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ANTIOXIDANT VITAMINS

Every one is talking about antioxidants ! A major pharmaceutical company runs full-page ads in newsmagazines pointing out the dangers of oxidative stress while mentioning that three of their multivitamins products can protect you from excess oxidation. Sales of vitamins have been increasing by 20 to 30 percent per year, and much of the growth can be credited to antioxidant formulas. Animal studies and several large controlled human trials point to the wisdom of taking antioxidant supplements, especially vitamin E to help prevent heart disease and cancer.

It is useful to know what oxidative stress is and which compounds normally found in our bodies protect us from the damaging effects of oxygen. This demonstrate how antioxidants can be protective, and it can also help you decide what might be the most important antioxidant for you to take.

This chapter explains antioxidant in the context of a regimen for good health.

OXYGEN RADICALS

Only some microorganisms (and plants), known as anaerobes, can live without oxygen; most, including humans, need oxygen. Anaerobes make energy by breaking down preformed carbohydrates and proteins, but energy-wise this process is inefficient. Most microorganisms and all animals (including humans) use oxygen to "burn" or oxidize foods into carbon dioxide and water. A great deal of energy is produced as a result of this process. Metabolizing one molecule of glucose with oxygen produces about four times as much energy as could produced if the same molecule were to be metabolized without oxygen. In our bodies, carbon from food is oxidized to carbon dioxide. Oxygen superoxide grabs electrons from a neighboring source and combines with hydrogen to form water. The reduction of oxygen is accomplished in special structures inside body cells called mitochondria. Carbon dioxide that results from this process is eliminated in our breath, urine, and sweat. Plants use the carbon dioxide we produce to make oxygen. This is a very nice ecosystem, and one we need to be careful not to disrupt.

But the system isn't perfect. Did you ever notice how rubber or plastic becomes brittle and cracks after some time has passed? This happens when these materials react with oxygen in the air to produce a modified plastic or rubber that is not as soft and flexible as the original. We live in an environment filled with oxygen, and this is exactly what happens to our bodies as we age. Our skin loses flexibility and starts to wrinkle; our organs don't work as well; our blood vessels get clogged with plaque, putting us at risk at a heart attack or stroke; and we are at a higher risk for cancer. Oxygen is not the only reason that our bodies deteriorate, but it is part of the picture.

Oxygen damage body tissues after long periods of exposure because tiny amounts of chemically reactive oxygen are produced in the everyday reduction of oxygen in the mitochondria. This reaction sometimes occur in other parts of our bodies as well. Reactive oxygen molecules that cause the problems described above are called free radicals. They will reach out to whatever is close by and attach to it. Let's say, for example, that the free radical combines with a lipid molecule in a kidney cell membrane. The lipid molecule is now a reactive radical itself and can react with another oxygen molecule to form a lipid peroxide radical. Meanwhile, a neighboring radical reacts with oxygen in the same process. This can continue until the kidney cell is permanently damaged. In theory, a single radical could destroy us with this chain reaction!

Actually, there are many different kinds of oxygen radicals. The most important are superoxides, hydroxy radicals, and perhydroxy radicals. These are extremely reactive and will combine immediately with anything nearby. There is another reactive from of oxygen as well, called singlet oxygen.

Oxidative injury is implicated in a long list of disease. Following are some of the more important examples.

DISEASES RELATED TO OXYGEN RADICALS

Hardening of the Arteries (Atherosclerosis)

We have "good cholesterol" and "bad cholesterol" in our bodies. Good cholesterol is attached to lipids called HDL (high-density lipoproteins). Bad cholesterol is attached to LDL (low-density lipoproteins). One reason that the LDL cholesterol is bad is that it can from plaques in our arteries. When a plaque cracks or is otherwise activated, a blood clot can from that blocks blood flow through the artery. If the clot is in an artery that supplies heart muscle, the blood supply to part of the heart is blocked. This lead to chest pain or a heart attack. If the clogged arteries carries blood to the brain, a stroke or TIA can develop. If the clogged artery is in the leg, pain develops on exercise, and in very severe cases leg amputation may be needed.

