Antioxidant Primer: Potential Health Benefits of Antioxidants and Pro-Oxidants
by Bill Sardi
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So much is said about antioxidants these days. The public has been educated to believe antioxidants are generally beneficial when consumed in foods and dietary supplements. Antioxidants counter the effects of what are called free radicals, unstable species of oxygen, and to a lesser degree, nitrogen. These free radicals can damage tissues in the body.
Yet, in recent years, a growing body of data points to certain health benefits from employing mega-dose antioxidants, such as vitamin C, curcumin and resveratrol, to actually generate free radicals to treat disease.
But before we get to these recent discoveries, maybe it is best to briefly background readers in the science of antioxidants.
Oxygen free radicals
The oxygen you breathe, the fat and iron/copper content of your meals, the frequency and calorie content of meals, and your age, to a large extent determine the amount of "rusting" going on in your body. Exercise, infection and exposure to radiation (solar, x-rays) also increase markers of oxidation.
Oxygen is a necessary and good thing in the human body, but also a potentially harmful factor. While much is made of toxins in the air, ranging from smog to radon gas, it is oxygen itself that is a primary toxin in the body. About 4 % of the oxygen humans breathe converts into a toxic byproduct called free radicals. These free radicals are the unstable "rusting agents" of the body.
Oxidation from the air we breathe
About 90% of the oxygen in the body is utilized in small compartments within living cells called mitochondria. There are a few hundred of these mitochondria in every cell. Mitochondria produce cell energy in the form of adenotriphosphate (ATP). Most of the generation of oxygen free-radicals that occurs within the human body takes placed within the mitochondria.
Exposure to greater than 21% oxygen can produce injurious side effects. Pure O2 for as little as six hours can cause chest soreness, cough and sore throat. High oxygen levels in incubators produces blindness in babies.
While oxygen (O2) and naturally produced hydrogen peroxide (H2O2) are sources of rusting in the human body, they generally act as cleansing agents and are not very reactive until they are brought into contact with unbound metals such as unbound iron and copper which then generate the most powerful of all rusting agents, the dreaded hydroxyl radical, which attacks and damages almost every tissue in the human body. The hydroxyl radical is believed to be the toxicant that triggers gene mutations.
Researchers at the University of California at Berkeley estimate that the number of oxidative hits to DNA per cell per day is about 10,000 in humans. Naturally produced antioxidant enzymes, produced within the body, can repair most, but not all, of the breaks in strands of DNA in human cells.
DNA damage accumulates with advancing age. Therefore, there is a greater need for antioxidants with advancing age. The "flame" of oxidation in the body increases with advancing age and is associated with unsuccessful aging (disability, disease). In old age there are about 2 million DNA breaks per cell per day!
With advancing age the importance of protecting DNA from oxidative damage becomes paramount. As an example of antioxidant DNA protection, supplementation with 100 mg of vitamin C, 100 mg (~100 IU) of vitamin E, 6 mg of beta carotene and 50 mcg of selenium has been shown to reduce breaks in chromosomes by half, with an even greater effect in smokers.
The antioxidant defense force
Your body makes some of its own antioxidants in the form of enzymes (glutathione, catalase, superoxide dismutase, coenzyme Q10), and also acquires antioxidants from your diet.
Think of "free radicals" as an opposing football team called The Offenders, that your body must defend against. The major "players" on the opposing defensive team are "free radicals" known as singlet oxygen, hydrogen peroxide, superoxide and hydroxyl radical. Here’s how they line up, and how the human body defends against them.
The antioxidant defense force works as a team. A gap in the defense force, just like a player missing on a football team, means there is a weakness that can result in damage to DNA and eventually result in tissue damage.
The antioxidant team has three layers of defense. The first line of defense against DNA damage is composed of antioxidant enzymes (catalase, glutathione, superoxide dismutase) produced in the body. These are derived from trace minerals, as shown in the chart above.
The second line of defense is antioxidant vitamins. These vitamin antioxidants donate an electron to neutralize a free radical, but in doing so, become unstable themselves. However, these vitamins also re-stabilize each other by donating electrons to each other. For example, vitamin E donates an electron to vitamin C so it can get back onto the field and perform its job. Vitamin C donates an electron to vitamin A so it can become an active antioxidant once it is used up. Vitamin A donates an electron to vitamin C, in a circuitous manner.
The third line of defense is comprised of the carotenoids (beta carotene, lutein, lycopene), CoQ10 and bioflavonoids, which back up the vitamins. In case there is not enough vitamin A stored in the liver, beta carotene can be summoned from storage in the skin, or from the daily diet, and converted into more vitamin A. In case vitamin E is in short supply, coenzyme Q10 can be substituted. Bioflavonoids help to prolong the action of vitamin C. They all work together as a team. Their biological action is synergistic, not just additive.
To prove this point, examine the chart below. When hamsters were exposed to a cancer-causing chemical that was applied inside their cheeks and then given antioxidants, it was found that a mixture of antioxidants provided the most protection against cancer.
