Antioxidant

Oxidative Stress and Antioxidants The Antioxidant Network aLipoic Acid and Diabetes

In this introductory chapter, oxidative stress in diabetes and implications of antioxidant treatment are considered. It is thought that free radicals may play a major role in aging and disease. Free radicals arise from radiation, environmental chemicals, cigarette smoke, and various other environmental sources. In addition, all through our life, we have a fire burning inside of us our own body metabolism, which generates free radicals. Finally, many environmental substances (as well as drugs and alcohol) are metabolized in our body, generating free radicals through cytochrome P450-mediated oxidations. Many free radicals can be cytotoxic. However, free radical reactions are also essential. They are essential for enzymes and for host defense mechanisms such as neutrophils, macrophages, and other cells of the immune system. Free radicals are important in the activation of transcription factors and in cell signal transduction and gene expression. But if free radicals are overproduced,...

Definition Of An Antioxidant

What is an antioxidant To find a definition, we went to the dictionary. Dor-land's Medical Dictionary reports (2), An antioxidant is one of many widely used synthetic or natural substances added to a product to prevent or delay deterioration by action of oxygen in the air. Examples of such products to which antioxidants may be added are rubber, paint, vegetable oils, and so on. But there are many other definitions of an antioxidant. For example, Halliwell and Gutteridge (3) defined an antioxidant as any substance that, when present at low concentrations compared to those of an oxidizable substrate, significantly delays or inhibits oxidation of that substrate. Another definition of an antioxidant (and the one I favor) is that of a metabolic antioxidant (4,5) An antioxidant is a substance which protects biological tissues from free radical damage, which is able to be recycled or regenerated by biological re-ductants. Thus, metabolic antioxidants have something similar to a catalytic...

The Antioxidant Network

The antioxidant network is composed of redox-sensitive antioxidant substances. I like to say that the hub of the antioxidant network is vitamin C. The antioxidant network usually gets activated by vitamin E (12). After vitamin E is oxidized by oxidants or lipid free radicals, then the vitamin E free radical is formed, which in turn activates vitamin C to regenerate vitamin E nonenzy-matically. Vitamin C itself becomes a radical, the vitamin C radical, in this process. Glutathione, with the aid of enzymes, can reduce the vitamin C radical (or dehydroascorbate, the completely reduced form of vitamin C). The oxidized glutathione thus produced can be reduced through enzymatic reactions that draw on cellular reducing power. There are also substances that we can obtain in our diet or that we can supplement like flavonoids, polyphenols, and lipoic acid that can also act in the antioxidant network (13,14). An example of how the antioxidant network works with respect to vitamin C, vitamin E,...

Free Radicals As Biochemical Entities And Damaging Species

Two recent reviews present excellent overviews of past and present free radical research in biology and medicine 1,2 . The first discovery of solution phase reactive oxygen chemistry is attributed to Fenton, who studied iron hydrogen peroxide chemistry 3 , whereas Gomberg in 1900 demonstrated the existence of an organic free radical. Radiation chemistry studies, beginning in the early twentieth century, led in 1954 to the discovery that free radicals are the molecular basis for oxygen toxicity 4 . The work of Weiss in the 1930s on metal-catalyzed peroxide decomposition, particularly with

The Perception of Antioxidants in America

The average American has come to perceive antioxidants as the first line of defense against aging and chronic disease. Even though scientific studies report conflicting results and do not yet provide specific guidelines, dietary supplement use in the United States, which includes antioxidants, continues to rise. Concern over dietary supplement usage and safety issues due to unquestioned consumer confidence in supplement effectiveness and safety is growing as well. This has prompted many health agencies such as the National Academy of Sciences, Institute of Medicine (IOM), National Institute of Health (NIH), and the World Health Organization (WHO) to study vitamin, mineral, and antioxidant efficacy and use, subsequently issuing statements that establish interventions, consumer education programs, and recommendations. Improvements in living conditions, food supply, and medical care have increased life expectancy in the United States to its current 77.9 year average.1 As a nation we are...

Free Radicals and Immune Cell Function

There are numerous links between free-radical reactions and immune cell functions. White blood cell membranes, as with all cellular membranes, are composed of lipids containing saturated and unsaturated fatty acids. Unsaturated bonds in fatty acids are highly susceptible to free-radical attack, one consequence of which is to adversely affect the integrity of the cell's membranes. For instance, oxygen-containing radicals and the products of their reactions have been shown to decrease the fluidity of white blood cell membranes (reviewed in Baker and Meydani, 1994) and synovial fluids, consequently reducing their function (Merry et al., 1989). Loss of membrane fluidity has been directly related to the decreased ability of lymphocytes to respond to challenges to the immune system (Bendich, 1990, 1994b). Free radicals can also damage DNA and result in mutations, altered capacity of cells to produce critical factors and derangement of the capacity to proliferate. Systemic free-radical...

Antioxidant Depletion by Alkylation Acetaminophen Toxicity

In addition to redox cycling reactions, naphthoquinones such as plumbagin, juglone or the related menadione (2-methyl-1,4-naphthoquinone vitamin K3) may also alkylate cellular components. The carbon atom in position 3 (Figure 3.5c, arrow) stands in conjugation with a carbonyl carbon and may thus be attacked by nucleophiles such as thiols in a Michael-type reaction. Similar structural features and reactivities are found with acrolein or N-acetyl-p-benzoquinoneimine (NAPQI), a metabolite of the important analgesic and antipyretic drug acetaminophen (Figure 3.5c). All these compounds readily alkylate protein-bound thiols or thiols of low molecular mass such as glutathione (g-glutamylcysteinylglycine, GSH). As GSH is an important cellular antioxidant and substrate of glutathione peroxidases (Equation 3.5), its depletion by alkylation will amplify the impact of concomitantly generated oxidants. In the case of the above-mentioned naphthoquinone derivatives, GSH depletion occurs, aggravating...

Clinical studies antioxidants in the elderly

There is evidence that a supplement containing only antioxidants can improve the immune cell profile of aged hospitalized patients. Elderly, who were hospitalized for at least 2 months following a stroke, were given a supplement of 8000 IU of vitamin A, 50 IU of vitamin E and 100 mg of vitamin C for 28 days. Supplementation resulted in an increase in total T lymphocyte numbers and T-helper cell markers as well as enhanced lymphocyte proliferation. It is not possible in this study to differentiate either the direct immunoenhancing effects of vitamin A or its weak antioxidant effects, from the stronger antioxidant effects of vitamins C and E. Improvement in the immunosuppressed state of long-term, hospitalized elderly may decrease the prolonged morbidity often associated with respiratory infections seen in this population (Penn et al., 1991).

Free Radicals are Formed in a Surprising Number of Enzyme Catalyzed Reactions

Free radicals (also simply called radicals) are highly reactive species because they possess one or more unpaired electrons. They are generated by homolysis, which is an intramolecular bond-rupturing reaction, and heterolysis, which is an inherently intermolecular reaction. Homolysis - This intramolecular bond-rupturing reaction generates two free radicals. While depicted (below) as generating products A and B , homolysis of reactant A-A would yield two A- free radicals.

Effect of Antioxidants

Antioxidants can retard lipid oxidation through competitive binding of oxygen, retardation of the initiation step, blocking the propagation step by destroying or binding free radicals, inhibition of catalysts, or stabilization of hydroperoxides (Halliwell, 1994). Antioxidants can scavenge the active forms of oxygen involved in the initiation step of oxidation, or can break the oxidative chain reaction by reacting with the fatty acid peroxy radicals to form stable antioxidant radicals which are either too unreactive for further reactions or form non-radical products.

Synthetic Antioxidants

Synthetic antioxidants which contain phenolic groups, such as gallic acid esters, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and tertiary butyl hydroxyquinone (BHQ), are the most widely used food synthetic antioxidants (Fig. 4.1). The effectiveness of phenolic antioxidants depends on the resonance stabilization of the phenoxy radicals determined by the substitution at the ortho and para positions on the aromatic ring and by the size of the substituting group (Shahidi et al., 1992). The presence of carbonylic and carboxylic groups in numerous phenolic compounds can also result in the inhibition of oxidative rancidity by metal chelation (Hudson and Lewis, 1983). In spite of the widespread use of phenolic antioxidants, there is increasing concern over their safety. The potential toxicity of some phenolic antioxidants in biological models has been described (Thompson and Moldeus, 1988). Thus the replacement of synthetic antioxidants by 'safe, natural' antioxidants such...

