UNDERSTANDING ANTIOXIDANTS

Candace F. McDaniel, D.O., Ed.D

Oxidative stress has been implicated as a contributory factor in many disease processes1,2,3 (Table 1). Natural antioxidant defenses have been found to be defective in many of the same diseases.1,4,5 If disease is associated with an imbalance of oxidative stresses and antioxidant defenses, it should be possible to limit oxidative damage and prevent disease progression by supplementing and/or enhancing natural antioxidant defenses.1 Potential health promoting interventions might support natural enzyme antioxidants, natural preventative antioxidants, and/or scavenging antioxidants.

What is a Free Radical Oxidant?
A Free Radical Oxidant (FRO) is a chemical species capable of independent existence that contains one or more unpaired electrons. The FRO species is energetically unstable and highly reactive. It seeks stability by removing an electron from a surrounding molecule and adding the electron to its own unpaired electron, thus becoming a stable molecule. The attacked molecule from which the electron was taken now possesses an unpaired electron and has become a free radical. In this way, a single free radical initiates a sequence of electron transfers called oxidation-reduction (redox) reactions.

What Do Free Radicals Do?
Free radicals disrupt the equilibrium of biological systems by damaging major cell constituent molecules. This disrupts cell membrane function, which may eventually lead to cell death. Free radicals attack substances such as DNA, breaking single and double strands and destroying DNA bases by attaching to phosphate groups anddeoxyribose sugars. This process is a likely etiology of aging. Free radicals can fragment, cross-link and aggregate proteins, which causes interference with sodium, potassium and ATP ion channels and leads to cell receptor failure.6 These events have been implicated as a cause of mutagenesis and carcinogenesis.7

What Are Antioxidants?
Antioxidants are substances that, even in relatively low concentrations, significantly inhibit the rate of oxidation caused by FROs. Antioxidants can be classified into groups based on how they work and where they are found. For convenience, five major classes of antioxidants have been delineated: natural enzyme antioxidants, natural preventative antioxidants, scavenging antioxidants, dietary antioxidants, and pharmacological antioxidants.1,5
Natural enzyme antioxidants are found in the intracellular environment and include superoxide dismutase (SOD), catalase, and glutathione peroxidase. Catalase is found inside the heme molecule. Glutathione peroxidase contains selenium and helps prevent formation of the highly destructive hydroxyl radical. It regenerates vitamin C, which in turn regenerates vitamin E. It requires nicotinamide-adenine dinucleotide phosphate (NADPH) and is produced from the pentose phosphate pathway.1
Natural preventative antioxidants are found in plasma, the straw-colored portion of the blood. Natural preventative antioxidants include transferrin, a major

iron transporting protein; lactoferrin, an iron binding protein in milk; ceruloplasmin, a copper-containing protein that enhances iron binding to transferrin; and albumin, a weak copper-binding protein that is the major antioxidant of plasma. Albumin has sulfhydryl or thiol groups which contribute to the scavenging antioxidant activity of plasma.1 Natural preventative antioxidants are decreased with hyper-glycemia.5
Scavenging antioxidants are found in the plasma and/or serum. They include uric acid, bilirubin, sulfhydryl or thiol, vitamin C, vitamin E, beta-carotene, ubiquinol, flavonoids, melatonin, possibly vitamin A and some estrogens.1,10 Scavenging antioxidants are either water or lipid soluble. Uric acid comprises at least 44% of the antioxidant activity of the plasma, and approximately 30% of plasma antioxidants remain unidentified.5 Vitamin C is a major water soluble antioxidant that inhibits lipid peroxidation and is regenerated intracellularly by glutathione peroxidase. Thiols are contributed by albumin in the plasma. Thiols such as acetylcysteine regenerate glutathione peroxidase. Vitamin E tocopherols are major lipid-soluble antioxidants that prevent lipid peroxidation in lipoproteins and biological membranes. Vitamin E is regenerated by vitamin C. Beta-carotene is a lipid-soluble vitamin A precursor that is synergistic with vitamin E and prevents lipid peroxidation. Ubiquinol, the reduced form of coenzyme Q-10, is lipid soluble and regenerates vitamin E.1 Flavonoids are polyphenolic compounds present in foods such as fruits, vegetables, tea, and wine that may play a role in the prevention of disease.7,8,9 Melatonin is an indole that scavenges the highly toxic hydroxyl radical, neutralizes the peroxyl radical and stimulates glutathione peroxidase in the brain.10 Estrogens are female hormones that may possess some antioxidant activity.

