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A Primer on Free Radicals and Antioxidants

NaturalNews.com printable articleOriginally published February 20 2008

A Primer on Free Radicals and Antioxidantsby Ben Kim (see all articles by this author) (NaturalNews) Contrary to popular belief, free radicals are not entirely bad for your health. Free radicals, by definition, are reactive elements that want to steal electrons from compounds that they come into contact with. The vast majority of free radicals that exist in your body at any given moment can be traced back to one of the following sources: * Everyday metabolic pathways that occur in your body to produce energy * Environmental toxins, such as industrial pollutants, household chemicals, and cigarette smoke * Physical stressors, such as unhealthy oils, food preservatives, and the wide variety of chemicals that are found in almost all highly refined foods * Emotional stress Free radicals inflict damage upon other compounds by stealing electrons from them, which initiates bouts of inflammation that can lead to scar tissue formation. For example, if enough free radicals steal electrons from the inner wall of one of your blood vessels, the resulting inflammation can lead to hardening of the vessel wall, which can cause compromised blood circulation in that area of your body. Just as free radicals can damage your tissues, they can also damage viruses, bacteria, and harmful substances that make their way into your blood; in these instances, free radicals act as important parts of your immune system, and serve to protect the health of your tissues. Free radicals that are formed inside of your cells via everyday metabolic processes are important to your natural defense mechanisms. These free radicals help to neutralize toxins, destroy waste products, and protect your tissues against harmful microorganisms. Free radicals become a significant cause of disease when you produce them in excessive quantities and/or are exposed to large amounts from the environment. When your body is bombarded by excessive free radicals, you have a higher risk of developing a variety of degenerative diseases - including cardiovascular disease and many types of cancer - due to the damage that free radicals can inflict on tissues that they come into contact with. Antioxidants found in fresh, minimally processed foods are helpful to your health because

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A Primer on Free Radicals and Antioxidants

they are able to provide the electrons that free radicals want. Once free radicals are neutralized by antioxidants, they become harmless, and are eventually eliminated from your body. Here are some practical notes on how to prevent free radicals from significantly compromising your health: * Avoid hydrogenated oils, fried foods in restaurants, and highly refined foods - all of these foods are typically rich in free radicals. * Avoid charcoal-grilled meats and animal products that have been cooked at high temperatures - these foods are also abundant in free radicals. * Eat plenty of fresh vegetables, such as romaine lettuce, celery, bell peppers, carrots, and tomatoes. Fresh vegetables and fruits are rich in natural antioxidants that can neutralize free radicals in your body. * If your life circumstances permit, drink fresh vegetable juices on a regular basis. Freshly pressed vegetable juices provide a wide range of nutrients, including antioxidants, that are easily absorbed into your bloodstream. To optimally support your blood sugar level, emphasize the use of greens like romaine lettuce, kale, and celery, and use only small amounts of sweet vegetables like carrots and red beets. Consider using a high quality super green food product if you don't have time to make vegetable juices on a regular basis. * Eat fruits that are rich in antioxidants, such as blueberries, pomegranates, raspberries, blackberries, strawberries, cherries, goji berries, papayas, mangoes, watermelon, and olives. * Don't overeat. Since free radicals are produced by your regular metabolic activities, overeating results in excessive free radical formation in your cells; these free radicals can spill out into your blood, and eventually damage your tissues. As you try to minimize the negative impact that free radicals can have on your health, don't forget the importance of acquiring restful sleep and striving to be emotionally balanced; a well rested body and a balanced nervous system are two of the most important requirements for a strong immune system that can protect your health against excessive free radicals.

About the authorBen Kim is a chiropractor and acupuncturist who lives in Ontario, Canada with his wife and two sons. He provides information on how to experience your best health as you age at his website, http://drbenkim.com.

All content posted on this site is commentary or opinion and is protected under Free Speech. Truth Publishing LLC

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Antioxidant Status, Diet, Nutrition, And Health

by Andreas M. Papas M.Sc., Ph.D. Senior Technical Associate, Health and Nutrition, Eastman Chemical Company, Kingsport, TN Adjunct Professor, James Quillen College of Medicine, East Tennessee State University, Johnson City, TN Senior Scientific Advisor, The Cancer Prevention Institute, Harvard University

Part I: Factors Affecting Antioxidant Status and Its Role in Health and Disease

INTRODUCTION

Most of us view free radicals and antioxidants as classic case of bad guys – the free radicals, and good guys – the antioxidants. This understanding, however, is incomplete because it ignores the complex roles of both free radicals and antioxidants in our body. It is rather more accurate (and relevant) to consider the antioxidant status when assessing the impact of free radicals and antioxidants on health and disease.

In this and a future paper I will attempt to integrate the basic chemistry of free radicals and antioxidants with practical aspects of diet and nutrition, and evaluate their effects on antioxidant status, health, and disease. This paper will focus on the factors affecting antioxidant status in humans. The second paper will address practical aspects of using antioxidants to prevent disease and improve health and will include: brief review of the role of the most important antioxidants; the effect of chemical form, formulation, bioavailability and dosage levels; safety issues; and major clinical trials now in progress.

FREE RADICALS – THE BAD GUYS?