Amyloid Deposition Apolipoprotein E And Free Radicals

Studies have demonstrated that ApoE-4 interacts with and precipitates PAP in vitro more readily than ApoE-3.62 Binding of PAP to ApoE-4 was observed in minutes, whereas binding to ApoE-3 required hours. Oxygen-mediated complex formation was implicated because binding was increased in oxygenated buffer and prevented by reduction with dithiothreitol or 2-mercaptoethanol. This finding again suggests that antioxidants may have therapeutic potential in AD (Figure 2.14). Antioxidant therapy Radical Scavengers Antioxidant therapy Radical Scavengers

Introduction Glutathione From Antioxidant to Redox Signal

Glutathione (GSH), the tripeptide Glu-Cys-Gly, is a low molecular weight thiol antioxidant present in high concentrations in most cells, with the exception of some bacteria and amoebae. Due to its thiol features, GSH may give rise to a variety of chemical reactions that are not typical of other nucleophiles, amino or hydroxyl groups (see Chapter 4). In fact, through nucleophilic addition or displacement, oxidation-reduction reactions, thiol disulfide (SH SS) exchange reactions (or thiol disulfide interchange reactions), GSH detoxifies electrophilic and oxidizing agents, preventing their attack on proteins and other macromolecules. The detoxification actions of GSH are often catalyzed by a variety of enzymes (such as glutathione transferase, glyoxalase, glutathione reductase, glutathione peroxidase, glutaredoxin), which form an efficient machinery capable of protecting cells even when GSH levels are low. Despite this, it should be mentioned, however, that few of the studies led to the...

The Antioxidant Controversy

The fact that a number of diseases are associated with oxidative stress drives the theory that antioxidants may represent an intervention strategy in these diseases. However, current evidence from clinical research has not unequivocally substantiated these theories nor demonstrated a causal role of pro-oxidants in age-related diseases. Neither has scientific evidence proved conclusively that dietary antioxidant supplementation can prevent disease or increase longevity in humans. Thus, debate and controversy has arisen among scientists, health care professionals, and the lay public alike regarding the efficacy and wisdom of using dietary antioxidant supplementation to prevent chronic diseases and delay aging.

Smokeless Tobacco Extract And Freeradical Scavenging Effects Of Common Antioxidants In Macrophage Cells

Antioxidants are potent scavengers of free radicals, serve as inhibitors of neoplastic processes and cancer at both initiation and promotion progression transformation stages of carcinogenesis, and provide protection from oxidative damage. A large number of synthetic and natural antioxidants have been demonstrated to induce beneficial effects on human health and disease prevention. In order to determine the possible sources of reactive oxygen species in response to smokeless tobacco, rat peritoneal macrophages (3*106 ml) and hepatic mitochondria and microsomes (1mg protein ml) from untreated female Sprague-Dawley rats were incubated with STE (200 g ml). STE resulted in rapid increases in chemiluminescence, with maximum increases occurring at approximately 6 min for the macrophages and 8 min for mitochondria and microsomes. Maximum increases in chemiluminescence of 1.4-, 3.2-, and 3.1-fold relative to control values occurred for macrophages, mitochondria, and microsomes, respectively....

Free Radicals In Biology

Living organisms are continuously exposed to oxidants from external sources, e.g. air pollution, ultraviolet (UV) radiation, natural radioactive gases and dietary constituents. The production of free radicals and various reactive oxygen species (ROS) is also an inherent phenomenon of the body's normal defence systems and metabolic reactions. There are a number of radicals, primarily oxygen centred, which are considered biologically relevant. A very simplified overview of their interrelations is provided in Scheme 1. There is an elaborate endogenous defence system to control the production and level of these species (Cotgreave et al., 1988). Excessive formation of ROS, however, may lead to degradation or inactivation of essential biomolecules. This has been suggested as a primary or secondary factor in an increasing number of pathophysiological conditions (see Section 1.3). Several excellent textbooks (see, for example, Sies, 1985, 1991 Halliwell and Gutteridge, 1989 Lazar et al., 1989...

In vitro interaction of flavanols with other antioxidants

While flavanols and their oligomers can have direct oxidant scavenging effects, it should be recognized that they can also have indirect effects through their interaction with other antioxidants 13-16 , The data presented in Figure 3 illustrate the above point. When plasma obtained from healthy adult humans (ascorbate 35-55 M and a-tocopherol 24-27 iM) was incubated in the presence of 50 mM AAPH, the consumption of ascorbate followed first order kinetics (k 0.11 min to.s 6.0 min). The consumption of a-tocopherol started once all the ascorbate was depleted (60 min), and also followed first order kinetics (k 4 x 103 min to.s 173 min) (Figure 3 A). When the plasma was oxidized in the presence of 100 fxM epicatechin (Figure 3B) the rate of ascorbate still followed a first order kinetics, but the rate of depletion was significantly reduced (kepi 0.07 min to.s 9.9 min). Interestingly, when plasma was oxidized in the presence of 100 piM (+)-catechin (Figure 3C), the rate of ascorbate...

Antioxidant activity

Oxidation of biomolecules has been identified as a free radical-mediated process (Mendis et al., 2004). Formation of free radicals is an unavoidable consequence in aerobic organisms during the oxygen metabolism, thus believed to be involved in many pathological diseases such as cancer, diabetes mellitus, aging, and Alzheimer's disease (AD Johansen et al., 2005 Kong et al, 2010 Rattan, 2006 Valko et al, 2006). In addition, deterioration of some foods, development of undesirable off-flavor and potentially toxic reaction compounds in food, has been identified as a result of free radical-mediated oxidation of fatty acids and lipids. Oxidation of lipids by reactive oxygen species (ROS) such as superoxide anion and hydroxyl radicals which shorten the shelf life of foods is attracting great concern in food and pharmaceutical industry hence, several synthetic antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ) are widely used to...

Antioxidant Activity of Flavonoids and Phenolic Acids

Free radicals are produced in the body as part of normal metabolism, for example superoxide, O2 - and nitric oxide, NO- which have important physiological functions. In general, free radicals are highly reactive and can attack membrane lipids for example, generating a carbon radical which in turn reacts with oxygen to produce a peroxyl radical which may attack adjacent fatty acids to generate new carbon radicals. This process leads to a chain reaction producing lipid peroxidation products (Halliwell, 1994). By this means a single radical may damage many molecules by initiating lipid peroxidation chain reactions. Because of the potential damaging nature of free radicals, the body has a number of antioxidant defence mechanisms which include enzymes such as superoxide dismutase, catalase, copper and iron transport and storage proteins, and both water-soluble and lipid-soluble molecular antioxidants. Oxidative stress may result when antioxidant defences are unable to cope with the...

Antioxidant Research Synopsis of Past and Current Study Results

Since 1902 the Medline biomedical database has recorded over 228 thousand publications listing the keyword antioxidant(s). This number is likely an underestimate of the true number of journal articles on this subject. It is beyond the scope of this book to review the sum total of this literature however, we can portray how our knowledge has evolved and some of the more popular current theories in the field of free radical biology and medicine. The first antioxidant article, cited in the Medline database, was in 1946 and the author suggested that vitamin C could be used to identify the day of ovulation.2 The next year in which the key word antioxidant was cited was 1950 when suddenly 356 articles were published. Arguably, this marks the date when a relatively large number of scientists within the biomedical community began to grapple with the therapeutic validity of antioxidants and began the serious study of their involvement in radical reactions within biological systems and their...

Antioxidant Enzymes

Free radical defenses of peripheral nerve are reduced relative to brain and liver, especially involving glutathione (GSH)-containing enzymes (9). Cuprozinc superoxide dismutase (SOD) is reduced in sciatic nerve of experimental diabetic neuropathy, and this reduction is improved by insulin treatment (10). Glutathione peroxidase (GSH-Px) is reported to be further reduced in experimental diabetic neuropathy in alloxan diabetic mice 7-21 days after induction of diabetes, and enzyme activity inversely regresses with glucose level (11). We recently evaluated the gene expression of the antioxidant enzymes, GSH-Px, SOD (cuprozinc czSOD and manganese mnSOD separately), and cata-lase (CAT) in L4-L6 dorsal root ganglia (DRG) and superior cervical ganglion (SCG) of rats that had been diabetic for 3 and 12 months (Kishi et al unpublished data). cDNA fragments for rat GSH-Px, czSOD, mnSOD, CAT, and cyclophilin was obtained by reverse transcriptase polymerese chain reaction of rat DRG RNA using...

