Antioxidants: What You Need to Know

As the name implies, antioxidants are substances that are capable of counteracting the damaging, but normal, effects of the physiological process of oxidation in animal tissue. Antioxidants are nutrients (vitamins and minerals) as well as enzymes (proteins in your body that assist in chemical reactions). They are believed to play a role in preventing the development of such chronic diseases as cancer, heart disease,stroke, Alzheimer's disease, Rheumatoid arthritis, and cataracts.

Oxidative stress occurs when the production of harmful molecules called free radicals is beyond the protective capability of the antioxidant defenses. Free radicals are chemically active atoms or molecular fragments that have a charge due to an excess or deficient number of electrons. Examples of free radicals are the superoxide anion, hydroxyl radical, transition metals such as iron and copper, nitric acid, and ozone. Free radicals containing oxygen, known as reactive oxygen species (ROS), are the most biologically significant free radicals. ROS include the radicals superoxide and hydroxyl radical, plus derivatives of oxygen that do not contain unpaired electrons, such as hydrogen peroxide, singlet oxygen, and hypochlorous acid.

Because they have one or more unpaired electrons, free radicals are highly unstable. They scavenge your body to grab or donate electrons, thereby damaging cells, proteins, and DNA (genetic material). The same oxidative process also causes oils to become rancid, peeled apples to turn brown, and iron to rust.

It is impossible for us to avoid damage by free radicals. Free radicals arise from sources both inside (endogenous) and outside (exogenous) our bodies. Oxidants that develop from processes within our bodies form as a result of normal aerobic respiration, metabolism, and inflammation. Exogenous free radicals form from environmental factors such as pollution, sunlight, strenuous exercise, X-rays, smoking and alcohol. Our antioxidant systems are not perfect, so as we age, cell parts damaged by oxidation accumulate.

Antioxidants block the process of oxidation by neutralizing free radicals. In doing so, the antioxidants themselves become oxidized. That is why there is a constant need to replenish our antioxidant resources.

How they work can be classified in one of two ways:

• Chain-breaking - When a free radical releases or steals an electron, a second radical is formed. This molecule then turns around and does the same thing to a third molecule, continuing to generate more unstable products. The process continues until termination occurs -- either the radical is stabilized by a chain-breaking antioxidant such as beta-carotene and vitamins C and E, or it simply decays into a harmless product.

• Preventive - Antioxidant enzymes like superoxide dismutase, catalase and glutathione peroxidase prevent oxidation by reducing the rate of chain initiation. That is, by scavenging initiating radicals, such antioxidants can thwart an oxidation chain from ever setting in motion. They can also prevent oxidation by stabilizing transition metal radicals such as copper and iron.

The effectiveness of any given antioxidant in the body depends on which free radical is involved, how and where it is generated, and where the target of damage is. Thus, while in one particular system an antioxidant may protect against free radicals, in other systems it could have no effect at all. Or, in certain circumstances, an antioxidant may even act as a "pro-oxidant" that generates toxic oxygen species.

Antioxidant Nutrients
Antioxidants from our diet appear to be of great importance in controlling damage by free radicals. Each nutrient is unique in terms of its structure and antioxidant function.

Vitamin E is actually a generic term that refers to all entities (eight found so far) that exhibit biological activity of the isomer tocopherol (an isomer is one of two or more molecules that have the same chemical formula but different atomic arrangements). Alpha-tocopherol, the most widely available isomer, has the highest biopotency, or strongest effect in the body. Because it is fat-soluble (and can only dissolve in fats), alpha-tocopherol is in a unique position to safeguard cell membranes -- largely composed of fatty acids -- from damage by free radicals. Alpha-tocopherol also protects the fats in low-density lipoproteins (LDLs, or the "bad" cholesterol) from oxidation.

Vitamin C, also known as ascorbic acid, is a water-soluble vitamin. As such, it scavenges free radicals that are in an aqueous (watery) environment, such as inside your cells. Vitamin C works synergistically with vitamin E to quench free radicals. Vitamin C also regenerates the reduced (stable) form of vitamin E.