EFFECT OF ANTIOXIDANTS ON TUMORS
Number of animals
Number of tumors
Mixture (all of above)
Pro-oxidant, anti-oxidant balance
In recent times there has been discussion among biologists about the antioxidant/oxidant balance in the human body. For example, researchers measured the pro-oxidant/anti-oxidant balance and report that oxidative stress rose numerically from 44.0 to 132.4 in the first hour following a heart attack or severe bout of angina chest pain. This may, for a time, overwhelm existing antioxidant defenses in the body. A correlation has been made between antioxidant imbalance and abnormal blood pressure, smoking and blood sugar.
These discoveries seem so belated, given that antioxidant imbalance has been known since the mid-1950s.
Mega-dose antioxidants to generate free radicals
Surprisingly, there has been recent interest in employing mega-dose antioxidants to beneficially generate free radicals.
It is widely known that cancer drugs work by inducing oxidation to destroy cancer cells. Unfortunately these chemotherapy drugs are non-selective for tumor cells and induce damage to healthy tissues that often result in the premature demise of the patient. The idea of using natural molecules to induce oxidation and cell death is that they are often non-toxic to healthy cells, transiently generating hydrogen peroxide (H2O2) to kill cancer cells, then converting to harmless H2O.
It was Nobel prize winner Linus Pauling along with Ewan Cameron who in 1976 employed mega-dose intravenous vitamin C to induce free radicals in the successful treatment of cancer. Dr. Pauling’s discovery was later belittled and dismissed by Mayo Clinic doctors who employed high-dose oral vitamin C, which cannot achieve tumor-cell toxic levels.
More than two decades later Dr. Pauling’s work was vindicated by the re-discovery that intravenous vitamin C can achieve concentrations that release bound-up iron and copper which combines with oxygen to transiently produce cancer-killing hydrogen peroxide.
In fact, it’s possible this anti-tumor effect of mega-dose vitamin C is only demonstrated among those individuals who have high dietary intake of iron. Of interest, high-concentration vitamin C induces hydrogen peroxide in connective tissue (the goo between cells), but not in blood where it would be destructive to red blood cells.
While highly concentrated levels of vitamin C in the blood circulation require iron to produce a cancer cell-killing effect, the opposite may be true for tumors promoted by estrogens. Estrogen appears to promote tumors, but only in a high-iron environment. Many tumors occur in females with the onset of menopause and the loss of iron control via menstruation. The iron chelating (key-lay-ting) antioxidant IP6, commonly found in bran, would be an antidote.
While vitamin C releases iron for use in the body, it has not been shown, either from dietary or supplemental sources, to increase the incidence of disease even in iron-overloaded subjects. Even intentionally trying to cause a toxic effect by consumption of high-dose iron and vitamin C at the same time did not cause tissue damage in humans.
Vitamin C that has been combined with lecithin, an emulsifier, has been shown to produce a superior anti-tumor effect even though it exhibits only 60% of the antioxidant activity of plain vitamin C.
There is considerable interest these days about vitamin D and its immune-enhancing effects to fight cancer. While not its sole mode of action, surprisingly vitamin D promotes oxidation in breast cancer cells which leads to their destruction.
Herbal remedies that promote oxidation
Herbal-derived molecules have also been demonstrated to beneficially generate free radicals. For example, artemisinin (botanical name Artemisia annua, also known as Sweet Wormwood or Sweet Annie) induces the formation of unstable oxygen species known as free radicals. Artemisinin is used to successfully treat malaria, utilizing free radicals to kill the parasite Plasmodium falciparum. An iron-chelating (binding) drug negates this effect.
The dose of herbal-derived molecules may determine whether it will serve to promote or counter oxidation. For example, low-dose curcumin, an antioxidant derived from turmeric spice, serves as an antioxidant, while high-dose curcumin has the opposite effect. Low-dose curcumin exhibits anti-cancer properties which is enhanced in a lab dish by the addition of low-dose antioxidants like glutathione. Some researchers believe the combination of low-dose antioxidants with curcumin is a better strategy than high-dose curcumin therapy for cancer as it is less harmful to normal cells.
Similar to vitamin C and curcumin, resveratrol, widely known as a red wine molecule, may exert antioxidant properties at lower doses but promote oxidation and cell death at higher doses.
Recently researchers at the University of Connecticut showed in animals that lower-dose resveratrol (175—350 milligrams/day, human equivalent dose) protects the heart during a heart attack, preventing mortal events, whereas mega-dose resveratrol (1750—3500 milligrams/day) promoted cell death, which would be appropriate for cancer treatment, but worsens the amount of tissue damage when a heart attack is chemically induced. Theoretically, resveratrol would work better than aspirin at preventing sudden-mortal heart attacks. In fact, about 50% of people who experience a sudden mortal heart attack were taking a baby aspirin on the day of their demise. The first-branded resveratrol pill to demonstrate this remarkable heart-protective effect was demonstrated at an even lower and safer dose.