Enzymatic Antioxidants

The enzymes superoxide dismutase (SOD), catalase and glutathione peroxidase (GSHpx) are the primary antioxidants within the cells (Halliwell and Gutteridge, 1989). SOD acts as a scavenger of superoxide anions by catalysing their dismutation into hydrogen peroxide. Catalase and glutathione peroxidase reduce hydrogen peroxide as well as alkyl hydroperoxides into water and alcohols, respectively (Scheme 3). Both enzymes use the endogenous tripeptide glutathione (y-glutamyl-cysteinyl-glycine) as the sacrificial reducing agent. PHARMACEUTICAL ANTIOXIDANTS Scheme 3 Enzymatic antioxidants

Nonenzymatic Antioxidants

The vitamins C (ascorbic acid, 200) and E (mainly (R,R,fl)-a-tocopherol, 201) are believed to be the major antioxidants in human plasma (Bendich etal., 1986 Halliwell and Gutteridge, 1989 Chow, 1991). Other extracellular defences in human plasma are transferrin (binds iron), lactoferrin (binds iron), ferritin (binds iron), caeruloplasmin (oxidizes Fen to Fern), haptoglobin (binds free haemoglobin), haemopexin (binds free haem), albumin (binds copper, traps HOC1), uric acid (202, binds iron and copper, scavenger), bilirubin (scavenger) and glucose (HO' scavenger). Several of the antioxidant proteins are acute-phase proteins related to inflammatory conditions. Further lipid-soluble antioxidants are 3-carotene (203), bilirubin

Antioxidant Activity of SOYISO

SOYISO have two (daidzein and glycitein) or three (genistein) phenol hydroxyl groups. Phenol hydroxyl groups can scavenge free radicals in vivo and in vitro. Generally, the more hydroxyl groups, the greater the antioxidant capacity (Cao et al., 1997), suggesting that these groups are the chemical basis for the antioxidant properties of isoflavones. Antioxidant activity of SOYISO in vitro and ex vivo studies There are many reports dealing with the antioxidant activity of SOYISO in vitro, at the level of the cell, in enzyme systems and in non-biological systems. antioxidant activity assay, Ruiz-Larrea et al. (1997) determined the order of antioxidant activity of several isoflavones to be as follows genistein daidzein genistin biochanin A daidzin formononetin ononin. However, using a similar method to that used above but measuring production of thiobarbituric acid-reactive substances (TBARS), Mitchell et al. (1998) observed only weak antioxidant activity by genistein and daidzein....

Antiapoptotic Properties Of Antioxidants

Numerous studies have reported the antiapoptotic property of endogenous as well as exogenous antioxidants. Some of these studies showing that antioxidants may protect from apoptosis in a variety of systems have been discussed. Mutations in human Cu Zn superoxide dismutase-1 cause approximately 20 of cases of familial amyotrophic lateral sclerosis. Expression of two familial amyotrophic lateral sclerosis-related mutant superoxide dismutases (A4V and V148G) caused apoptosis of differentiated PC12 cells, superior cervical ganglion neurons, and hippocampal pyramidal neurons, suggesting that superoxide dismutases may have an antiapoptotic function in neuronal cells (Ghadge et al., 1997). The antiapoptotic property of Mn-superoxide dismutase, a mitochondrial antioxidant, has been also reported (Briehl et al., 1997). Thioredoxin peroxidase is a member of a newly discovered family of proteins that are conserved from yeast to mammals and to which the natural killer enhancing factor belongs....

Antioxidant Response and Adaptation to Exercise

An acute bout of strenuous exercise has been shown to alter cellular and tissue antioxidant status profoundly (Ji and Leichtweis, 1997). This is primarily caused by the high levels of ROS production during exercise, but other factors such as altered blood flow, energy status, and availability of reducing power may also influence antioxidant function in the various tissues (Ji, 1995). A good example is the effect of acute exercise on GSH homeostasis (Fig. 6.2). As the most abundant nonprotein thiol source, GSH concentration in the cell is remarkably high (in the millimolar range). GSH not only serves as a substrate for GPX and GST to reduce hydrogen- and organic-peroxides, but also scavenges singlet oxygen and *OH, and reduces tocopherol radicals and semidehydroascorbate radical, thereby preventing lipid peroxidation (Meiser and Anderson, 1983). GSH can be recycled by GR using NADPH as the cellular reducing power. Liver is the primary organ for de novo GSH synthesis and supplies 90 of...

Links Between Wholefood Antioxidants and Heart Disease Cancer and Vision Loss

Antioxidant deficiencies have well-established links to the promotion of specific diseases. This is discussed more fully in other chapters. Antioxidant compounds are accumulated from the diet or synthesized in the body and prevent the chemical oxidation of proteins, lipids and other essential compounds. Industrialization has led to increased environmental pollutants in our air, food and water. Many of these pollutants have the capacity to deplete the body's antioxidant reserves. Antioxidant deficiencies resulting from dietary deficiencies and or increased environmental oxidant stress may be linked to the development of many diseases including heart disease, cancer and vision loss. Red wine is a whole-food product that has been widely associated with antioxidant effects (Renaud and de Lorgeril, 1992 Frankel et al., 1993). It was one of the first whole-food products shown to have measurable antioxidant effects in vivo, including increased resistance of low-density lipoproteins (LDL) to...

Problems Associated with Dependence on One Antioxidant

Over 4000 flavonoids from plant sources have been identified (Kandaswami and Middleton, 1994), in addition to countless non-flavonoid compounds with antioxidant capacities. Indeed, in the 1930s investigators suggested that flavones might be essential to the human diet and they were termed vitamin P (Rusznyak and Szent-Gyorgyi, 1936). The substances that make up this bewildering variety of compounds differ widely in their antioxidant activities and their ability to affect both enzyme function and blood clotting activities. Synergistic effects of a balanced mixture of different antioxidants obtained from the diet may be required by the body for optimal health maintenance. About half of the plasma antioxidant capacity comes from albumin and urate, the remainder represents the antioxidant gap (Miller and Rice-Evans, 1996). This gap is filled by the activities of single molecules, for example the vitamins a-tocopherol and ascorbate, flavonoids such as quercetin, isoflavonoids such as...

Problems with the Evaluation of Wholefood Antioxidant Consumption Studies

Evaluation of in vivo study outcomes is complicated by many factors that are difficult to objectively address. Given the low baseline incidence of heart disease, cancer and macular degeneration, large long-term interventional studies may be required to fully appreciate whole-food effects on these diseases. Furthermore, the same whole-food products can differ widely in their antioxidant content because of environmental influences and food processing techniques, so surveys of antioxidant intake may not reflect true intake levels. Possible genetic differences influencing human antioxidant status have not been investigated but may also be found to play a role in explaining why individual effects of whole-food antioxidants vary. One of the greatest problems surrounding the study of whole-food effects on in vivo antioxidant capacity has been the lack of assays for complete quantification of plasma antioxidant capacity. A problem with testing the concentrations of individual antioxidants is...

Introduction And Historical Background A Role of Free Radicals in Biological Regulation

Free radicals in biological materials were originally viewed as byproducts of enzymatic reactions and as a source of cellular damage, mutagenesis, cancer, and aging-related degenerative processes 58 . Today we know, however, that nitric oxide and superoxide are generated by various isoforms of nitric oxide synthase and NAD(P)H oxidase, respectively, and that both radicals as well as the superoxide-derived reactive oxygen species (ROS) play an important role in biological regulation. In 1977 Mittal and Murad 117 reported the first suggestive evidence that superoxide-derived hydroxyl radical may stimulate the activation of guanylate cyclase, which produces the ''second messenger'' cGMP. Ignarro and Kadowitz 69 and Moncada and colleagues 134 discovered independently the role of nitric oxide as a key regulatory agent in the regulation of vascular tone and in the inhibition of platelet adhesion in 1985 and 1987, respectively. Roth and Droge reported in 1987 that the superoxide radical or...

Antioxidants and Arterial Disease

Vitamin E effects on experimental atherosclerosis have been investigated since the 1940s. In early studies conducted using the cholesterol-fed rabbit model, Dam (1994) found that dietary a-tocopherol did not affect atherosclerosis, and Bruger (1945) and Moses et al. (1952) reported the intramuscular administration of vitamin E did not inhibit experimentally induced atherosclerosis. More recently, several authors have found that vitamin E may inhibit atherosclerosis in rabbits (Brattsand, 1975 Wilson et al., 1978) and chickens (Smith and Kummerow, 1989). Bocan et al. (1992), working with rabbits, found antioxidant therapy (vitamins C and E) to alter progression of diet-induced fatty streaks but to have no effect on progression as regression of more complicated iliac femoral lesions. Singh et al. (1995) fed rabbits a high-fat diet for 12 weeks then randomized them to treatment with fruits, vegetables and mustard oil, vitamins C, E, and p-carotene, a high-fat diet or a low-fat diet....

Dilemma about Antioxidants

We are left with this dilemma - consumption of a diet containing appreciable amounts of antioxidants and high plasma levels of antioxidants appeared to be protective in relation to CHD and yet trials in which selected single antioxidants are added to the diet provide scant and inconsistent evidence of a protective effect. Several possible explanations come to mind. First, consumption of a diet high in vitamins, carotenes, and flavonoids reflects intake of a wide variety of these substances, some of which may still be unidentified. It could be that several of these compounds work in concert whereas single components fed individually are without effect. It is also possible that other dietary components (trace minerals, for instance) may be effectors of carotenoid action. Virtually all nutritional studies are based on replacing one component of the diet with another without considering how these specific substances may interact with the rest of the diet. As an example from fibre...