In the past decade it has become apparent that the free 0 radical oxidation of LDL is important to the process of plaque formation. This is one of the most important findings for heart disease and stroke prevention to date and provides many ways for people to help decrease their risk of heart disease.

Unmodified LDL does not begin the process of plaque formation. It can be inappropriately oxidized in the artery wall, though. Once LDL reacts with an oxygen radical, it is seen as a foreign substance by body defense systems and is attacked by protective cells called macrophages. Unfortunately, the process can be destructive, and the oxidized LDL sets up an inflammation in the outer layer of the artery that leads to a "fatty streak" and, later, a plaque deposit. Both can start the process of blood clotting. Chemicals, including antioxidant vitamins, that neutralize free radicals can help block plaque formation and may reduce the risk of heart attack and stroke.

The Complications of Diabetes

High glucose levels in blood and tissues that result from diabetes lead to increased LDL oxidation. Diabetes have an increased incidence of coronary and vascular diseases, and antioxidants have the potential of decreasing some of the LDL oxidation associated with diabetes.

Cancer

Exposing DNA in our cell nuclei to free radicals may result in DNA strand breaks and mutations, leading to cancer. Chronic inflammation and injury generate free radicals as part of the process, which helps explain why these conditions increase the risk for the development of cancers. For example, the hepatitis viruses often cause a chronic liver infection that sharply increases the risk of liver cancer. The inflammation caused by inhaled asbestos results in high risk of lung cancer. Antioxidants have the potential to decrease cancer risks by neutralizing the free radicals causing damage.

Inflammation

Body cells whose job is to engulf and destroy bacteria and damaged tissue particles accomplish this by producing short bursts of hydrogen peroxide and superoxide. For reasons that are not well understood, the process can get out of hand and these chemicals set off reactions like the one outlined earlier, leading to tissue injury. The reaction products of free radicals are detected in synovial fluid. The chain reaction sequence described earlier is probably important is spreading the inflammation and damage. Arthritis is one example of this situation, and antioxidants have the potential to help prevent inflammation.

Reperfusion Injury

If blood flow to an organ or tissue is temporarily shut off and then restarted, the influx of oxygenated blood causes injury over and above that caused by the temporary oxygen loss. Apparently, a lack of oxygen reduces the ability of body tissues to neutralize radicals. When radicals are generated with the influx of oxygen, damage results. This is a problem in organ transplantation and heart surgery, where blood supply is temporarily interrupted during the procedure. Antioxidants have the potential to reduce this injury.

Aging

Radical reactions certainly play a role in declining body function as we age. The immune system weakens, blood vessels get stiff and clogged, and organ function begins to decline. DNA strand breaks result in mutations that may start cancers. Cigarette smoke, ionizing radiation, and certain chemicals all increase the amount of free radicals and accelerate the aging process. For example, the wrinkled facial skin of the longtime smoker is due to free radical damage to the fabric to the skin by way of reactions discussed here. Antioxidants have the potential to minimize some aspects of the aging process.

Eye Disease

Premature infants who receive life-saving oxygen sometimes suffer damage to the retina of their eyes because the protective systems that neutralize oxygen free radicals are not yet in place. Degeneration of the retina, common in the elderly, is thought to be due in part to the inability of eye tissue to neutralize free radicals. Antioxidants have the potential to help prevent certain eye diseases.

Other Diseases

We could cite many other examples of conditions where oxygen radicals are thought to play an important role. If oxygen radical reactions could be blocked or minimized by drug or vitamin treatment, we might not cure disease, but we would certainly have a valuable treatment and prevention strategy.

THE BODY'S DEFENSES AGAINST FREE RADICALS

If radical reactions went unchecked, we would all have a very short lifespan. Fortunately, we are well equipped to survive in an oxygen - rich atmosphere. The burning questions are : Can we further enhance these protective mechanisms with dietary supplements? If we accomplish this, will it result in better health? We believe the answer to both questions is a resounding yes.