Atoms consist of the positively charged nucleus and negatively charged electrons. Electrons orbit around the nucleus in pairs and each pair has its own region of space. When an electron from a pair is removed the molecule becomes very unstable and very reactive. A free radical is any chemical species, capable of independent (although extremely short) existence with one or more unpaired electrons.1-3

Many free radicals are extremely reactive. Free radicals seek frantically electrons in order to pair their unpaired electrons. Because most of the molecules in our body do not have unpaired electrons, free radicals steal electrons from normal molecules. This process, called oxidation, is the same process that causes our cars to rust and slices of apple to turn brown.3

http://www.tocotrienol.org/newpub1.htm (1 of 20) [4/27/2009 3:16:43 PM]

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The half-life of one of the most damaging free radicals, the hydroxyl radical, is one billionth of a second. This means that it will attack the first molecule in its path – fat, protein, DNA, sugar. Other common free radicals have very short half-lives from tiny fractions of a second to less than ten seconds. The damaged normal molecules become free radicals. These free radicals attack other molecules starting a chain-reaction.

Damaged enzymes and other proteins, lipids, sugars, and DNA lose their normal function and can become harmful. For example, damaged DNA provides the wrong genetic information, leading to cancer. Oxidized low-density lipoprotein (LDL) has been implicated in atherosclerosis and heart disease.4 It is for this reason that free radicals have been implicated in every major chronic disease.2

Who are these free radicals and their accomplices? Quite a few free radicals are produced in our body.1-3 The following are among the most damaging:

The hydroxyl radical is the leader of the pack. It is the most reactive oxygen radical known to chemistry. It is produced from water exposed to X-rays or gamma-rays. Also from hydrogen peroxide present in our body.

● Superoxide radical is produced from oxygen when an electron is attached. ● Nitric oxide and nitrogen dioxide. Nitric oxide is produced in our body. Nitrogen dioxide is

found in polluted air and smoke. The vascular endothelial cells, the phagocytes which are part of our immune system, and some brain cells produce nitric oxide.

Non-radical reactive oxygen species: Most scientists group with free radicals non-radical compounds that are strong oxidants or can be converted easily to free radicals. Some examples: 1-3

Hydrogen peroxide produces the extremely damaging hydroxyl radical. Injury or hemolysis releases unbound iron, which promotes the conversion; UV radiation does the same.

Singlet oxygen is an extremely reactive form of oxygen. Oxygen has two unpaired electrons arranged in such a way that oxidizes other molecules very slowly. If the electrons are rearranged, oxygen is converted to singlet oxygen. Light and compounds sensitive to light produce singlet oxygen.

Ozone is not a free radical nor does it start free radical reactions. It is, however, a strong oxidant. At the stratosphere, ozone provides a protective shield against the harmful UV rays but in the atmosphere ozone can be harmful.

TABLE 1 summarizes the most important free radicals and active oxygen species for human health.

Table 1Active Oxygen and Related Species

Radicals Non-radicals


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O2•– superoxide H2O2 hydrogen peroxide

HO• hydroxyl radical 1O2 singlet oxygen

HO2• hydroperoxyl radical LOOH lipid hydroperoxide

L• lipid radical Fe=O iron-oxygen complexes

LO2• lipid peroxyl radical HOCl hypochlorite

LO• lipid alkoxyl radical NO2• nitrogen dioxide

•NO nitric oxide RS• thiyl radical

P• protein radical

Where are these free radicals produced? Free radicals are part of life.3 We consume approximately 3.5 kilograms of oxygen every day 2.8 percent of the oxygen is not properly used and forms free radicals Several kilograms of peroxides (harmful oxidized lipids) are produced in our body every year Life is an incurable disease… —Cawley, 1656

Free radicals are produced in every tissue of our body. Three major sources of free radicals are:

Lipid oxidation. Lipid material in our body plays critical role in membranes, LDL, hormones, and many tissues including nerve tissue. Lipid material is very susceptible to oxidation from free radical attack. Oxidation of a single lipid molecule by a one radical could start a chain reaction, which can oxidize all lipid material.1 For these reasons, lipid peroxidation is probably one of the most destructive consequences of free radical attack in our body.2,4

The mitochondria. We produce energy primarily by using oxygen to oxidize glucose in the mitochondria. We also burn lipids and proteins. We produce energy as ATP (adenosine triphosphate). ATP is the energy currency of the cell, the central form of energy used to synthesize cell components and to drive all movements. Even under normal conditions, electrons deviate from their normal path and combine with oxygen or other molecules to form free radicals. If the oxygen concentration increases as in strenuous exercise, more electrons deviate and form free radicals. Also if one of the components of the electron transport chain is faulty due to genetic disease or other reason, electrons are not transported properly and leak out. Excess production of free radicals ruptures the membrane of the mitochondria and opens the floodgates of free radicals. 2,3

The immune system. Please see below.


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Do free radicals have any redeeming value? Free radicals are not always bad. Actually our body needs them and puts them to very good uses.2

Free radicals are formidable weapons in the arsenal of our immune system. The phagocytes produce free radicals and use them to kill invading bacteria and viruses.

The singlet oxygen and nitric oxide (NO) play a very important role in regulating cell growth and cell to cell communication. NO dilates blood vessels and lowers blood pressure (the 1998 Nobel Prize in Medicine was awarded for the research on the role of NO).

Free radicals are important part of our metabolism and do have useful functions. It is the excessive production of free radicals at the wrong time and place that causes harmful oxidative stress.

ANTIOXIDANTS – THE GOOD GUYS?