Ferryl iron and protein free radicals

This review will focus on the nature and role of free radicals produced in association with the ferryl (FeIV) oxidation state in proteins. Table 1 lists the classes of proteins known, or suspected, to use FeIV in catalysis. The nature of the associated free radicals, where this is known, is also shown. In most cases FeIV is present associated with an oxygen atom, giving a net ionic charge of 2+. This structure can be represented chemically as Fen-0 , Fe4+-02- or FeIV 0 . The latter is most common and will be used in this review. There have been suggestions that FeIV may be present in proteins, unbound to oxygen, e.g. in mitochondrial cytochrome c oxidase 1-3 furthermore it is possible to synthesize model compounds that contain FeIV bound to other than oxygen ligands. Although these are usually sulphur 4-6 , more recently both phosphorus and chlorine-ligated compounds have been made 7,8 , However, because of its prominence in biology, unless otherwise stated in this review the term...

Antioxidant Vitamins and CHD

Oxidized LDL is now known to be more atherogenic than native LDL (see also Chapters 2 and 13). The extent of oxidation of LDL reflects the balance between oxidative stress and antioxidant defence. In the Indian diet, common oxidants include linoleic acid and cholesterol oxide. Although the Indian urban diet contains more fruit and vegetables than the rural diet, it also contains more fat and oxidants. The Indian Lifestyle and Heart Study in Elderly, comprising 595 subjects aged 50-84 years, showed that 70 patients (11.7 ) had diabetes and 72 (12.1 ) had CHD (Singh et al., 1995a). This study showed that the consumption of fruits, vegetables and legumes is half of that suggested by the World Health Organization (400 vs. 200 g day-1) (Singh et al., 1995a). One-third of the diabetic patients also had CHD. Dietary intake and plasma levels of vitamins C and E and p-carotene were significantly lower in patients with diabetes or CHD (Table 16.1). Similar observations have been made in other...

Antioxidant Vitamins and CoQ10 in Diabetes in Relation to Vascular Disease

The evidence concerning the role of antioxidants and free radicals in human diabetes is limited (Oberley, 1988 Packer, 1993 Wolff, 1993). A low intake and plasma level of vitamins C and E and p-carotene has been observed in patients with diabetes compared to control subjects (Tables 16.1-16.4). There is increased utilization of antioxidant vitamins and ubiquinol in diabetes. Plasma copper levels are higher and magnesium and zinc levels are lower in diabetes and CHD (Mateo et al., 1978 Noto et al., 1983). Free copper ions are known to catalyse ascorbate oxidation and substances such as aldos reductase inhibitor may block such reactions by binding free copper ions (Jiang et al., 1991). Zinc deficiency is associated with insulin resistance, and zinc therapy is capable of modulating insulin action (Kinlaw et al., 1983). Zinc may work as an antioxidant through superoxide dismutase. Zinc deficiency may also decrease the zinc copper ratio and thereby increase the adverse effects of copper...

Antioxidants and LDL Oxidation

The role of dietary factors in protecting against the change from native to oxidized LDL has received considerable attention. An overview of epidemiological research suggests that individuals with the highest intakes of antioxidant vitamins, whether through diet or supplements, tend to experience 20-40 lower risk of coronary heart disease (CHD) than those with the lowest intake or blood levels (Gaziano, 1994 also see Chapter 13). Vitamin E is the major lipid-soluble antioxidant present in LDL preventing the formation of lipid hydroperoxides from polyunsaturated fatty acids. Vitamin C can scavenge free radicals in the cytoplasm and may also regenerate vitamin E (Leake, 1993). -Carotene, a vitamin A precursor, does not have a confirmed antioxidant mechanism (Frei, 1995), although it is contained within LDL (Duthie and Wahle, 1990). The antioxidant vitamins cannot be synthesized from simple precursors. They are derived mainly from fresh fruit and vegetables. Vitamin E is obtained from...

Inhibition Of Diabetic Complications By Antioxidant Treatment

In patients with diabetes mellitus, oxidative stress is increased by enhanced production of free radicals and by antioxidant depletion, resulting in an increased susceptibility to oxidative damage and possibly development of late diabetic complications. Endogenous antioxidant proteins such as superoxide dismutase, glutathione peroxidase, and metal-binding proteins may protect the body against the effect of prooxidant reactions. Multiple antioxidants, including a-lipoic acid, vitamins C and E, urate, carotenoids, flavonoids, the amino acid methionine, and protein-bound zinc and selenium, are interacting addi-tively in these biological systems. In vitro and in vivo studies using antioxidants support the concept of radical-mediated diabetic complications.

Antioxidants and CVD Intervention Studies

Largely negative results have been produced from intervention studies using antioxidant vitamin supplementation with a clinical endpoint such as a cardiovascular event. These have been considered in Chapter 13. A number of reasons have been put forward for these negative findings. One possibility is that the complex mixture of antioxidant micronutrients found in a diet high in fruit and vegetables may be more effective than large doses of one or two antioxidant vitamins. There are several trials underway at present to assess the effects of antioxidant vitamin supplementation on cardiovascular disease (CVD). In each of these trials, doses of vitamin E greater than 200 mg day-1 are being used, and these should be sufficient to increase serum levels at least two- to threefold. The Women's Health Study is a primary prevention trial investigating the effects of vitamin E, p-carotene and aspirin on CVD and cancer in 40,000 women aged 50 years and over (Buring and Hennekens, 1992). In...

Antioxidant Defense Systems In The Brain

In the above sections, we have reviewed several cellular factors about SNpc DA neurons that can underlie the production of ROS and which, by virtue of pathological changes, can participate directly or indirectly in subjecting SNpc DA neurons to oxidative stress. Defense mechanisms exist that limit the levels and the role of ROS in inflicting damage on cellular components (1), as illustrated in Fig. 3. Therefore, while it is unquestionable that a number of factors may contribute to increasing ROS production in SNpc DA neurons, their role must be placed in the context of the natural antioxidant protective arsenal. This suggests that oxidative damage can only be incriminated in PD pathogenesis if the rate of ROS production exceeds that of ROS scavenging. Thus, regardless of the magnitude of ROS production in PD, one may wonder whether there is any evidence supporting the

Dietary Supply of Antioxidants in the Developed World

Vitamin C and p-carotene are available from fruits and or vegetables, and vitamin E from vegetable oils. Southern European countries consuming the classical Mediterranean diet show that optimal plasma levels of these antioxidants can easily be achieved. This diet is characterized by a preference for fresh products and frequent consumption of fruit vegetables legumes and oils with high vitamin E content. In contrast, major parts of populations in the USA or in northern parts of Europe do not consume optimal amounts of antioxidant nutrients. The availability of lower-priced convenience foods in the USA acts against the consumption of freshly prepared foods. Thus, only 10 of Americans achieved five servings of fruit and vegetables daily (Patterson et al., 1990) as recommended by the United States' national food guide, the Food Guide Pyramid (Achterberg et al., 1994). Only a quarter consumed fruits or vegetables rich in vitamin C or the carotenoids, and 41 had no fruits or vegetables on...

Free Radicals In Biological Systems And In The Environment

A free radical is an atom or molecule that possesses one or more unpaired electrons. Since electrons are more stable when paired together in orbitals, radicals are generally unstable and are therefore highly reactive with a variety of substrates. Free radicals of importance in biological systems include reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS include superoxide anion X hydroxyl radical ('OH), lipid radical (LOO ), peroxy (XOO ) radicals, and singlet oxygen ( O2). Hydrogen peroxide (H2O2) and lipid hydroperoxides (LOOH) are not truly free radicals, but they are lumped with the ROS because of their increased reactivity with biomolecules. RNS include nitric oxide (NO), a diatomic free radical that is synthesized by a family of enzymes called NO synthases (NOS), and peroxynitrite (ONOO ) formed by the reaction of NO with . Nitrite radical

Role of Oxidative Stress and Antioxidants on Adhesion Molecules and Diabetic Microangiopathy

Each cell can mobilize an armory of antioxidant defense systems. Under normal metabolic conditions, the production of free radicals and the antioxidant capacity are balanced. Hyperglycemia in diabetes mellitus is associated with an increased production of free radicals. Furthermore, observational studies indicate lower levels of antioxidants like vitamin E, vitamin C, carotene, ascor-bate, and thiols in patients with diabetes mellitus (1,2). Imbalance between free radical production and the antioxidant defense system leads to oxidative stress. In diabetic patients, oxidative stress can be demonstrated by increased levels of lipid peroxidation products (3-8). There is a body of evidence that vascular and neurological complications in patients with diabetes mellitus are a consequence of oxidative stress (9-12).