First let us consider our natural protective mechanisms and then see how several vitamins fit in. The most direct way to block free-radical-induced damage is to neutralize the radical where it is generated. A critically important nutrient, vitamin E, is well poised to do this. The chemistry of vitamin E is nearly perfect for its task. It dissolves in fat, so it can move in and through the lipidlike cell membranes. It can pick up that lone unpaired electron from a carbon-centered or oxygen radical to form a less reactive vitamin E radical.

Vitamin E is considered a chain-breaking free-radical scavenger because it removes the radical and stabilizes it. The vitamin E radical is chemically much more stable than other radicals. As such, it doesn't do damage to neighboring molecules. Eventually, however, we need to regenerate the E and to neutralize the vitamin E radical. This is done with the help of another remarkable vitamin, vitamin C. Unlike vitamin E, vitamin C dissolves in water and can accept the unpaired electron from E sitting in the lipid membrane. Now the radical is the vitamin C in the fluid outside the cell membrane. The vitamin C by enzymes with the aid of NADH, a coenzyme form of niacin. Now we are out of danger thanks to three vitamins.

More protective modalities exist as well. An enzyme called superoxide dismutase is also very important. This enzyme causes the inactivation of superoxide to form less reactive hydrogen peroxide and oxygen. There are two superoxide dismutase enzymes. One is in cell mitochondria and contains manganese. The other is found in fluid outside the cell and contains copper and zinc.

Hydrogen peroxide, generated by the breakdown of superoxide, requires either of two other enzymes, glutathione peroxidase or catalase, to convert the reactive hydrogen peroxide molecule to water and oxygen. You may have seen catalase in action if you have ever put hydrogen peroxide liquid on an a open wound. The "fizz" is the oxygen released by the action of catalase in the wound on the added hydrogen peroxide.

Earlier we mentioned singlet oxygen as another reactive molecule. The carotenoids, precursors of vitamin A, are chemically designed to neutralize singlet oxygen. Beta carotene is the most well known carotenoid, but there are many others. Other chemicals in the body can also react with radicals to render them harmless. These includes melatonin, coenzyme Q10, bioflavonoids, lycopene, and uric acid, but their exact roles are less well established.

Table 1. Antioxidant Vitamins and Minerals

Vitamin or Mineral	Function as Antioxidant/ Free radical remover
Critically important
Vitamin E	Fat Soluble; chain-breaking free- radical scavenger
Vitamin C	Water Soluble; free-radical scavenger and antioxidant
Dietary carotenoids	Neutralize singlet oxygen; Antioxidant
Selenium	Essential for functioning of glutathione peroxidase, needed to stop polymerization
Less Critically important
Thiamin	Necessary for regeneration of glutathione
Riboflavin	Necessary for regeneration of glutathione
Niacin	Necessary for regeneration of glutathione
Copper, manganese, zinc	Necessary for regeneration of superoxide dismutase
Of uncertain importance
Melatonin	Strong fat-soluble antioxidant
Coenzyme	Q10 Strong fat-soluble and water-soluble antioxidant
Bioflavonoids	Common dietary antioxidants

And there are yet more protective mechanisms. Earlier we said that lipid peroxides are dangerous because they undergo complex reactions that can damage a cell or membrane. Several vitamins and one mineral are involved in stopping this dangerous reaction. An enzyme called glutathione peroxidase stimulates the conversion of organic peroxides to relatively harmless organic alcohols. This critical enzyme requires selenium to function. In the reaction, glutathione is oxidized to glutathione disulfide. In order to regenerate glutathione, a series of enzymatic reactions occurs involving thiamin, riboflavin, and niacin.

Oxidative stress is the term used to describe a risk for damage from oxygen radical reactions due to an imbalance between oxidants and antioxidants. Oxidative stress can lead to damage and disease. Table 1 present a summary of the antioxidants vitamins and minerals and their role in protection from the damage of oxidative stress.

