Antioxidants
Description
Antioxidants are those substances, or molecules, that react with reactive oxygen molecules (i.e. free radicals and singlet oxygen), thereby limiting or reducing them (i.e. catabolism). Antioxidants (free radical scavengers) are found naturally in food, or are available as dietary supplements and botanical products; many of which are very familiar to most consumers, these days.
There are seven different types, or species, of antioxidants. For each free radical, there is a complementary antioxidant or "free radical scavenger" specifically acting against a free radical species. These pairings are provided in the "Therapeutic Approaches" section of this topic.
Antioxidants
First line defense protection against free radicals often comprises:
· Vitamin A
· Beta carotene
· Vitamin C
· Vitamin E
· Selenium
· Zinc
Free radicals
Free radicals are generated as an ordinary process of oxygen metabolism.
Free radicals are highly reactive chemical (i.e. oxygen) species that target the sulfhydryl bonds in proteins, nucleotides in DNA and polyunsaturated fatty acids in cell membranes. Excess free radicals need to be controlled, or reduced, since they can cause cell injury, dysfunction or death, resulting in inflammation or eventual degenerative disease states.
The human body is under constant attack by reactive oxygen molecules. (Byers, 1992) The nuclear DNA in every human cell receives an estimated 10,000 oxidative "hits" per day. (Ames, 1993)
While it is easy to assign free radicals to an entirely destructive role, they also participate in essential physiological functions, including prostaglandin production and phagocytosis.
Similarly, iron performs as an antioxidant. Unfortunately, iron is also a prooxidant and may contribute to e.g. Parkinson's disease. (Pezzella, 1997)
Oxidative stress
Oxidation is a complex process that, in many respects, defies comprehension. It may be helpful to think of free radicals and antioxidants as co-players in a team game, rather than opposing forces in a war.
Oxidative stress describes the condition of oxidative damage resulting when the critical balance between free radical generation and antioxidant defenses is unfavorable. (Sies, 1991)
Both are essential to the state of health, so long as the correct balance is maintained.
This "balance" occurs in terms of energy, not even between atoms of one or the other but involving their respective electrons. Electrons are in a balanced state when they orbit the nucleus in pairs. When one electron is donated (i.e. oxidation) the survivor is thrown out of balance and constitutes a "free radical", or unpaired electron. It aggressively seeks a replacement electron to get back in balance, paradoxically, termed a "redox" or reduction reaction. There is a chain reaction, as each atom robs the next and so on down the line.
Since an electron transfer involves a donor and an acceptor, oxidation and reduction always go together. In a sense, the "antioxidant" donor and "free radical" acceptor merely exchange roles!
The birth of the field of free radical biology is credited to the late Dr. Linus Pauling, as far back as the 1920s. It is not a coincidence that Pauling went on to champion vitamin C, which is the most abundant water-soluble antioxidant in the body. (Frei, 1989)
Toxicity
Some antioxidants are proven and safe (i.e. alpha-tocopherol, beta-carotene, catechin, coenzyme Q10, Ginkgo biloba, melatonin, pycnogenol, Vaccinium myrtillus, vitamin C etc.), while others may have an antioxidative effect (to "quench" free radicals) but are potentially toxic (i.e. BHT). The reader is advised to read the section on "Toxicity" to become knowledgeable about some of the risks of supplementing with antioxidants that are potentially toxic.
Increased dietary levels of antioxidants may reduce the immediate incidence of free radical species and the long-term incidence of certain degenerative diseases.
Diseases which may originate with oxidation:
A wide range of diseases have been identified with either an excess generation of free radicals, or an inadequate antioxidant defense system. (Cheeseman, 1993)
· Atherosclerosis
· Cataractogenesis
· Emphysema
· Malaria
· Multiple sclerosis
· Muscular dystrophy
· Nephrotic syndrome
· Pancreatitis
· Parkinson's disease
· Rheumatoid arthritis,
· Repurfusion injury following organ transplantation etc.
References:
Ames, BN et al., Oxidants, antioxidants and the degenerative diseases of aging. Proc. Natl. Acad. Sci. USA. 1993, 90:7,915-7,922.
Byers, T & Perry, G: Dietary carotenes, vitamin C, and vitamin E as protective antioxidants in human cancers. Annu. Rev. Nutr. 1992, 12:139-159.
Cheeseman, KH & Slater, TF: An introduction to free radical chemistry. Br. Med. Bull. 1993, 49:481-493.
Frei, B et al., Ascorbate is an outstanding antioxidant in human blood plasma. Proc. Natl. Acad. Sci. USA. 1989, 86:6,377-6,381.
Pezzella, A et al., Iron-mediated generation of the neurotoxin 6-hydroxydopamine quinone by reaction of fatty acid hydroperoxides with dopamine: a possible contributory mechanism for neuronal degeneration in Parkinson's disease. J Med Chem, 1997 Jul 4, 40:14, 2211-6.
Sies, H (Ed): Oxidative Stress: Oxidants and Antioxidants. NY. Academic Press, 1991.