Selenium Antioxidant Actions

As we already discussed, selenium itself is not a direct radical quencher. It is necessary for the proper function of the selenoproteins, many of which are important components in the endogenous antioxidant defense system. Selenium functions as a cofactor to the glutathione peroxidases that catalyze the reaction using GSH to reduce hydrogen peroxide to water. It also reduces lipid peroxides to the corresponding alcohols. Similarly the selenoprotein enzymes, thioredoxin reductases, reduce intramolecular disulfide bonds and regenerate vitamin C from its oxidized state.

Vitamin E As An Antioxidant

Vitamin E is liposoluble and as such is mostly present in cell membranes and in low-density lipoproteins (LDL). Free radicals are created both in metabolic processes and as a result of environment pollution (e.g., superoxide, hydroxyl radicals, nitrogen dioxide, ozone, heavy metals, halogenated hydrocarbons, ionizing radiation, and cigarette smoke). Oxygen-derived free radicals are particularly abundant, as the human organism produces them in a number of reactions (mitochondrial respiratory chain, drug hydroxylating reactions in the endoplasmatic reticulum, cyto-solic enzymes, etc.). A conservative calculation may indicate the production of 100 kg of oxygen-free radicals in the life span of an individual. The highly reactive free radicals modify cell constituents, including DNA, proteins, and the polyunsaturated fatty acids of phospholipid. In the latter case, free radical production is amplified by chain reactions. Free radical damage of cell membranes, of nucleic acids, and of...

Cell Antioxidant Defenses

Historically, ROS production has been thought to be harmful to the cell 1,14,15 . This idea is supported by the fact that levels of ROS are tightly regulated by multiple defense mechanisms involving small antioxidant molecules, which often contain sulfhydryl groups, and ROS-scavenging enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase 5 . Antioxidant enzymes are induced by exposure of cells to ROS and signaling molecules, such as cytokines. Deficiencies or alterations in the cell's inherent antioxidant defenses modulate the fate of ROS in the cell, hence its redox status. In this regard, it is important to note that the composition of antioxidant enzyme systems varies from tissue to tissue and even from one cell to another in a given tissue, a factor that could explain the varied responses of different cell types to oxidant challenge. In eukaryotic cells the intracellular concentration of O2- is tightly regulated by the activities of the two principal...

Human Intervention Trials on Effects of Antioxidant Supplements on Risk or Progression of Coronary Heart Disease

A number of studies show that vitamin E decreases the oxidative susceptibility of LDL. Animal investigations as well as human epidemiological data show that antioxidants decrease the risk or progression of coronary heart disease. Intervention trials will be now discussed aiming to assess the effects of antioxidant supplements on risk or progression of heart disease in various groups. A large double-blind trial (the CARET study) in the United States evaluated the effects of combined daily supplementation of 30 mg synthetic 3-carotene and 25,000 IU vitamin A or placebo on the incidence of cancer and cardiovascular disease. Objects of the study were 18,314 smokers, former smokers, and workers exposed to asbestos over an average follow-up period of 4 years. In the supplemented group, the relative risk of death from cardiovascular disease was 26 higher than in the group on placebo. Researchers observed that favorable effects of antioxidants may be particularly difficult to achieve with...

Other Nonantioxidant Properties Or Effects Of Vitamin E

In vitro results suggest that despite a-tocopherol action as an antioxidant, y-tocopherol could also be required. Its function would be to effectively remove the peroxynitrite-derived nitrating species present in the atherosclerotic plaque that may participate in the development of the process (Christen et al., 1997). Relevance of this report for cellular, animal, and human situations would be worth investigating, especially in the light of the report (Cl ment et al., 1995) indicating a stimulation by y-tocopherol of a-tocopherol uptake of in rat tissues. In summary, the anticoagulant effect of the oxidized product of a-tocopherol, although demonstrated in vitro, does not appear to be important in vivo. This may be due to its rereduction or to prevention of a-tocopherol oxidation by other antioxidants, such as ascorbic acid.

Preventive Antioxidants

Research along these lines renewed relevance. Despite the promise represented by this class of antioxidant principles, progress in the field appears to have been limited (see Weiss et al. (1993) and references therein for an account), at least as judged by the number of patents and original articles that have appeared.

The Antioxidants of Life

As we have seen, antioxidant studies in humans have produced conflicting results. While it is apparent they play a vital role in the biology of life, their ability to improve our health and prolong our life has yet to be proven beyond a shadow of a doubt. Health professionals have not reached a unified consensus about what to recommend to their patients, and public perceptions of antioxidants, while clearly more positive and trusting, pose serious safety concerns. What we do know is that there are many synergistic interactions between compounds within the food matrix, bodily enzymes and hormones, and antioxidants themselves. It may very well be these synergies that account for the health benefits we attribute to antioxidants alone. There are a number of biological substances and compounds that exhibit antioxidant activity. Some are exogenous vitamins, some are endogenous enzymes, some are mineral cofactors, and some exert their effects by modulating endogenous oxidative defense...

Inhibition of Apoptosis by Bcl2 A Pro or an Antioxidant Activity

The antiapoptotic gene bcl-2 is one of the best-studied survival genes in the inhibition of apoptosis. bcl-2 is the first member of a family of genes consisting of pro- and antiapoptotic members that participate in the control of apoptosis 67 . bcl-2 was discovered as a result of its translocation into the immunoglobulin locus in follicular B cell lymphomas 68 and has been shown to prevent apoptosis in a variety of situations and to promote tumor development in vivo 69 . In growth factor-dependent cell lines bcl-2 expression prevents apoptosis in response to withdrawal of growth factors like IL-3, IL-4, NGF, BDNF, NT-3, and GM-CSF 70-72 . Bcl-2 also abrogates cell death induced by c-myc overexpression in serum-starved fibroblasts 73 . All members of the Bcl-2 family of proteins regulate apoptosis some members are pro-apoptotic whereas others are antiapoptotic. These protein share homology clustered within four conserved regions, namely Bcl-2 homology (BHI-4) domains, which control the...

Antioxidant Nutrient Combinations

We were the first research group to report relationships between the risk for cataracts and various indices of antioxidants (for review, see Taylor and Jacques, 1997). However, it is not clear whether the nutrients are acting additively or synergistically. Thus, until this question is resolved (in progress), there may be only limited use to such discussion. Nevertheless, the following are considered to be important data. The first, and perhaps most important, study in terms of revealing the utility of diet indicates a significant fivefold decrease in risk ratio for cataract between persons consuming 1.5 servings of fruits and or vegetables daily (Jacques and Chylack, 1991) (Fig. 22.3). Relationships between multiple antioxidant nutrients and cataract risk are further supported by multivitamin use data. Leske and co-workers (1991) found that use of multivitamin supplements was associated with decreased prevalence for each type of cataract 60 , 48 , 45 and 30 , respectively, for...

Protective Role of Antioxidants in Eye Health

As with our general health, good nutrition is essential for maintaining healthy vision. As with other diseases discussed in this book, it is the antioxidant nutrients which play a crucial role. Seddon et al. (1994) studied the effect of antioxidant supplementation in patients with an advanced form of AMD. In those subjects given a multivitamin-mineral antioxidant supplement containing vitamin E (400 mg day 1), vitamin C (500 mg day 1), selenium (250 g day 1) and p-carotene (9 mg day 1), distance visual acuity stabilized over a 18 month period whereas in those given placebo it declined. The supplements successfully halted or reversed the degenerative macular changes in 60 of subjects. This study suggests that vitamins A, C, E and p-carotene have a protective effect in preventing or slowing down the degenerative changes in the macula in early or late stages of AMD. Carotenoids have been shown to have a protective role against damaging ultraviolet (UV) light and free radicals. Two...

Exercise Antioxidant Capacity and Myocardial IR Injury

The myocardium contains numerous endogenous mechanisms of protection against ROS including enzymatic and non-enzymatic antioxidants. Primary enzymatic antioxidants include superoxide disumtase (SOD), catalase (CAT), and glutathione peroxidase (GPx). In mammals, SOD exists in cytosolic and mitochondrial isoforms. The cytosolic isoform requires CuZn as a cofactor whereas Mn is the cofactor in the mitochondrial isoform. Important non-enzymatic antioxidants in the cell include reduced glutathione (GSH), vitamin E, and vitamin C (Powers et al., 1999). In general, enzymatic and non-enzymatic antioxidants act in concert to convert ROS to less reactive forms. SOD, CAT, and GPx defend against ROS by quenching superoxide and hydrogen peroxide. Specifically, SOD converts superoxide to hydrogen peroxide while CAT and GPx convert hydrogen peroxide to oxygen and water. GPx utilizes GSH as a reducing equivalent producing oxidized glutathione (GSSG). In the presence of aqueous and lipid phase...