Dietary antioxidants are commonly found in tea, wine, fruits, and vegetables.7,8,9 Green tea, called “sencha,” particularly has large amounts of vitamin C and phenolic compounds.7 Wines contain polyphenols, vitamin C and some B vitamins.8 Fruits and vegetables, harvested at maturity, contain various flavonoids, carotenoids, lycopenes, zeaxanthins, phenols, indoles and luteins.11 Dietary antioxidants are the safest antioxidants for long-term consumption.
Pharmacological agents that have direct or indirect antioxidant activity include acetylcysteine, which donates thiols; SOD, which is prolonged by conjugation with albumin; catalase; glutathione peroxidase, which is enhanced by selenium supplementation; deferoxamine, which is an iron chelator; Probucol, a lipid-soluble drug that prevents oxidation of lipoproteins and is regenerated by vitamin C; salicylates, which are free radical scavengers; lazaroids, or 21-aminosteroids, that are inhibitors of iron-dependent lipid peroxidation; mannitol, which is a hydroxyl radical scavenger; dimethyl sulfoxide, or DMSO, which is a hydroxyl radical scarveger; dimethyl thiourea, or DMTU, which is a hydroxyl radical scavenger; Captopril, an angiotensin converting enzyme inhibitor; Amiodarone, a cardiac antiarrhythmic agent; Allopurinol, used in treating gout and/or hyperuricemia; Adenosine, a cardiac anti-arrhythmic and albumin;1Carvedilol, a cardiac beta-blocker; Rezulin, a new diabetic medication. All of the above drugs have well-documented toxicities and side effects. They require medical supervision and generally are not suitable for long-term use.

An attempt has been made to simplify the complex, interdependent relationships between antioxidant molecules and allude to what the human body requires to maintain health and ward off disease. Oxidation has been implicated as a cause of or a result of many diseases.2 It appears that supplementing dietary antioxidants and enhancing natural antioxidants with nutraceuticals may be an achievable, valid means to the goal of improving health for all. The light of knowledge is beginning to penetrate the dark ignorance of nutrition and biochemistry and their profound influence on health and disease. These natural processes have been operational since the beginning of time, only awaiting comprehension and application. The antioxidant and other yet unknown benefits of food and the importance of diet are now becoming recognized and utilized for their potential to promote health and possibly prevent disease.

Candace McDaniel earned her doctorate in Osteopathic Medicine (DO) from Oklahoma State University College of Osteopathic Medicine and her doctorate in education (EdD) from the University of Tulsa, Oklahoma. Dr. McDaniel is currently the Medical Director of Fisher Institute for Medical Research.

References
1. Maxwell SRJ. Prospect for the use of antioxidant therapies. Drugs 1995;49(3):345-361.

2. Barhoumi R, Burghardt RG, Busbee DL, McDaniel HR. Enhancement of glutathione levels and protection from chemically initiated glutathione depletion in rat liver cells by glyconutritionals. Proc Fisher Inst 1997;1:12-16.

3. Parke DV. Chemical toxicity and reactive oxygen species. Int J Occup Med Environ Health 1996;9(4):331-340.

4. Vijayalingam S, Parthiban A, Shanmugasundaram KR, Mohan V. Abnormal antioxidant status in impaired glucose tolerance and non-insulin-dependent diabetes mellitus. Diabet Med 1996;13(8):715-719.

5. Asayama K, Uchida N, Nakane T, Hayashibe H, Dobashi K, Amemiya S, et al. Antioxidants in the serum of children with insulin-dependent diabetes mellitus. Free Radic Biol Med 1993;15(6):597-602.

6. Sevenian A, Hochstein P. Mechanisms and consequences of lipid peroxidation in biological systems. Annu Rev Nutr 1985;5:365-375.

7. Scholes RG. Radiation effects on DNA. Br J Radiol 1983;56:221-231.

8. Watkins TR, ed. Wine: Nutritional and Therapeutic Benefits. American Chemical Society. Washington, DC. 1997.

9. Rice-Evans CA, Miller NJ, Bolwell PG, Bramley PM, Pridham JB. The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radic Res 1995;22(4):375-383.

10. Reiter RJ. Oxidative processes and antioxidative defense mechanisms in the aging brain. FASEB J, 1995;9(7):526-533.

11. DeCava J. Vitamin A. In: Health Science Series #5: The Real Truth About Vitamins And Antioxidants. Brentwood Academic Press. Columbus, Georgia. 1996:83-101.

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