Method of Action
The birth of the field of free radical biology can be credited to Dr. Linus Pauling as far back as the 1920s. A variety of additional terms have been developed but the theme remains constant. Pro-oxidants may be termed: free radicals, hydroxyl radicals, lipid peroxides or superoxides etc.
Harman (1956) was the first to note (in print) that free radicals increase with metabolic activity and are related to alterations in biological oxidation/reduction reactions. His interest area was gerontology. He suggested that aging and its associated diseases represent side-effects of free radicals at the cellular level. He even anticipated the protection of antioxidants!
Fridovich (1970s) featured superoxide as a key oxidant, created as a consequence of the univalent reduction of molecular oxygen to a free radical.
Sies (1985) coined the term: "reactive oxygen species" (ROS) as a state of oxidative stress i.e. a disturbance of the pro-/anti-oxidant balance in favor of the pro-oxidant state.
All oxidant damage in biological systems arises from molecular oxygen. Molecular oxygen can scavenge carbon-based free radicals to form organic peroxyl radicals and organic hydroperoxides.
An free radical derives its instability and reactivity from having an odd number of electrons and a single unpaired electron in its outer orbit. A free radical can be reduced in 2 one-electron steps to hydrogen peroxide.
In the two step process, superoxide anion is an intermediate. The antioxidant can also be reduced enzymatically so no superoxide is released, such as through the action of superoxide dismutase (SOD).
Hydrogen peroxide or organic hydroperoxides can diffuse through cell membranes with no subsequent cell damage, whereas antioxidants, such as hydroxyl radicals or superoxide radicals, are not capable of exiting the cell.
All biological molecules containing iron can potentially donate the iron and act as chain reaction initiators and propagators. Chain reactions initiated by chelated iron and peroxides can cause tremendous cellular damage. Often the resultant antioxidants are less reactive but have a longer half-life, allowing for extended time to damage cells. Chain carriers facilitating this process are chelated ferrous ion, hydroxyl radical (.OH), alkoxyl radical (.OR), and the superoxide anion or organic peroxyl radical (RO2). Of these radicals, .OH and RO2 are the most harmful.
The susceptibility of certain tissues to free radical damage provides a model for understanding the role of antioxidants. The lung is an excellent model system for studying damage from antioxidants. With the simple act of breathing, the lung is brought into constant contact with oxygen-derived free radicals. The lung is subject to oxidant stresses from exposure to oxygen in the air and airborne sources of antioxidants, such as smog and ozone. In the lung, antioxidants mainly result from the monovalent reduction of molecular oxygen. The most reactive oxygen metabolite is hydroxyl radical, .OH, whose existence seems from all evidence to be dependent upon the availability of iron chelates.
Antioxidants are also normal products of cell metabolism. For example, activated macrophages release oxygen metabolites necessary for bacterial killing during the respiratory burst. Enzymatic (superoxide dismutase - SOD, catalase and glutathione peroxidase) and non-enzymatic (reduced glutathione, vitamin E, vitamin C) antioxidants provide resistance to oxidant stress in the lungs.
Erythrocytes offer another model for understanding the scavenging effects of certain antioxidants. Erythrocytes are highly susceptible to peroxidation. Their membranes are continuously exposed to high concentrations of oxygen, contain a highly reactive transition metal catalyst and are rich in polyunsaturated fatty acids. Auto-oxidation is controlled very efficiently by protective antioxidant mechanisms, such as the cellular enzymes as superoxide dismutase, glutathione peroxidase and vitamin E, and the compartmentalization of potentially reactive cellular structures.
Therapeutic Approaches
The following list of Free Radical species includes the typical name for the species and the antioxidant (free radical scavenger) reducing, or limiting, its activity.
The list is followed by a discussion of some of the more therapeutically important antioxidants available through the diet or supplementation.
| Free Radical | Free Radical Scavenger |
| Superoxide anion radical | Superoxide dismutase (SOD) |
| Vitamin C (ascorbate) | |
| Reduced Glutathione (GSH) | |
| Tyrosamine | |
| Hydrogen peroxide | Glutathione peroxidase |
| Catalase | |
| Hydroxyl radical | Mannitol |
| Polyunsaturated fatty acids | |
| Methionine | |
| Guanine, cytosine, uracil | |
| Uric acid | |
| Vitamin C (ascorbate) | |
| Benzoate | |
| Butanol, ethanol | |
| Singlet Oxygen | Histidine |
| Beta-carotene | |
| Alpha-tocopherol | |
| Polyunsaturated fatty acids | |
| GSH | |
| Uric acid | |
| Bilirubin | |
| Cholesterol | |
| Polyunsaturated | Beta-carotene |
| fatty acid radical | Alpha - tocopherol |
| Organic/fatty acid | Glutathione peroxidase |
| hydroperoxides | Possibly other peroxidases |
| Oxidized protein | GSH |
| Sulfhydryl amino acids |
Some very strong antioxidants, such as the botanical Silybum marianum, do not work directly on specific free radical species. Rather, these scavengers prevent the depletion of reduced glutathione (GSH) by alcohol and liver toxins, while also increasing the basal GSH level of the liver by 35%. This may be the basis for the benefits conferred by Silybum on several types of liver diseases, including cirrhosis, chronic hepatitis, fatty infiltration of the liver due to alcohol or certain chemicals, subclinical cholestasis of pregnancy, cholangitis and pericholangitis. The antioxidant activity of Silybum marianum is many times more potent than that of alpha-tocopherol.