Antioxidants in Respiratory Tract Lining Fluids

The fluids which line the respiratory tract form a first line of defence against the potential adverse effects of inhaled oxidants (Cross et al., 1994). Various antioxidants are present in ELF, including low-molecular-weight chain-breaking antioxidants, antioxidant enzymes and transition metal-binding proteins (Fig. 24.2). In particular, several small chain-breaking antioxidants are present in substantial concentrations. Uric acid is the major low-molecular-weight antioxidant in upper respiratory tract fluids (Peden et al., 1993). It is co-secreted with lactoferrin CAB International 1999. Antioxidants in Human Health (eds T.K. Basu, N.J. Temple and M.L. Garg) into the upper airways, and is closely associated with mucin. In plasma, urate is the most potent scavenger of ozone, and it probably has the same action in the respiratory tract (Cross et al., 1992). Urate can also chelate transition metals and this may contribute to its antioxidant activity. Ascorbate is the most important...

Roles as a Protectant Antioxidant

While NO is often considered a cytotoxic compound, it can also function as an antioxidant in cells by its reaction with other radical molecules, thereby breaking the chain of free radical propagation (Wink et al., 1993 Halliwell et al., 1999). Several reports of NO as a protectant against senescence and oxidative stress in plants have appeared. In a variety of both climacteric and non-climacteric fruits and flowers, of vegetables and legume species, NO emission decreases with maturation and during senescence (Leshem and Haramaty, 1996 Leshem et al., 1998). Moreover, exogenous application of NO markedly delays senescence and maturation of these tissues (Leshem et al., 1998). NO is thought to delay senescence both by down-regulating ethylene emission and by acting as an antioxidant. NO can, therefore, be regarded as a naturally occurring plant growth effector. More recently, the same authors (Leshem et al., 1998) have shown that NO fumigation can be advantageously replaced, in the case...

Chainbreaking Antioxidants

We have chosen to discuss the synthetic chain-breaking antioxidants in relation to their chemical structural features, rather than therapeutic classifications based on the aims of the individual research groups. We felt that this was perhaps a more practical approach, especially since most promising, biologically relevant, antioxidant compounds are potentially We have attempted to categorize the chain-breakers into phenols, amines, steroids, chalcogenides and miscellaneous compounds. This classification has been based on the principal functional groups present, and regarded as important for the antioxidant effects observed. In several cases, of course, substances carry multiple functionalities (amine and phenol, phenol and chalcogen, etc.). These have been classified as miscellaneous if it is not stated by the authors that a certain structural feature is essential for the antioxidant performance. Further, the labelling of hindered phenols as synthetic compounds or tocopherol analogues...

Cigarette Smoking and Pulmonary Antioxidants

Cigarette smoking is a major risk factor for the development of pulmonary disease, including emphysema, chronic bronchitis and lung cancer. Amongst its many toxic components, cigarette smoke contains substantial quantities of free radicals in both gas and particulate tar phases (Churg and Cherukupalli, 1993). These include superoxide and nitric oxide, which may combine to produce peroxynitrites, the highly damaging hydroxyl radical (Zang et al., 1995), tar semiquinone-free radicals and various xenobiotic electrophiles (Pryor, 1992). In addition, cigarette smokers have increased numbers of pulmonary inflammatory cells which will provide a secondary source of increased free radical production (MacNee et al., 1989), and circulating leukocytes have an increased oxidative burst (Ludwig and Hoidal, 1982), which will make a significant contribution to oxidative damage in the airways (Fig. 24.3). Smoking is associated with increased levels of lipid peroxidation products in plasma, exhaled...

Antioxidant Therapy and Respiratory Disease

As discussed above, depletion of antioxidants will increase tissue sensitivity to oxidant injury in a variety of respiratory diseases. This therefore raises the possibility that augmenting lung antioxidant levels will be effective in preventing or treating respiratory disease. The aim of such treatment would be to increase antioxidant levels in ELF or in epithelial cells lining the airways and alveoli. There are two potential routes for the administration either systemically or via inhalation of an aerosol. So far as antioxidant enzymes are concerned, options for increasing levels are at present very limited. Liposome-encapsulated enzymes could be administered by inhalation and might be taken up by epithelial cells (Tanswell and Freeman, 1987). Superoxide dismutase bound to a heparin-like molecule can attach to the surface of vascular endothelial cells and help to protect them against oxidant injury (Inoue et al., 1990). In the longer term, it may be possible to selectively increase...

Antioxidants and Memory Performance a Review

In a cross-sectional study involving 260 non-institutionalized men and women, aged over 60 years, Goodwin et al. (1983) found that subjects with low blood levels of vitamins C and B scored worse on tests for abstract thinking ability and memory, while subjects with low levels of riboflavin or folic acid scored worse on categories tests. The nutritional analysis was based on diet history. Similarly, in a cross-sectional study involving 28 healthy persons aged over 60, Tucker et al. (1990) observed several significant correlations (e.g. for plasma carotene and vitamin C) but in somewhat contradictory ways. Demanding tasks correlated preferentially with nutrition status. The authors suggested that task performance and brain physiology are sensitive to changes in nutrition but this viewpoint has not been proven. La Rue et al. (1997) examined the association between nutritional status (measured in 1980 and 1986) and cognitive performance (1986) in 137 normal elderly community residents...

Other Antioxidant Genes Or Genes Regulated By An Altered Redox State On Chromosome

A number of other genes localized on chromosome 21 may have an antioxidant function and or be regulated by the redox state of the cell. The CBS gene, for example, which is localized at 21q22.3 and codes for the enzyme cystathionine- 3-synthase, may play a role in the antioxidant protection of the vascular endothelial cell. Indeed, cystathionine- 3-synthase, together with serine, catalyzes the conversion of homocysteine (Hey) to cystathionine, and elevated levels of Hey have been proposed as an important risk factor for coronary artery disease (Clarke et al., 1991), possibly via the reduction of GPX1 activity, the increased generation of H202, and the subsequent decrease in NO' bioavaibility and increased LDL oxidation (Upchurch et al., 1997 Nishio and Watanabe, 1997). Interestingly, patients with DS are protected against the development of atherosclerosis (Yla-Herttuala et al., 1989) and have lower levels of plasma homocyst(e)ine than control individuals with various types of mental...

Protecting Transcription Tissue Specificity and Antioxidant Protection

Mitochondria rely on a complex network of defenses to prevent both short- and long-term consequences of exposure to oxidants. Mitochondrial antioxidant defenses are complex, including both hydrophilic (e.g., glutathione) and hydrophobic low molecular weight antioxidants (e.g., vitamin E, coenzyme Q), enzymatic free radical scavengers (e.g., Mn-superoxide dismutase and glutathione peroxidase), and organelle-specific defenses such as the proton gradient. We have taken several approaches in attempting to

Free Radicals and the Antioxidant Defence System

To better comprehend the relationship between changes in brain membrane lipids and schizophrenia, we must look at the question of free radical biochemistry and oxidative stress. A consequence of aerobic metabolism is the generation of potentially toxic free radicals, which are chemical species with unpaired electrons (primarily the reactive oxygen species, superoxide and hydroxyl radicals). They are generated in vivo during many normal biochemical reactions involving oxygen, including the mitochondrial electron transfer chain, NADPH-dependent oxidases, and oxidation of PUFA and catecholamines (Kalyanaraman, 1989 Cohen, 1994 Rice-Evans, 1994). The superoxide radicals produced during these reactions are dismutated to hydrogen peroxide. Hydrogen peroxide is itself not a free radical, but is susceptible to autoxidation to yield the hydroxyl radical, one of the most reactive free radical species. Complex protective strategies have evolved against free radical toxicity. Under normal...

Antioxidants In Clinical

Although most of the previously mentioned compounds that have neuroprotective capacities with respect to oxidative cell death are still being studied at the level of preclinical research, employing cultured nerve cells or brain slice preparations and, therefore, in vitro, a validation of these very promising data is necessary. Future clinical trials will show whether the concept of antioxidants as preventive drugs or as therapy for neurodegenerative disorders, or AD in particular, will hold this promise. A first clinical trial employing vitamin E was recently successfully completed. There, in a multicenter clinical trial on AD patients suffering from a moderately severe impairment, vitamin E effectively slowed down the progression of the disease (90). Of course, it is still open as to whether the vitamin E effect is due to its antioxidant and neuroprotective capacity or due to other modu-latory functions of this compound. Nevertheless, this first success raises high hopes with respect...