Professor Barry Halliwell of King’s College in London defines antioxidants as any substance that delays or inhibits oxidative damage to a target molecule.2

● Antioxidants protect from damage from free radicals in several ways: ● Prevent the formation of excess free radicals. ● Scavenge the free radicals after they are formed before they damage other molecules. ● Repair damaged molecules or replace them with new ones.

In the battle against free radicals, antioxidants themselves become free radicals. They react, however, very slowly and can be regenerated back to their original form6 or be disposed safely.

The body’s antioxidant defenses: Our cells can survive onslaughts of free radicals because they have developed formidable antioxidant defenses. A number of antioxidants working as a team make up these defenses. Some antioxidants like enzymes and proteins are produced in our body. Others like vitamin E, vitamin C, and phytochemicals (such as carotenoids and flavonoids) come from our diet. The most important components of the antioxidant system in humans are:5

Endogenous components

● glutathione (GSH, also present in foods) and Se-glutathione peroxidase ● Fe-catalase ● NADPH ● ubiquinol-10 (reduced coenzyme Q10)

● Mn, Cu, Zn-superoxide dismutase (SOD) ● uric acid ● lipoic acid ● hormones with antioxidant activity (melatonin, DHEA, etc.)


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● metal binding proteins including albumin (and albumin bound thiols and bilirubin), Fe and Cu-binding proteins (transferrin, ceruloplasmin) and Fe-complex binding proteins (heptoglobin, hemopexin)

Dietary and exogenous antioxidants

● tocopherols and tocotrienols (vitamin E) ● ascorbate (vitamin C) ● vitamin A and carotenoids ( ● -carotene, lycopene, lutein, etc.) ● Se (and other metals essential for the function of antioxidant enzymes) ● phytochemicals with antioxidant activity ● dietary and other supplements (CoQ10, glutathione, lipoic acid, etc.)

● food antioxidants (BHA, BHT, propyl gallate, TBHQ) ● allate, TBHQ, rosemary extract)

Antioxidants work as a system. Each antioxidant brings its own strengths. Vitamin C, for example is water-soluble, it works best in the cytoplasm. Vitamin E is fat-soluble and plays a key role in protecting membranes and lipoproteins. Proteins such as ferritin bind and sequester oxidizing metals such as iron and copper. Some enzymes repair damaged molecules. Other enzymes destroy free radicals or repair damaged molecules: the enzyme superoxide dismutase destroys superoxide radicals, peroxidases and catalase destroy peroxides, DNA repair enzymes reverse damage to the DNA.

The system can pick the slack and helps regenerate some antioxidants that have been converted to free radicals. Scientists believe that vitamin C and other antioxidants help regenerate vitamin E.6

Beyond antioxidant function: other biological effects of antioxidants.

Recent research indicates that antioxidants have significant and sometimes quite different metabolic effects, which may be independent or only partially related to their function as antioxidants. The following are major examples of such effects:

Signal transduction.7 Tocopherols, tocotrienols, and other antioxidants affect protein kinase C (PKC) and other important events in cell growth and communication. Quercetin has been suggested to enhance the transforming growth factor to post-transcriptional levels. Lycopene and other antioxidants may also play a role in cell communication.

Blocking estrogen-binding sites. It is believed that some flavonoids such as genistein, diadzein, and quercetin may help reduce the risk of breast, ovarian, and some other cancers by reducing the number of receptor sites available to estrogens.

Inhibition of interleukin 1b?(IL-1b)?and monocyte-cell adhesion, a crucial event in atherogenesis.


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These effects seem to be mediated by inhibition of PKC and NFkB.4

Control of extracellular fluids. LLU-alpha,a metabolite of gamma-tocopherol, may inhibit the 70 pS K+ channel in the apical membrane in the kidney. LLU-alpha is considered an endogenous natriuretic factor.8

Enhancing the action of drugs. Vitamin E and another antioxidant compound attenuated the effect of cancer drug 5-fluorouracil on tumors of human colon cancer cells transplanted into mice. The researchers suggested that vitamin E enhanced the action of the drug by turning on the gene p21 in cancer cells thus inducing death of the cells by apoptosis.9

Post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coen-zyme A (HMG-CoA) reductase. This enzyme is important for the synthesis of cholesterol. Tocotrienols inhibit its activity.10

Anticoagulant effect. Alpha-tocopheryl quinone, resulting from the oxidation of alpha-tocopherol appears to have strong anticoagulant properties.11

ANTIOXIDANT STATUS

Antioxidant status is the balance between the antioxidant system and prooxidants. This balance is dynamic and, in the human body, is probably tipped slightly in favor of oxidation, which is essential for the production of energy.3,5

A serious imbalance favoring oxidation is defined as oxidative stress. It may result from:

● excessive production of ROS and free radicals and/or ● weakening of the antioxidant system due to lower intake or endogenous production of

antioxidants or from increased utilization.

Oxidative stress can cause cell damage and is believed to contribute to aging12 and the development of chronic disease.1-3 Thus, prevention of oxidative stress may be important for good health and prevention of disease (discussed below).

Factors affecting antioxidant status. The antioxidant status is affected either from increased dietary supply of antioxidants or from endogenous production.5 It is also affected by the production of free radicals and ROS, which cause increased utilization of antioxidants. Major factors affecting the antioxidant status are summarized in Table 2.