Similarly, anthocyanosides, like Vaccinium myrtillus with a 25% anthocyanidin content, prevent free radical damage with their potent antioxidant action.
Catechin, (+)-cyanidanol-3, is found in black and pale catechu, black cutch and gambier. This naturally occurring flavonoid has strong free radical scavenging effects. It has been shown to prevent carbon tetrachloride, ethanol and bromotrichloromethane hepatotoxicity, probably owing to its sparing effect on glutathione.
Ginkgo biloba, rich in terpenes, flavonoids, proanthocyanidins, and gingko heterodies (flavoglycosides), has shown free radical scavenging activity.
Vitamin C (ascorbate) is capable of scavenging superoxide radical and hydroxyl radical.
Vitamin E (alpha-tocopherol) is the best documented free radical scavenger. Vitamin E, particularly, alpha-tocopherol, may be the most important lipid-soluble free radical scavenger circulating in the blood plasma. Dietary tocopherol enhanced the endurance of rats doing heavy exercise, while protecting against the exercise-induced lipid peroxides which are normally produced. Supplementation with vitamin E may therefore be of some benefit for individuals engaged in strenuous exercise. Vitamin E and selenium work synergistically to protect against oxidative stress.
Beta-carotene (pro-vitamin A)
There is growing epidemiological and clinical evidence beta-carotene may protect against certain cancers in humans. It has been used successfully to treat various pathologies triggered by light that are possibly mediated by singlet oxygen radical.
Superoxide Dismutase (SOD)
SOD is an enzyme available as an injectable generic drug called orgotein. SOD is a metalloenzyme, and thus requires the presence of adequate concentrations of metals, such as zinc, copper and manganese. SOD molecules circulate extracellularly, providing free radical scavenging effects against superoxide anion radicals.
Treatment approaches:
Naturopathic treatment (after Murray) may include antioxidants, usually several. Let's take arthritis, asthma and hayfever as examples.
Arthritis
An extensive arsenal of antioxidants has been launched against arthritis, including:
B15 12.5 mg
Niacinamide 900 - 4,00 mg
Vitamin C 500 - 1,000 mg (plus bioflavonoids)
Vitamin E 600 iu
Manganese SOD 5 - 15 mg
Selenium 50 - 200 mcg
Sulfur
Zinc 30 - 45 mg
Asthma
Vitamin C with Quercetin
Vitamin E
Selenium
Hayfever
An identical selection to that for asthma:
Vitamin C with Quercetin
Vitamin E
Selenium
Toxicity Factors
Toxicity varies with the antioxidants. Please refer to the "Toxicity" section of the individual antioxidant, for specifics.
A number of touted "antioxidants" were intentionally excluded from discussion because of their toxicity. Most notable is the popularized recommendation to supplement with either butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). BHT and BHA are two common food preservatives that prevent polyunsaturated fats from going rancid. Although both are listed as "generally recognized as safe" (GRAS) by the U.S. Food and Drug Administration (FDA), the FDA limits the amount of either BHT or BHA to 200 ppm of fat or oil content, including essential (volatile) oils.
Quantities of BHT or BHA popularly recommended as antioxidants or "anti-aging" supplements, considerably exceed these levels. A review of the safety of BHT and BHA at the levels popularized and recommended was published in 1983. This review concluded experimental animal given BHT or BHA at levels above those recommended by the FDA showed evidence of mutagenicity, carcinogenicity and teratogenicity.
Further, although the literature suggests BHT may prolong the life span, it can have a negative effect on the lungs, kidneys, myocardium and clotting factors. BHT also adversely affected metabolism of lipids by the liver and had demonstrable teratogenicity. BHT or BHA supplementation should therefore be avoided during pregnancy.
Research shows that while BHT ameliorates the toxicity and carcinocenicity of some chemicals and physical agents, it potentiates the toxicity and carcinogenicity of others.
Finally, toxicology of any antioxidant or free radical scavenger warrants particular attention in patients with various diseases or conditions. Although beta-carotene, alpha tocopherol, and vitamin C have very low toxicity, some antioxidants, such as BHT, are hazardous to certain vulnerable populations. In a review by Babich of ten studies done in humans, the following conditions were found to predispose individuals to a highest risk of BHT intoxication:
Cardiovascular disease
Vitamin K deficiency
Hepatic disease (including abnormalities of lipid metabolism)
Pulmonary disease
Renal disorders
Intestinal disorders
The fetus was exceptionally sensitive to BHT intoxication. Therefore, caution should be exercised with any antioxidant supplement, until its toxicology has been established in both animals and humans.
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