Antioxidant Therapy in AD

Pycnogenol, which represents a group of flavonoids called proantho-cyanidins, may be a prime candidate in the treatment of disorders associated with oxidative damage (Rong et al., 1994). It was shown to be a more potent scavenger of free radicals than vitamin E and ascorbic acid (Bagchi, 1997). One component of pycnogenol, procyanidin C-1 3,3',3 -tri-0-gallate, has been reported to be 50 times more potent than vitamin E under in vitro conditions (Uchida et al., 1987). The high potency of this antioxidant certainly warrants investigation for comparison with vitamin E in animal models of AD. Sex hormones have been shown to protect against the effects of oxidative stress. Oestrogen was found to protect cultured hippocampal neurons against Ap toxicity (Goodman et al., 1996). Lipid peroxidation induced by FeSO4 and Ap was also significantly attenuated in neurons and isolated membranes pretreated with oestrogens and progesterone, suggesting that these hormones may possess antioxidant...

Role of Free Radicals Oxidative Stress

The development of oxidative stress plays a major role in the pathogenesis of myocardial ischemic-reperfusion injury. Ischemic adaptation, which involves repeated episodes generally four times (4XPC) of ischemia and reperfusion initially, i.e., after the first episode of ischemia-reperfusion (1XPC) , produces oxygen-free radicals and develops oxidative stress, as expected. However, the amount of free radical generation does not increase progressively with each consecutive episode of ischemia-reperfusion. At the end of the fourth episode of ischemia-reperfusion (4XPC), the amount of free radicals actually begins to decline as compared to that produced after IX PC. After acute ischemia and prolonged reperfusion following ischemic adaptation, the amount of free radicals oxidative stress in the heart becomes significantly less compared to those in ischemic-reperfused hearts (without adaptation) (Cordis et al., 1998). In concert, a number of oxidative stress-inducible genes as well as heat...

Antioxidants and Their Use in Disease Prophylaxis

Antioxidants are essentially free radical scavengers. Enzymes such as superoxide dismutase, glutathione peroxidase and catalase are part of the endogenous mechanisms that the body possesses to combat oxidation. Superoxide dismutase metabolizes the superoxide ion (O2-) to hydroperoxide (H2O2) which is them acted upon by glutathione peroxidase (Burk et al., 1995a). Vitamin E (a-tocopherol) and p-carotene are antioxidants that can be obtained from the diet (Awad et al., 1994). Both in vivo and dietary antioxidants have a role in the prevention of lipid peroxidation, and isoprostanes provide a more accurate means of assessing their effectiveness. Recently it was observed that reactive oxygen species can act as signalling molecules in the regulation of gene expression. Extracellular radicals can initiate cell signalling, and intracellular radicals can act as second messengers. Therefore the intake of dietary antioxidants enables alteration of radical-affected signalling pathways....

Antioxidant Vitamins

Vitamins A, C, and E represent the main exogenous sources of antioxidant protection. They are efficient free radical scavengers that act by converting free radicals into less damaging compounds, hence avoiding their deleterious effects (55,56). Studies based on dietary histories have shown that people with diets high in antioxidant vitamins tend to be protected against certain neurodegenerative diseases. Other studies have also shown that patients who have decreased blood levels of these vitamins are more prone to some of these diseases than healthy controls. This, however, does not imply automatically that vitamins taken as dietary supplements will provide equivalent protection. Diets rich in fruits and vegetables contain myriads naturally occurring antioxidants, which may be more efficient and possibly essential coadjuvants to these vitamins (57,58). Furthermore, diets rich in antioxidant vitamins may be a marker for other potentially unknown protective lifestyle practices, which...

Other antioxidant mechanisms

Another small water-soluble molecule that may have significance in providing antioxidant protection is uric acid which accumulates in human tissues as the end-product of purine metabolism and is present in plasma at concentrations between 0.25 and 0.45 mM. Ames et al. 49 showed in 1981 that urate is a powerful scavenger of singlet oxygen, peroxyl radicals and OH'. In view of the fact that man has lost the gene that encodes for the enzyme urate oxidase it was suggested that this genetic deficiency compared to other animals might be beneficial to the human species by providing an antioxidant mechanism unique to man. Uric acid is also a powerful scavenger of lipid hydroperoxides and of ozone 1 , and of hypochlorous acid produced by myeloperoxidase in phagocytes 50 . 1 Halliwell, B. and Gutteridge, J.M.C. (1989) Free Radicals in Biology and Medicine, 2nd edition, 543pp., Clarendon Press, Oxford.

Oxidative DNA Damage is Linked to Dietary Antioxidant Levels

Divided into four matched groups, received daily for 12 weeks 15 mg of either a p-carotene, lutein, lycopene or a placebo. Blood concentrations of these and other dietary antioxidants were measured by HPLC before and after supplementation. We found no significant effect of the supplements on DNA damage however, levels of oxidized bases (especially endonuclease Ill-sensitive sites), measured only at the end of supplementation, showed a significant negative correlation with several of the carotenoids measured at the same time. Surprisingly, this correlation tended to be at least as strong with pre-supplementation carotenoid concentrations (Collins et al., 1998a). Figure 30.1 shows, as an example, the negative correlation between endonuclease III sites measured after supplementation and p-carotene concentrations before and after supplementation. This supports the idea that carotenoids (or some other associated phytochemicals) taken up as part of the normal diet modulate the amount of...

Supplementation with Antioxidants Can Protect DNA Against Oxidation

In the study mentioned above (Duthie et al., 1996), the main purpose was to investigate the effects of daily supplementation with a mixture of 100 mg of vitamin C, 25 mg of p-carotene and 280 mg of a-tocopherol (vitamin E). After 20 weeks, there was indeed a significant decrease in the levels of oxidized pyrimidines in lymphocytes from smokers and non-smokers (Fig. 30.2), indicating protection against endogenous oxidative damage, and this was reflected in an increased resistance of the lymphocytes to oxidation incurred on incubation with H2O2 (Fig. 30.3). A similar increase in resistance of lymphocytes is seen immediately following a single very large dose of any of these three antioxidants (Fig. 30.4 Panayiotidis and Collins, 1997), and this provides a useful assay for putative antioxidant effects of other dietary constituents that can be administered in a purified form. The fact that a dietary constituent has a demonstrable antioxidant activity in these assays is no guarantee that...

Antiinflammatory Agents And Antioxidants In Cancer Chemoprevention

Free radicals are generated by normal physiological processes, including aerobic metabolism and inflammatory responses to eliminate invading pathogenic microorganisms. A chronic cell injury initiates an inflammatory response and the activation of cytoquines or receptor molecules to recruit mast cells and leukocytes to the damaged place. This ''respiratory burst'' leads to an increased uptake of oxygen, and the subsequent release of free radicals from leucocytes reactive oxygen species (ROS) as hydroxyl and superoxide radicals, and nitrogen oxide reactive species (RNOS) as nitric oxide, peroxynitrite, and nitrous anhydride.

Antioxidants The Great Hope The Great Deception

The discovery of superoxide dismutase by McCord and Fridovich in 1969 confirmed the existence of oxidative stress in vivo. Thus, a race began to increase longevity by the administration, induction or overexpression of antioxidants. Unfortunately, attempts in mammals to increase longevity using antioxidants have largely failed 9 . Apart from the various social, cultural and economic implications of such developments, there are also issues with relevance to medicine, pharmacology and, as we will see, biochemistry. For instance, there will be a significant increase in age-related illnesses, which will have to be addressed by the further development of drugs against such diseases. Here, issues surrounding disease prevention (e.g. cancer), inflammatory diseases, cardiovascular diseases and neurodegenerative diseases will become of major importance. Nutrition and food supplements (e.g. antioxidants) will need to be addressed. At the same time, there appears to be a need for a closer look at...

Molecular Mechanisms of Antioxidant Regulation

Because of the diverse chemical structure of the antioxidants, it is rather difficult to understand the exact mechanisms and sites of action of antioxidants downregulating agonist-induced cell adhesion (Fig. 10). Previous studies have suggested that activation of the agonist-induced transcription of cell adhesion molecules (e.g., E-selectin, ICAM-1, and VCAM-1) in cells are dependent, at least in part, on the activation of redox-sensitive transcription factors NF-kB and AP-1 (Marui et al., 1993 Voraberger et al, 1991). Among the thiol and related antioxidants studied, PDTC and high concentra-

Antioxidant Supplementation in Atherosclerosis Prevention Study ASAP Study

The findings of the study suggest that antioxidant vitamin (vitamins E and C) supplementation significantly retards carotid atherosclerosis progression in men, especially those who are at increased oxidative stress and have insufficient dietary antioxi-dant status (smokers). Both supplements were safe, and the bioavailability of the supplements was good. The authors suggested that the lack of beneficial effect in women is due to the higher baseline levels of vitamin C in the population studied and insufficient statistical power in women, who had smaller baseline carotid wall thickness and less atherosclerotic progression during the study.