Beta-carotene, also a water-soluble vitamin, is the most widely studied of the 600 carotenoids identified to date. It is thought to be the best quencher of singlet oxygen (an energized but uncharged form of oxygen that is toxic to cells). Beta-carotene is also especially excellent at scavenging free radicals in low oxygen concentration.

Selenium is a trace element. It is a mineral that we need to consume in only very small quantities, but without which we could not survive. It forms the active site of several antioxidant enzymes including glutathione peroxidase.

Similar to selenium, the minerals manganese and zinc are trace elements that form an essential part of various antioxidant enzymes.

Antioxidant Enzymes
The antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) serve as your primary line of defense in destroying free radicals.

SOD first reduces (adds an electron to) the radical superoxide (O2^-) to form hydrogen peroxide (H2O2) and oxygen (O2).

Catalase and GPx then work simultaneously with the protein glutathione to reduce hydrogen peroxide and ultimately produce water (H2O).

(The oxidized glutathione is then reduced by another antioxidant enzyme -- glutathione reductase.)

Together, they repair oxidized DNA, degrade oxidized protein, and destroy oxidized lipids (fat-like substances that are a constituent of cell membranes). Various other enzymes act as a secondary antioxidant defense mechanism to protect you from further damage.

Other Antioxidants
In addition to enzymes, vitamins, and minerals, there appear to be many other nutrients and compounds that have antioxidant properties. Among them is coenzyme Q10 (CoQ10, or ubiquinone), which is essential to energy production and can also protect the body from destructive free radicals. Also, uric acid, a product of DNA metabolism, has become increasingly recognized as an important antioxidant. Additionally, substances in plants called phytochemicals are being investigated for their antioxidant activity and health-promoting potential.

Since antioxidants counteract the harmful effects of free radicals, you would think that we should consume as much as of them as possible. The truth is, although there is little doubt that antioxidants are a necessary component for good health, it is not clear if supplements should be taken and, if so, how much. Once thought to be harmless, we now know that consuming mega-doses of antioxidants can be harmful due to their potential toxicity and interactions with medications. Remember -- antioxidants themselves may act as pro-oxidants at high levels.

So, is there any basis for the hoopla? The experimental (intervention) studies completed so far have had mixed results:

• The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC) involved Finnish men who were heavy smokers and alcohol drinkers. The volunteers were either given 20 milligrams (mg) of synthetic beta-carotene, 50 mg of vitamin E, a combination of the two, or a placebo. After eight years, the men who took vitamin E had 32 percent fewer diagnoses of prostate cancer and 41 percent fewer prostate cancer deaths compared to men who did not. However, after only four years, there were 16 percent more cases of lung cancer and 14 percent more lung cancer deaths in the beta-carotene-only group.

• In the Carotenoid and Retinol Efficacy Trial (CARET), volunteers were either smokers or asbestos workers. They were given a combination of 30 mg of synthetic beta-carotene and 25,000 International Units (IU) of retinol (pre-formed vitamin A) or placebo. This study was stopped early due to the fact that preliminary findings suggested that there was a 28-percent increase in lung cancer rates in the beta-carotene group compared to the placebo group.

• The Physicians' Health Study (PHS) of 22,000 physicians, 11 percent of whom were smokers and 40 percent were past smokers, showed neither a protective effect nor a toxic effect after 12 years of follow-up. The participants were randomized to receive either 50 mg of beta-carotene every other day or placebo. (A second PHS underway is testing beta-carotene, vitamin E, vitamin C, and a multivitamin with folate in healthy men age 65 and older for slowing cognitive decline.)

• A 1997 study published in the Journal of the American Medical Association found that 60 mg of vitamin E a day strengthened the immune system in a group of healthy patients at least 65 years old, and 200 mg generated a four-to-six fold improvement after four months. However, 800 mg of vitamin E resulted in worse immunity than receiving no vitamin E at all.

• In 2001, the Age-Related Eye Disease Study (AREDS), a randomized, placebo-controlled clinical trial, showed that high-dose supplementation of 500 mg of vitamin C, 400 IU of vitamin E, 15 mg of beta-carotene, 80 mg of zinc, and 2 mg of copper significantly reduced development of advanced age-related macular degeneration (AMD) compared to placebo. In addition, the antioxidant-plus-zinc group had significant reduction in rates of at least moderate visual acuity loss.