CAN ANTIOXIDANT SUPPLEMENTS PREVENT CANCER AND HEART DISEASE?

Cancer and heart disease kill more people than any other disease. Basic research indicates that oxidative stress plays a role in these diseases, and animal research has indicated potential for antioxidant vitamins to help in preventing them. Here we will focus on studies of the potential effects of antioxidant vitamins in heart disease and cancer. Radicals may be involved in the development of other diseases, but they will be discussed only briefly because evidence for their effect is more limited.

Epidemiological or population studies show generally that dietary antioxidant vitamins have value in preventing heart disease and cancer. In recent years several placebo-controlled human studies targeting this effect have been completed. The results of these specific studies are encouraging but not in uniform agreement; two large studies of the preventive benefit of beta carotene that produced negative results have caused considerable on this tissue.

Dietary Studies

Early epidemiological studies of dietary habits supported the idea the antioxidants from dietary sources were associated with a reduced risk of heart disease and some cancers, especially lung cancer. These studies rely on huge data collections from several study populations. The Framingham Study is an example. Here a large segment of the population of Framingham, Massachusetts, has been followed for many years. Blood samples have been periodically taken, questionnaires completed, diets monitored, and the volunteers watched for changes in health status. This study and many similar studies from around the world consistently find that vegetable and fruit consumption is related to the risk for coronary heart disease and some cancers. That is, the more fruits and vegetables you eat, the lower your risk. At the high end of fruit and vegetable consumption is related to the risk for coronary heart disease and some cancers. That is the more fruits and vegetables you eat, the lower your risk. At the high end of fruit and vegetable intake, risk decreased by more than 50 percent compared to those eating the fewest fruits and vegetables.

What is it in the fruits and vegetables that may be protective? When the diets are analyzed, intake of Vitamin E, vitamin C, beta carotene, flavonoids, and the mineral selenium are related to disease risk, that is, the smaller the intake, the higher the risk. While these studies suggest a strong benefit for antioxidant vitamin intake, in one of their limitations that is impossible to control for all confounding variables. For example, it is possible that people eating a diet high in vitamin E have a lower risk for heart disease because they live a healthier lifestyle in general.

Population Studies of Vitamin Supplement Use

Several more recent large-scale human studies have looked not only at diet but also at vitamin supplements taken by the populations being studied. These results address the issue of antioxidant vitamin supplement value more directly, but there is still the question of whether people who take supplements also have other healthy lifestyle practices, which may account for some of the observed results. Nevertheless, the value of vitamin E supplements over and above the amount obtained from a standard multivitamin now seems apparent for help in the prevention of coronary disease.

For example, the Health Professionals Follow-up Study has followed 51,529 male health professionals since 1986. Participants filled out detailed questionnaires on their diet and supplement use. Based on the results of four years of observation, and after controlling for other risk factors, a lower risk of heart disease was noted with increasing vitamin E dietary intake in 39,910 men. Those at the high end of dietary intake had a 36 percent smaller chance of developing heart disease. Of special interest is the observation that people taking vitamin E capsules in daily doses between 100 and 250 IU per day had a 46 percent lower risk of heart disease compared to people who did not take a supplement. Supplements had to be taken for at least two years in order for them to have a protective effect. Dietary carotene intake did not have a protective effect, except in smokers and former smokers, nor did total vitamin C intake. Multivitamin use was only modestly protective and only in people who took multivitamins for more than ten years.

The Nurses Health Study of 89,245 nurses followed from 1980 to 1988 and showed that vitamin E had a similarly strong protective effect against heart disease. The greatest effect, a decrease in risk of almost 50 percent, was found in women who took more than 100 IU per day for at least two years, compared to those who took no vitamin E supplement. Vitamin C supplements and beta carotene intake were not protective. Again, taking a multivitamin was only modestly protective.