Table 2

Determinants of Antioxidant Status in Humans

(from reference 5 with permission)


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Antioxidant effect Prooxidant effectGenetic factors

Diet

● Antioxidant vitamins (A, C, E)

● Antioxidant food components and phytochemicals

● Minerals, components of antioxidant enzymes (Se, Zn, Cu, Mn, Fe)

● Food antioxidants and supplements

Alcoholic drinks (wine and other) containing antioxidants

Exercise program

Genetic factors

Diet

● Lipids, especially PUFA

● Divalent minerals (Cu, Fe)

● Prooxidant nutrients and phytochemicals

Environment

● Pollutants

● Tobacco smoke

● UV radiation

Alcohol

Injury, disease, and medications

● Trauma, injury/ reperfusion

● Other diseases

● Drugs and medical treatment (radiation therapy, etc.)

Physiological stage or conditions

● Prematurity

● Aging

● Strenuous exercise


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Stress

● Physiological

● Emotional

Evaluation of antioxidant status. There is very strong interest and large potential benefits in accurate and easy-to-use methods for evaluating the antioxidant status in humans. Such methods can be used to assess the status both in health and disease and make diet and other changes to reduce oxidative stress.

Antioxidant status can be evaluated by direct measurements of components of the system such as glutathione, tocopherol, ascorbate and others, or more commonly, indirectly by measuring oxidative stress. Because free radicals and ROS are extremely reactive and have very short life, they can be measured directly only by electron spin resonance. In practice, the electron spin trap is used to measure radical spin adducts. Most other methods measure adducts, end-products, or other compounds which are indicators of oxidative damage. These include lipid hydroperoxides, oxidized DNA, TBARS, malondialdehyde, conjugated dienes, oxidized LDL, volatile hydrocarbons, eicosanoids, H2O2, and others.13

Due to strong preference for non-invasive methods for humans, the focus has been on indicator products present in breath (volatile hydrocarbons, H2O2), urine (TBARS, malondialdehyde, eicosanoids) and blood (TBARS, oxidized LDL, H2O2, glutathione, and others).

Antioxidant status: what is optimal? Scientists agree that a significant imbalance in the antioxidant status favoring prooxidants is harmful. Would tipping the balance in favor of prooxidants, however, be beneficial? The answer is probably not for several reasons.2,5 We derive our energy from oxidation, which requires at least slightly prooxidant conditions. In addition, it is not practical or even desirable to eliminate production of reactive oxygen species and free radicals because, at least some, are essential components of our body’s defense mechanism against invading microorganisms.

We do not know whether it is possible to create, under practical conditions, an imbalance favoring antioxidants. Even if this were possible, it would probably be undesirable because it would cause significant changes in the metabolism with unknown consequences for health. For this reason, the current focus is on preventing or reversing oxidative stress but not in creating an overall environment which completely inhibits oxidation and production of free radicals.

A number of very important issues, some of them controversial, are closely related to the antioxidant status.14 These issues are:


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● Prooxidant effects of antioxidants ● Optimum dose and safety of antioxidants ● Use of antioxidant nutritional supplements ● Antioxidant status of the digesta (the content of the digestive tract).

At this time we do not have sufficient knowledge to establish normal or preferred ranges of antioxidant status. Before we are able to do so, we need to find accurate and easy-to-use measures of the antioxidant status oxidative stress. In addition, we need to understand better the benefits and risks of changing the antioxidant status. While this is a very daunting and challenging task, there is significant reason for optimism based on the scope and quality of ongoing research.

There are, however, significant practical applications of the available knowledge to date. For example, consumption of antioxidant rich fruits and vegetables has been increasing. Use of antioxidant vitamins, primarily E and C, has also increased, even though use of high doses remains controversial. Some laboratories are providing estimates of antioxidant status based on a battery of tests and some health professionals use them to recommend changes in diet, behavior such as smoking, use of nutritional supplements, and other changes. The accuracy and use of these tests are limited now but is likely to increase substantially with the advent of new knowledge.

FREE RADICALS IN AGING AND CHRONIC DISEASE

Free radicals in aging. Every major theory on aging assumes a role for free radicals. The free radical theory hypothesizes that the accumulation of deleterious side reactions of free radicals produces degenerative changes.12 Free radicals fit well other major theories of aging such as the telomere, mitochondrial DNA, glycosylation and immunological theories of aging.

Oxidative stress and chronic disease. In addition to aging, oxidative stress is believed to contribute to the development of chronic disease including heart disease, cancer, cataracts and neurodegenerative diseases such as Alzheimer’s.2 The evidence is rather compelling as seen from the examples below.2-4

● Oxidized LDL appears to contribute significantly to atherosclerosis. ● DNA damage has been associated with development of cancer ● Nitrogen and lipid radicals have been implicated in the pathogenesis and progression of

neurodegenerative diseases including Alzheimer’s ● Free radicals have been shown to contribute to the development of cataracts in animal

models ● Free radicals contribute significantly to ischemia-reperfusion injury ● Free radicals have been implicated in the skin damage from photoaging, UV radiation, ozone

and environmental pollutants

ANTIOXIDANTS IN DISEASE PREVENTION AND TREATMENT

Basic research has elucidated several plausible mechanisms for beneficial health effects of several


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different antioxidants. In addition, a large number of observational epidemiologic studies have suggested that individuals with high dietary intake or serum levels have significantly lower risk for several chronic diseases including heart disease, some cancers, and cataracts.2-5 In contrast, the emerging evidence from major clinical intervention studies has been mixed. Particularly disappointing were the results of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study15 (ATBC or Finnish study) and the Beta-Carotene and Retinol Efficacy Trial16 (CARET) which suggested that beta-carotene not only did not reduce the risk of lung cancer in high risk individuals, but appeared rather to increase it. These results may due, at least in part, to the limitations of conducting such studies which require selection of the test population, dose and form of antioxidants from insufficient information.