There are several possible explanations to account for the results.

• The amount of antioxidants in supplements may be so high compared with that in the diet that it leads to a toxic effect.
• Other nutrients may be present in fruits and vegetables that work in sync with antioxidants and are necessary to provide a protective effect.
• The study participants may have been too old to start taking antioxidants, or they may have led lifestyles that were too unhealthy for the antioxidants to make a positive difference.

Furthermore, literally hundreds, if not thousands, of observational studies (where investigators look for associations without giving participants supplements to take) have linked diets rich in antioxidant-rich fruits and vegetables to a lower risk for diseases like cancer, heart disease, stroke, cataracts, Parkinson's, Alzheimer's, and arthritis. So, despite the disappointing findings of trials, scientists remain certain of the many potential benefits of dietary antioxidants -- they simply haven't figured out exactly how the different antioxidant systems work together in our bodies to protect us from free-radical damage.

The American Heart Association, for one, does not recommend using antioxidant supplements "until more complete data are in," but instead, suggests "people eat a variety of foods daily from all of the basic food groups." Moreover, in April 2000, the Food and Nutrition Board of the Institute of Medicine, an advisory group that is part of the National Academy of Sciences, reported that Vitamin C, vitamin E, selenium, and carotenoids like beta-carotene should come from food, not supplements. After examining available data on the beneficial and harmful health effects of antioxidants, the panel concluded that there isn't enough evidence to support using large doses of these nutrients to combat chronic diseases. In fact, the group warned that extremely high doses of antioxidants may lead to health problems, including diarrhea, bleeding, and the risk of toxic reactions.

Since 1941, the Food and Nutrition Board has determined the types and quantities of nutrients that are needed for healthy diets by reviewing scientific literature, considering how nutrients protect against disease, and interpreting data on consumption of nutrients. For each type of nutrient, the Board has established a Recommended Dietary Allowance (RDA)-a daily intake goal for nearly all (98 percent) healthy individuals, and a "tolerable upper intake level" (UL)-the maximum amount of a nutrient that healthy individuals can take each day without risking adverse health effects. In some cases, the Board has decided there isn't enough evidence to determine the amount at which a particular nutrient is essential or harmful to health.

Over the last several years, the Board has been updating and expanding the system for determining the RDA and UL values, which are now collectively referred to as the Dietary Reference Intakes, or DRIs. The following recommendations were made for consumption of antioxidants in the 2000 report, "Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids":

Although research may look promising, particularly with regard to vitamin E, food remains the smart choice for where to obtain your antioxidants. Studies consistently demonstrate that for optimum health, you should eat at least five servings of fruits and vegetables everyday as part of a balanced diet. Below is a list of where to find specific antioxidants. If you are interested in taking antioxidant supplements, talk to your doctor about what is right for you.

• Vitamin E is found in vegetable oils, walnuts, peanuts, almonds, seeds, olives, avocado, wheat germ, liver, and leafy green vegetables.

Photo courtesy U.S. Department of Agriculture

• For good sources of vitamin C, look to citrus fruits (like oranges and grapefruit), broccoli, leafy green vegetables, tomatoes, peppers, potatoes, cantaloupe, and strawberries.

Photo courtesy U.S. Department of Agriculture

• Common sources of beta-carotene include cantaloupe, mangoes, papaya, pumpkin, peppers, spinach, kale, squash, sweet potatoes, and apricots.

Photo courtesy U.S. Department of Agriculture

• You can find selenium in seafood, beef, pork, chicken, Brazil nuts, brown rice, and whole wheat bread.

Photo courtesy U.S. Department of Agriculture

Phytochemicals are found in a variety of sources. Some phytochemicals that are currently under study for their antioxidant activity and ability to reduce disease risk are listed below.

Of course, in addition to eating plenty of fruits and vegetables, getting regular exercise and abstaining from tobacco use are critical to a healthy lifestyle.

For more information on antioxidants and related topics, check out the links on the next page.