effects of antioxidants such as vitamin A against lung cancer and the effects of other natural antioxidants against a variety of cancers support the free radical mechanisms of cancer initiation and progression. Antioxidants compounds provide profound protection to laboratory animals against cancer, even those affected with cancer-producing viruses and exposed to high concentrations of the potent chemical carcinogens. Selenium, ascorbate, tocopherols, retinols, and other nutrient derived anti-oxidant factors have been found to be clearly protective. Similar protection against malignant transformation is afforded cultured cells and tissues by supplementing with critical antioxidants. There are many indications that nutrient antioxidants such as ascorbate, selenium, tocopherol, retinols, and beta carotene are likely to play an important role in human cancer prevention. Dietary supplementation with these antioxidants nutrients stimulates host immunological defenses. In addition, these nutrients may damage malignant cells directly, through their tendency to redox cycling with consequent oxygen radical production. Antioxidant therapy has a very favorable risk-benefit ratio.

Substantial evidence exists that the activity of the mitochondria superoxide dismutase enzyme is markedly diminished in cancer transformed cells (so far without exception). Under normal aerobic conditions the bulk of the superoxide generated in the aerobic cells is generated in the mitochondria, hence if superoxide cannot be detoxified (dismutated by mitochondrial SOD enzyme) it stands to damage the inter-mitochondrial respiratory enzyme assemblies. An electron microscopy study found mitochondrial abnormalities to be a consistent feature of tumor cells. Taken as a whole the results of research are in complete agreement with clinical reports both of which make a case for the suitability of using antioxidant nutrients and SOD to treat cancer.


The building blocks of our biological machine are vitamins, minerals, amino acids, fatty acids, and protein and peptides. Oxygen is the power source that fuels this machine. With this in mind, many researchers view a free radical, antioxidant imbalance as the underlying mechanism of all degenerative disease. Oxidative stress reactions appear to play a major role the chain of events which are part of biologic degeneration, and it is proposed that all biologic stresses encourages biologic damage by pathways which consistently involve excessive generation of free radicals. If the antioxidant defense system fails to neutralize the leakage of even I free radical molecule, irreparable cellular damage can result. If free radicals attack our tissues in large numbers then our antioxidant defenses may be overwhelmed, and this may result acute or chronic disease. The numerous conventional medical approaches to inflammation and degenerative organ pathology involves the use of expensive anti-inflammatory agents, calcium blockers, and lipid-lowering drugs which may provide temporary symptomatic relief, but almost always have significant undesirable side effects. Usually the underlying pathology is unaffected by these treatments and the patient’s health continues its down hill spiral. Antioxidant therapy is the valid alternative to conventional palliative therapy. Using our understanding of the antioxidant defense system of the body and our realization that free radical damage represents the underlying cause of most if not all inflammatory and degenerative diseases we can clearly understand the benefits of using a therapeutic modality that is effective on the primary level of pathology.

Indications for Antioxidant Therapy

  • To support healthy animals that are regularly exposed to environmental oxidative stress such as air pollution, water pollution, food additives and contaminants.
  • To support healthy animals that are exposed to emotional stress, physical trauma, and infectious organisms.
  • To support healthy middle aged pets at risk of developing geriatric problems
  • To support pets, young and old, that are struggling with inflammatory disease, allergies, immune deficiencies, auto immune disease, and cancer.
  • To support debilitated geriatric pets that already have degenerative disease
  • To support the body in recovering from trauma, and surgery
  • To support the body in resisting the aging process

This paper is for the most part a summary of the information provided in the below listed text:
Antioxidant Adaptation & Its Role in Free Radical Pathology by Stephen A Levine, Ph.D. and Parris M. Kidd, Ph.D. Publisher Allergy Research Group copyright 1985, 1986

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