A number of clinical studies showed great promise. The epidemiological and clinical evidence on the role of antioxidants in health and disease will be discussed in a future article. This is a brief discussion of promising studies primarily with vitamin E.

Aging and immunity: Studying healthy elderly people, researchers at Tufts University, reported that vitamin E increased the power of disease-fighting T-cells, improved delayed-type hypersensitivity skin response (DTH) by 65 percent and antibody response to hepatitis B six-fold. It also increased significantly the antibody titer to tetanus vaccine.17

Heart disease: A study, now in its fifth year, has been evaluating fifty patients diagnosed with stenosis of their carotid artery. One group of 25 received approximately 650 milligrams of tocotrienols plus tocopherols. The other group of 25 received a placebo. In the treated group 10 patients showed regression of stenosis, 12 remained stable and 3 patients showed minor worsening. In contrast, in the placebo group 15 patients showed worsening of the stenosis, 8 remained stable and only 2 showed minor improvement.18

In the Cambridge Heart Antioxidant Study (CHAOS) of 2,000 men and women in Britain, the risk of non-fatal heart attack was significantly lower in those who took supplement of 400 to 800 international units (IU) of vitamin E every day.19

Cancer: In the Finnish study (also known as the ATBC study), with over 29,000 elderly male smokers, those taking vitamin E for six years had 32 percent fewer diagnoses of prostate cancer and 41 percent fewer prostate cancer deaths than men who did not take vitamin E. There was also a non-significant sixteen percent reduction in colon cancer.20

Cataracts: A Canadian study, compared the consumption of vitamin supplements by 175 cataract patients with that of 175 cataract-free controls. People in the control group were taking significantly more supplements of vitamins C and E than the cataract group.21

Alzheimer's disease: A collaborative study at major medical centers across the United States found that in Alzheimer's patients taking large doses of vitamin E (2,000 IU/day), progression of the memory-robbing disease was delayed by approximately seven months.22


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CONCLUSIONS

The antioxidant status in the human body is dynamic and is affected by many factors including diet, environment, physiological stage such as aging, exercise, injury and disease, and others. The antioxidant defense includes a variety of antioxidant systems, which evolved over a very long time. It is very important to consider individual antioxidants as components of systems with major interdependence and interactions.

Ongoing and future research will help determine the role of antioxidant status in health and disease. It will also establish normal or preferred ranges of antioxidant status and methods for its accurate evaluation. This research will also help resolve major controversies on the optimum intake of antioxidants, prooxidant effects and safety and make possible the development of nutrition and public health recommendations on the use of antioxidants.

REFERENCES

1. Noguchi N, Niki, E. Chemistry of active oxygen species and antioxidants. In Antioxidant Status, Diet, Nutrition and Health, Papas AM Editor, CRC Press, Boca Raton, 1998; 3-20

2. Halliwell B. Antioxidants and human disease: a general introduction. Nutr Rev 1997;55:S44-49

3. Davies KJ. Oxidative stress: the paradox of aerobic life. Biochem Soc Symp 1995;61:1-31 4. Papas AM. Determinants of antioxidant status in humans. In Antioxidant Status, Diet,

Nutrition and Health, Papas AM editor, CRC Press, Boca Raton, 1998;21-36 5. Niki E, Tsuchiya J, Tanimura R, et al. The regeneration of vitamin E from alpha-chromanoxyl

radical by glutathione and vitamin C. Chem Lett 1982;6:789-792 6. Õzer NK, Azzi A. Beyond antioxidant function: other biochemical effects of antioxidants. In

Antioxidant Status, Diet, Nutrition and Health, Papas AM Editor, CRC Press, Boca Raton, 1998;449-460

7. Wechter WJ, Kantoci D, Murray ED Jr, et al. A new endogenous natriuretic factor: LLU-alpha. Proc Natl Acad Sci U S A 1996;93:6002-6007

8. Chinery R, Brockman JA, Peeler MO, et al. Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21WAF1/CIP1 via C/EBPbeta. Nat Med 1997;3:1233-1241

9. Parker RA, Pearce BC, Clark RW, Gordon DA, Wright JJ. Tocotrienols regulate choles-terol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem 1993;268:11230-11238

10. Dowd P, Zheng ZB. On the mechanism of the anticlotting action of vitamin E quinone. Proc Natl Acad Sci U S A 1995;92:8171-8175

11. Harman D. Free-radical theory of aging: Increasing the functional life span. Ann NY Acad Sci 1994;717:1-15

12. Handelman GJ, Pryor WA. Evaluation of Antioxidant Status in Humans. In Antioxidant Status, Diet, Nutrition and Health, Papas AM Editor, CRC Press, Boca Raton, 1998;37-62

13. Papas AM. Current issues and future research. In Antioxidant Status, Diet, Nutrition and Health, Papas AM Editor, CRC Press, Boca Raton, 1998;601-620


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14. Parthasarathy S, Santanam N, Augè N. Antioxidants and Low Density Lipoprotein Oxidation. In Antioxidant Status, Diet, Nutrition and Health, Papas AM editor, CRC Press, Boca Raton, 1998;189-210

15. ATBC Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. New Engl J Med 1994;330:1029-1035

16. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of the combination of beta-carotene and vitamin A on lung cancer incidence, total mortality, and cardiovascular mortality in smokers and asbestos-exposed workers. N Engl J Med 1996;334:1150-1155

17. Meydani SN, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial. JAMA 1997;277:1380-1386

18. Kooyenga DK, Watkins TR, Geller M, et al. Benefits of tocotrienols in patients with carotid stenosis over three years. Atherosclerosis, 1999; (in press)

19. Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-786

20. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 1998;90:440-446.