The final example is a study of 11.178 elderly people, ages 67 to 105 years, over a period of about ten years. In this population, at high risk for death from heart disease and cancer, vitamin E supplements had a striking effect. People who took vitamin E supplements separate from a multivitamin had a 37 percent lower risk of death due to heart disease. The risk for death due to cancer was 41 percent less in vitamin E users. Those who used both vitamin E and vitamin C supplements were somewhat better protected, with a 52 percent smaller risk of disease.

There was a trend for people to benefit from the combination of vitamins C and E in reducing cancer death, but vitamin C use alone did not protect against death from heart disease, cancer, or other causes. This study is the best one to demonstrate an advantage of taking both vitamin E and vitamin C. Multivitamin use was not shown to be protective in this study.

Primary Prevention Studies

The previous studies provide reasonable evidence that antioxidant vitamins, especially vitamin E, are useful to help prevent heart disease. The evidence for protection against cancer is weaker. More definitive proof of protection is obtained from studies in which healthy people without any evidence of disease take a placebo or an antioxidant vitamin and are followed for a sufficient length of time or until disease develops. These studies are called primary prevention trials. As you might imagine, primary prevention trials are expensive are very difficult to conduct. As a result, these large vitamin studies are generally funded by government health agencies.

For example, the ATBC study followed 29, 133 Finnish smokers for five to seven years. The volunteers received either 20mg of beta carotene, 50 mg of vitamin E, both vitamins, or an inactive placebo. Neither vitamin alone nor the combination had a protective effect against lung cancer. In fact, more lung cancers were found in the beta carotene group. This study has been criticized because of the low dose of vitamin E, because of the fact that synthetic beta carotene was employed, and because the smokers tested may have already had cancer before they entered the study.

A second study (CARET) gave 18,314 smokers , former smokers, or people exposed to asbestos either a combination of 30 mg of beta carotene and 25,000 IU of vitamin A or placebo. The study was stopped after four years because, as with the ATBC study, a significant increase in deaths due to lung cancer was seen in the beta carotene/vitamin A group.

A third study, the Physicians' Health Study, was remarkable in that 22,071 healthy physicians took either 50 mg of beta carotene or placebo every other day and were followed for twelve years. This study lasted longer and studied a healthier population than the other two. Beta carotene had neither a beneficial nor harmful effect in this study.

Another study, published by the same group of Finnish investigators who did the ATBC trial, looked at the effect of 50mg of vitamin E on prostate cancer in male smokers studies in ATBC. The researchers found that men who took 50 mg of vitamin E for five to eight years had a 23 percent smaller risk of developing prostate cancer, and those who did get prostate cancer were 41 percent less likely to die.

These large studies were disappointing for beta carotene proponents. We cannot say much about vitamin E from these studies because either it was not tested, the dose used was too low, or the results, as in the prostate cancer study, need to be confirmed.

Secondary Prevention Trials

A secondary prevention trials looks at whether the treatment will prevent a second occurrence of the disease being studied in a group of people who have already experienced the disease or who are at proven risk of the disease. Vitamin E has been shown to provide a benefit in several of these secondary prevention studies.

For example, 2,002 patients with heart disease were given a placebo or 400 IU per day of vitamin E for seventeen months. The vitamin E group had about 80 percent fewer nonfatal heart attacks, but the number of fatal heart attacks was about the same for both the E-treated and placebo groups.

Another study followed 156 men who had previous coronary bypass surgery. Vitamin E, at doses over 100 IU per day, reduced the worsening of heart disease compared to placebo. No benefit was seen for vitamin C, for multivitamin use, or for increased intake of dietary vitamin E.

In another study, patients with a previous colorectal adenoma who had had their polyps removed received either 400 IU of vitamin E with 1 gram of vitamin C per day or an inactive placebo. There was no difference between the placebo and vitamin E groups in the number of patients who needed surgery to remove adenomas after one year of treatment.

EVIDENCE OF ANTIOXIDANT SUPPLEMENT BENEFIT IN OTHER DISEASES

In older placebo-controlled studies, vitamin E has also been shown to be of some help in people with intermittent claudication, a painful condition due to poor circulation in the limbs. The origin of this disease is the same as a heart attack or stroke, atherosclerotic narrowing of the arteries, so it is not surprising that vitamin E can be helpful by virtue of its ability to reduce plaque formation and to decrease platelet stickiness.

An exciting finding was that vitamin E treatment somewhat slowed the rate of progression of Alzheimer's disease. A total of 341 patients received a drug called slegiline, a very high dose of vitamin, both or placebo. People taking vitamin E experienced a greater delay in disease progression than those taking selegiline alone or placebo. More recently, a study at New York's Memorial Sloan - Kettering Cancer Center found that one form of vitamin C, dehydroascorbic acid, can get through the blood-brain barrier, allowing large amounts of vitamin C directly into brain tissue. The researchers conclude that this technique may prove to be an important therapeutic advance in treating Alzheimer's disease and other conditions that result from damaged brain cells. Clearly, more studies of vitamins E and C in Alzheimer's disease are needed.

The final example has to do with the signs of aging. Free-radical reactions progressively damage the immune system as we get older. Investigators in Boston gave doses of 60, 200, or 800 IU of vitamin E per day or placebo to eighty0eight elderly subjects for four months. Tests of immune function and antibody response to vaccinations showed that vitamin E improved immune function. The effect was generally better in the group receiving 200 mg per day.

RECOMMENDATIONS FOR TAKING ANTIOXIDANTS VITAMINS

Taking antioxidant vitamins is a modest and inexpensive action you can take to decrease the risks of cancer, heart disease, and other conditions associated with aging. The operative word here is modest. It is very important to bear in mind that the largest benefit of vitamin intake is smaller than the benefit that can be achieved by making important lifestyle adjustments such as stopping smoking, losing excess weight, and exercising. While there is disagreement over the value of antioxidant supplements, there is uniform agreement that a diet high in vegetables and fruits and fiber is protective. Your mother was right : Eat your vegetables.

Having improved your lifestyle, can you expect further benefit by taking high doses of antioxidant vitamins? We believe that the evidence says yes for vitamin E, yes for vitamin C in combination with vitamin E, and no for beta carotene; it's inconclusive for the other antioxidant supplements. Here are our recommendations for taking antioxidant vitamin supplements.

1. Take a multivitamin supplement with minerals every day. Make sure the supplement contains selenium and folic acid and 100 percent of the RDA for each of the eleven vitamins. This product will provide all of the vitamins you need for optimum antioxidant status, except vitamins E and C, and will provide adequate amounts of selenium. A generic product containing 100 percent of the RDA value of all vitamins and selenium can be purchased for $4 to $8 per 100 tables. This is inexpensive and safe insurance.
2. Take 200 to 400 IU of natural vitamin E everyday. Higher doses are not needed and lower doses have proven to be less effective in human studies. Natural vitamin E is absorbed and utilized better that the synthetic form, though most clinical studies have used the synthetic. The label should say d-alpha tocopherol. If it does not or says d1-alpha tocopherol, it is synthetic vitamin E.
3. Take 250 to 500 mg of vitamin C every day. Generic, synthetic vitamin C is fine. As discussed, the vitamin C works together with vitamin E in removing damaging oxygen radicals. Vitamin C without vitamin E does not appear to be especially helpful.
4. Eat a few carrots everyday and increase your intake of other vegetables. The carrot will provide a nice mixture of carotenoids, and the other vegetables will provide flavonoids shown to have protective antioxidant properties. Avoid taking a synthetic beta carotene supplement. Evidence from large human clinical trials says it does nothing for, or might be even harmful to, smokers or former smokers. Beta carotene, at least the synthetic variety, is not the magic ingredient in vegetables that provides protection.
5. Avoid specialty antioxidant products. They are expensive and often contain ingredients of unproven value.
6. Don't give up on this program. Studies show that vitamin E will benefit you only after you have taken it for many months