21. Robertson J McD, Donner AP, Trevithick JR. A possible role for vitamins C and E in cataract prevention. Am J Clin Nutr 1991 Supplement;35:346S-351S

22. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med 1997: 336:1216-1222

Part II: Antioxidants in health and disease prevention and management

Part I of this paper reviewed the chemistry of free radicals and antioxidants and the factors affecting antioxidant status in humans. This part summarizes basic considerations and provides practical recommendations for the use of antioxidants for the maintenance of good health and management of disease

BASIC CONSIDERATIONS

Antioxidants work as a system. Each antioxidant brings its own strengths. Vitamin C, for example, is water-soluble and works best in the cytoplasm. Vitamin E is fat-soluble and plays a key role in protecting membranes and lipoproteins. The system can pick the slack and helps regenerate some antioxidants. In addition, antioxidants have significant metabolic effects, which may be independent or only partially related to their function as antioxidants.1

For these reasons, our objective should be to maintain a strong antioxidant system. No single antioxidant can perform all the antioxidant functions in our body. Statements that one antioxidant is more potent than others are in most cases meaningless.

For vitamin E the form used is of paramount importance. Vitamin E has received major attention


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because:2

● A large body of research supports its benefits in aging, heart disease, some cancers, Alzheimer's and other chronic diseases.

● The effective levels for disease prevention and management are significantly higher than what we can get from our diet, even a well balanced diet.

Why is the form of vitamin E so important? Unlike some vitamins which consist of a single compound, vitamin E consists of eight different compounds, four tocopherols and four tocotrienols (designated as alpha, beta, gamma and delta). Our food contains all eight compounds. Most vitamin E supplements, however, contain only alpha-tocopherol because it was thought that only this one was important. Recent research proved this understanding wrong. Particularly important is the emerging research on the role of tocotrienols.2

Alpha-tocopherol is available commercially in the naturally occurring d-alpha and the synthetic dl-alpha-tocopherol form. Unlike the natural form, which is a single entity, the synthetic is a racemic mixture of eight stereoisomers. Recent research, led by the National Research Council of Canada, showed conclusively that the naturally occurring form is more bioavailable than the synthetic and that the assigned IU value significantly underestimates this advantage.3 A recent report showed that the transfer of the synthetic from the mother to the fetus was very poor compared to the naturally occurring form.4

Alpha-tocopherol is also available in the free tocopherol or the esterified form (usually as acetate and succinate). In the esterified form the antioxidant group is blocked. When taken orally, esterases hydrolyze the ester to the free tocopherol form. When applied topically on the skin, the esterified form must enter into the skin before enzymes release the free tocopherol form. Most commercial skin care products contain esterified alpha-tocopherol, usually the synthetic dl-alpha-tocopheryl acetate.2

Only products that contain all eight members of the vitamin E family - tocopherols plus tocotrienols – in their natural unesterified form provide the full spectrum of benefits of vitamin E.

Product chemical form, formulation and bioavailability determine the effective dose. Beta-carotene provides an excellent example.

Naturally derived beta-carotene is a mixture of the cis and trans forms and usually contains small amounts of alpha and gamma-carotenes, other carotenoids, and many other natural components. Although the significance of taking the trans form versus the mixture of cis and trans is not clear (cis is converted in the body to trans), the other carotenoids and natural components can have a biological effect.5

Absorption of beta-carotene from fresh raw vegetables may be as low as 10-20%. It is higher in cooked vegetables and juices In commonly used commercial products, beta-carotene is formulated as water dispersible beadlets and its absorption can be as high as 90%. Thus from an intake of 10


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milligrams of beta-carotene from raw vegetables only 1-2 milligrams is absorbed while as much as 9 milligrams may be absorbed from a commercial formulation (4.5 to 9 times more). The implications are very high both for the dose delivered to the body but also for its impact on the antioxidant status of the digestive system (non-absorbed antioxidants can have a major effect).

Other antioxidants for which the chemical form and/or formulation are very important include vitamin E (please see above), other carotenoids, and coenzyme Q10 (CoQ10).

The product chemical form, formulation and bioavailability are important considerations in choosing antioxidant products and the dose to be used.

Disease conditions, physiological status and medications have a major impact on absorption, secretion and requirement for antioxidants. Pancreatic insufficiency and/or a diminished bile acid pool affect significantly absorption of lipophilic compounds including antioxidants. For example, malabsorption of lipohilic antioxidants such as vitamin E and carotenoids is well documented in cholestatic and cystic fibrosis patients. Diseases associated with inflammation, infection or substantial change in the microflora of the gut can reduce the absorption of nutrients and antioxidants. Inflammatory bowel disease (IBD) is associated with malabsorption, due to inflammation, diarrhea, and resection of the gut. Colonization of the gut by harmful fungi or bacteria, liver damage and diarrhea are common causes of malabsorption in AIDS patients. The potential effect of medications on overall absorption is well documented (please see reference 2 for details.)

The overall stress (including emotional stress) caused by disease, prescription medications and complications increase the production of free radicals and the demands on the antioxidant system. Finally the physiological status such as aging and menopause can increase the demands on the antioxidant system; aging also affects absorption.

Special formulations can overcome, at least in part, malabsorption. For example, d-alpha-tocopheryl polyethylene glycol 1000 succie (TPGS), a water-soluble form of vitamin E is absorbed well by cholestatic patients.6

Higher dose and special formulations may be required in the management and treatment of disease and for different physiological stages such as aging and menopause.

Food versus supplements. Food is by far the preferred source of antioxidants. For some antioxidants, such as vitamin E, it is almost impossible, to obtain from the food the amounts believed to be required for prevention of disease and wellness.2 For most antioxidants, it is difficult to obtain from the food therapeutic levels. Synthetic antioxidants can be identical to the natural (vitamin C) or quite different both in the molecule or the group of compounds commercially available (vitamin E).

While food is the preferred source of antioxidants, supplementation may be needed to achieve effective levels for prevention of disease and wellness and for therapy.

Safety should be a major consideration. Most antioxidants have a wide margin of safety.7 Pro-


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oxidant effects of antioxidants at high doses have been clearly demonstrated in vitro, but their occurrence in vivo appear rare and their significance remains controversial. Safety, however, must be seriously considered when high levels are used and in disease conditions where interactions with medications can take place. For example, high doses of beta-carotene appeared to have adverse effects in smokers. Vitamin E decreases platelet aggregation and can affect anticoagulant therapy.2 Vitamin C can be harmful in hemochromatosis patients.

Safety of large doses of antioxidants becomes a major consideration in specific disease conditions or in people receiving some specific medications.

PRACTICAL RECOMMENDATIONS

Recommendations are provided for the following antioxidants: Vitamin E (tocopherols plus tocotrienols) Vitamin C Carotenoids (beta-carotene, lycopene, lutein, astaxanthin) CoQ10

Lipoic acid Selenium

This is only a partial list of antioxidants which have practical significance based on research. The practical significance of many antioxidants has not been evaluated. A very large number of phytochemicals (flavonoids, sterols, tannins), some hormones (melatonin), and enzymes such as superoxide dismutase (SOD) have antioxidant properties. They will not be discussed here either because their biological effects appear to be in large part related to other properties or because they cannot be easily obtained from the food or as supplements.

Vitamin E (tocopherols plus tocotrienols)

It is extremely important to take products that contain natural tocopherols plus tocotrienols in order to get the full range of benefits of the vitamin E family of compounds. While individual needs differ, the following general guidelines are helpful.

● The 100/100 level –100 IU plus 100 mg of mixed tocopherols and tocotrienols. For healthy young adults with no family history of chronic disease.

● The 200/200 level – 200 IU plus 200 mg of mixed tocopherols and tocotrienols. For young adults with some risk factors and healthy people without risk factors up to 40 years old.

● The 400/400 level – 400 IU plus 400 mg of mixed tocopherols and tocotrienols. This is the level for people over 40 and those their family history for chronic disease, age, level of stress, diet and other factors want to take a higher level.

● Commercial products that contain tocopherols plus tocotrienols in the above ratios are now available (for a list, please see www.vitamine-factor.com)


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Special conditions:1

● Higher levels (under the physician's direction) can be used for people over 60 or with significant risk factors (800/800) and people at high risk or diagnosed with Alzheimer's (1000/1000).

● For people that are at higher risk of heart disease due to family history, increased cholesterol levels, and/or previous heart attacks, high tocotrienol extracts (supplying 100-300 mg tocotrienols/day) are recommended (in addition to the basic levels above).

● People with malabsorption due to cholestasis, cystic fibrosis and other conditions can benefit from the water-soluble form d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) at levels up to 30 IU/kg body weight.6

● Large doses of vitamin E can affect anticoagulant therapy. For this reason, the doses of both vitamin E and anticoagulant therapy must be calibrated by the physician for the specific conditions of the patient.

Vitamin C

Vitamin C is available as ascorbic acid or as mineral salt (often referred as ester C) to reduce its impact on the acidity of the stomach.

● Basic recommendation: 200 milligrams per day. Research from the National Institutes of Health reported that this is an adequate intake level for healthy adults.9

● 200-1,000 milligram per day. This range is for people with increased needs due to smoking, family history of disease and other risk factors.

Special conditions

● Higher levels of vitamin C, even higher than 10 grams per day, have been made popular by Linus Pauling and have been used primarily as adjunct therapy for several diseases. It is important that such doses be administered with the supervision of a physician. Levels above 1.0 gram/day increase the risk of kidney stones.9

● Vitamin C accentuates Fe toxicity in conditions of impaired iron metabolism such as hemochromatosis or transfusion therapy because it enhances the absorption of iron and conversion to its prooxidant form.

Carotenoids

At last count there about 635 identified carotenoids and many of these may have antioxidant and other health benefits. Research to-date has focused on beta-carotene, lycopene, lutein and more recently on astaxanthin. The research evidence for beta-carotene has been controversial especially


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due to the indications of harmful effects in smokers.8,10 It has been suggested that mixture of carotenoids might be safer and more effective. A mixture containing approximately 2-4 mg/day of each of the above carotenoids might be beneficial.

Special conditions10

● Higher doses of carotenoids can help reduce the risk of chronic diseases of the eyes (cataracts, macular degeneration) and some cancers.

● Beta-carotene. Doses of 2-5 mg/day are considered safe and may help reduce the risk of cataracts and some cancers and boost some immune responses. Doses above 15 mg/day (especially of the highly absorbable water-dispersible form) should be avoided for smokers.

● Lycopene. At doses of 5-15 mg/day it can help decrease the risk of some cancers especially prostate cancer. Even higher doses, up to 30 mg/day have been used.

● Lutein. At doses of 4-20 mg/day may reduce the risk of chronic eye diseases. ● Astaxanthin: There is only limited research on its benefit and effective dose. Doses of 4-10

mg/day may be used to reduce the risk of chronic eye diseases.

Coenzyme Q10 (CoQ10)

Because of its role in the normal function of the mitochondria, CoQ10 has been used to treat heart disease, and is being evaluated for its role in delaying aging and neurodegenerative diseases including Alzheimer's.11 Supplementation in the range of 10-30 mg/day has been suggested for the maintenance of a strong antioxidant system. It is important to note that absorption of CoQ10 is poor; commercial products formulated for increased absorption are now available.


● Therapeutic dosages of 200-400 mg/day have been used for the treatment of heart disease. ● High levels (100-400 mg/day) have also been used for the treatment of muscle and

neurodegenerative diseases. ● There is no known toxicity concern at these levels.

Lipoic acid

Alpha-lipoic acid (thioctic acid) is a naturally occurring metabolitev and has been used, primarily in Europe, for treatment of diabetes and neurologic diseases. It has been suggested that it interacts with vitamin C and glutathione, which may in turn recycle vitamin E.12 Supplements of 50 mg/day lipoic acid have been suggested for the maintenance of a strong antioxidant system.


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● Therapeutic dosages of 200-1000 mg/day have been used for the treatment of diabetes and associated complications.

● Therapeutic doses up to 1200 mg/day have been used for the treatment of neuropathy

Selenium

Although not an antioxidant, selenium is a cofactor of the important antioxidant enzyme, glutathione peroxidase. There are strong indications for the role of selenium in prevention of chronic diseases, especially cancer.13 An intake of 200 micrograms per day supports a strong antioxidant system.

Special conditions

● Supplementation with selenium above 400 micrograms/day might be beneficial for prevention and treatment of cancer and other diseases. Due to the high toxicity of selenium such supplementation should be under the supervision of a physician.

Other antioxidants

A number of compounds have significant biological effects including antioxidant activity supported by clinical evidence. These include phytosterols, isoflavonoids, and extracts of gingo biloba, St. John's wort and saw palmetto.

REFERENCES

1. Õzer NK, Azzi A. Beyond antioxidant function: other biochemical effects of antioxidants. In Antioxidant Status, Diet, Nutrition and Health, Papas AM Editor, CRC Press, Boca Raton, 1998;449-460

2. Papas AM. The Vitamin E Factor, HarperCollins Publishers, Inc., New York, NY. 1999 (www.vitamine-factor.com)

3. Burton GW, Traber MG, Acuff RV, et al. Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr 1998;67:669-684

4. Acuff RV, Dunworth RG, Webb LW, et al. Transport of deuterium-labeled tocopherols during pregnancy. Am J Clin Nutr 1998;67:459-464

5. Parker RS. Absorption, metabolism, and transport of carotenoids. FASEB J 1996;10:542-51 6. Sokol RJ, Butler-Simon N, Conner C, et al. Multicenter trial of d-alpha-tocopheryl

polyethylene glycol 1000 succinate for treatment of vitamin E deficiency in children with


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chronic cholestasis. Gastroenterology 1993;104:1727-173 7. Diplock AT. Safety of antioxidant vitamins and beta-carotene. Am J Clin Nutr 1995;62:1510S-

1516S 8. ATBC Study Group. The effect of vitamin E and beta-carotene on the incidence of lung

cancer and other cancers in male smokers. New Engl J Med 1994;330:1029-1035 9. Levine M, Rumsey SC, Daruwala R, Park JB, Wang Y. Criteria and recommendations for

vitamin C intake. JAMA 1999;281:1415-23 10. Rock CL. Carotenoids: biology and treatment. Pharmacol Ther 1997;75:185-97 11. Biofactors, 1999;9:87-378 (several review papers on CoQ10) 12. Packer L, Witt EH, Tritschler HJ. alpha-Lipoic acid as a biological antioxidant. Free Radic Biol

Med 1995;19:227-50 13. Clark LC, Dalkin B, Krongrad A, et al. Decreased incidence of prostate cancer with selenium

supplementation: results of a double-blind cancer prevention trial. Br J Urol 1998;81:730-734

ANDREAS M. PAPAS, Ph.D.

Author of The Vitamin E Factor paperback and editor of the scientific book Antioxidant Status, Diet, Nutrition and Health, Dr. Papas is Senior Technical Associate at Eastman Chemical Company and Adjunct Professor, of the College of Medicine of East Tennessee State University and Senior Scientific Advisor, Cancer Prevention, Institute Harvard School of Epidemiology. A Fulbright Scholar, Dr. Papas is a graduate of the University of Illinois and an expert on vitamin E and antioxidants.

Correspondence to:

Andreas M. Papas, Ph.D.

Eastman Chemical Company P.O. Box 1974 Kingsport, TN USA 37662-5230

TEL: (1)-800-695-4322 x-8747 (US and Canada) (1)-423-229-8747 (international)

FAX: (1)-423-224-0414

E-mail: [email protected]

Web page: www.vitamine-factor


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