Epidemiological Studies Showing Protective Effects of Antioxidants on Coronary Heart Disease in Humans

A study in 19 western European countries and 5 non-European countries evaluated the association between dietary antioxidant intake and coronary and carotene levels and risk of angina Inverse correlation between dietary intake of vitamin C, vitamin E, 3-carotene, and phenolic antioxidant-rich foods and coronary heart disease mortality. Increasing risk for subsequent myocardial infarction with decreasing serum 3-carotene levels and a suggestive trend with decreasing serum lutein levels Serum antioxidant levels and the risk of myocardial infarction have been investigated in two studies in the United States. Their data demonstrate a significant increasing risk for subsequent myocardial infarction with decreasing serum carotenoid levels. A protective association with serum vitamin E levels was suggested only among individuals with high serum cholesterol concentrations (Morris et al., 1994 Street et al., 1994). Numerous studies have also investigated the association between varying levels...

Antioxidants and the Redox Biology of Life

According to a November 30, 2006 Wall Street Journal1 article, resveratrol supplements are the current hot supplements in America. They have become so popular with Americans that retailers are unable to keep up with consumer demand. A plant phytochemical, flavonoid and stilbene, and antioxidant molecule, media portrayal of resveratrol as a possible antiaging elixir that is life-prolonging has greatly boosted sales of this dietary supplement. The buzz about resveratrol commenced when investigators from Harvard Medical School published a paper in the journal Nature in August 2003 about this phytochemical, which is found in red wine and grape skins.2 The investigators found that resveratrol directly influenced critical genes and prolonged lifespan by 30 to 70 percent in yeast cells, citing unpublished data of preliminary results that the lifespan of fruit flies and earthworms could also be extended. Subsequent studies have demonstrated resveratrol's capability to improve health and...

Interactions Between Antioxidants And Essential Fatty Acids

There are multiple defects of vasa nervorum endothelium and possibly smooth muscle in diabetes that cause reduced nerve blood flow and function. The NO deficit is compounded by diminished PGI2 synthesis and increases in endo-thelin-1 and angiotensin II. Recently, it was shown that relaxation mediated by endothelium-derived hyperpolarizing factor (EDHF) is also affected by diabetes. In the rat mesenteric vascular bed, EDHF was 76 reduced after 8 weeks of diabetes. In common with the NO defect, the EDHF deficit was attenuated by antioxidant treatment with a-lipoic acid (89). Vasodilator prostanoid synthesis is also deleteriously affected by oxidative stress high levels of lipid peroxides inhibit cyclooxygenase (90), and a-tocopherol treatment corrected the lowering of the PGI2 thromboxane A2 ratio found in diabetic rats (91). C. Synergy Between Antioxidant and n-6 Essential Fatty Acid Treatments Low doses of an ARI or evening primrose oil (which contains GLA) had modest effects on NCV...

Role Of Free Radicals In Brain Disease A Schizophrenia

Antioxidant defenses have been reported to be weak in schizophrenia and oxidative stress to be present. Abdalla et al. (1) found an increase in superoxide dismutase and a decrease in glutathione peroxidase, which would result in an excess production of H2O2. Neutrophils from the blood of schizophrenics produce more superoxide anion than normal controls (52). Levels of measures of oxidative stress, such as malonyl-dialdehyde (MDA) and pentane production, are also raised (67). There is a highly significant negative correlation between glutathione peroxi-dase activity in blood cells and the degree of cortical atrophy in the disease (7,8). Hawkins and Pauling (39) and Kanofsky et al. (43) have reviewed the evidence of defective vitamin C function in schizophrenia. Cadet and Lohr (10) have suggested that the overactivity of dopa-minergic neurons during the acute phase generates excess free radicals, which leads to neuronal damage and subsequent chronic disability. An-tioxidant enzymes will...

Free Radicals Derived From Catecholamines

Neuromelanin Anatomy

Catecholamines are themselves potent antioxidants but they are easily oxidized to highly neurotoxic o-quinones (Fig. 2). Vulpian (95) noted in 1856 that adrenal gland tissue exposed to air turns red. This red pigment was later identified as adrenochrome, but it was thought for many years that this pathway of catechola-mine metabolism never occurred in vivo. Recently, however, conclusive evidence has been obtained that this pathway does indeed occur in the body, particularly in the brain where it may be of great functional importance (91). This pathway runs as follows. If we take dopamine as the simplest example, dopamine is first oxidized to dopamine quinone. This step is reversible by some antioxidant such as ascorbate or glutathione. Dopamine quinone then cyclizes spontaneously and irreversibly to form dopaminochrome. This may then be converted by the enzyme DT-diaphorase to the relatively nontoxic o-hydroquinone. Or it may be converted by the enzyme NADPH cytochrome P450 reductase...

Antioxidant effects

Algae as intertidal organisms require an endogenous antioxidant capacity to withstand UV irradiation and the effects of desiccation from daily tidal fluctuations (Yuan and Walsh, 2006). In brown algae, this antioxidant protection encompasses mainly by phlorotannins (Yan et al., 1996). Therefore, they have received the greatest attention and have been investigated extensively since they are high free radical scavengers in nature and less toxic than synthetic antioxidants such as BHA and BHT (Jung et al., 2008). Unregulated production of free radicals in the cellular systems is responsible in causing cellular damage by oxidizing macromolecules, DNA, proteins, and lipids in the cell. Therefore, antioxidative therapeutics have great demand to act against free radicals. In this aspect, phlorotan-nins serve as one of the most promising natural antioxidants. Numbers of studies have shown the radical scavenging potential of phlorotannins isolated from marine brown...

Enzyme catalysis by ferryl ion and free radicals

Lactoperoxidase Iron

The redox potentials of FeIV species are close to those of many organic free radicals 16 , This fact is extensively used by biology. Free radicals are either coupled with ferryl formation to generate a strong two-electron oxidant (e.g. the porphyrin cation radicals in myeloperoxidase and catalase) or generated subsequently at a more distant site on the protein (e.g. the reactive tyrosine radicals in ribonucleotide reductase and prostaglandin H synthase). There are even cases where the free radical products of the ferryl reactions may be let loose outside the protein, e.g. the veratryl-alcohol radical synthesized by lignin peroxidase which has been proposed to degrade extracellular lignin 17 , This latter point emphasizes that in the absence of a controlling protein milieu these FeIV species can be as reactive as the hydroxyl radical 18 and can therefore be quite destructive if synthesized inappropriately (see section 5). Fig. 3. Nature of free radical associated with compound I in...

Molecular Properties of aTocopherol Antioxidant and Nonantioxidant Functions

It is commonly believed that phenolic compounds such as vitamin E play only a protective role against free radical damage and that vitamin E is the major hydrophobic chain-breaking antioxidant that prevents the propagation of free radical reactions in membranes and lipoproteins. The antioxidant properties of vitamin E are well known (33), especially in connection with the prevention of low density lipoprotein (LDL) oxidation (34), although the correlation between LDL oxidation and atherosclerosis is not always evident (35,36). Alternative studies have suggested that a-tocopherol protection against LDL oxidation may be secondary to the inhibition of protein kinase C (PKC). This enzyme is responsible for triggering the release of reactive oxygen species with consequent lipid oxidation (37,38) (Table 14.1). The nonantioxidant properties of tocopherol have been indicated by several experiments in which the four tocopherol analogs had effects that could not be correlated with their...

Exercise and Antioxidant Signaling

World War Battle Britain

Finkel and Holbrook (2000) elegantly stated that the best strategy to enhance endogenous antioxidant levels may actually be oxidative stress itself, based on the classical physiological concept of hormesis. Hormesis is a Greek word meaning a sublethal dose of toxin can increase the tolerance of the organism to withstand higher doses of toxins. Exercise at high intensity is a form of oxidative stress due to the generation of ROS that exceeds the defense capacity in skeletal muscle (McArdle et al., 2001 McArdle and Jackson, 2000). However, it has been consistently observed that individuals undergoing exercise training have high levels of antioxidant enzymes and certain non-enzymatic antioxidants in muscle and demonstrate greater resistance to exercise-induced or imposed oxidative stress (Ji, 1995 Sen, 1995). Presumably, these adaptations result from cumulative effects of repeated exercise bouts on the gene expression of antioxidant enzymes. The question arises as to how exercise could...

Strategies For Antioxidant Therapy

In the broadest possible definition, an antioxidant is any chemical that attenuates the rate of oxidative degradation of the material or substrate under study. Halliwell and Gutteridge (1989) defined an antioxidant as any substance that, when present at low concentrations compared to those of an oxidizable substrate, significantly delays or inhibits oxidation of that substrate . However, when considering pharmaceutical relevant antioxidants, one may also need to include compounds that do not behave exclusively as peroxidation inhibitors. Thus, for the present discussion, an antioxidant of biological relevance may be defined as a chemical that inhibits the pathological consequences of oxidative insult by reacting with biologically relevant oxidants or radicals. PHARMACEUTICAL ANTIOXIDANTS Scheme 2 Antioxidant mechanisms PHARMACEUTICAL ANTIOXIDANTS Scheme 2 Antioxidant mechanisms In the pharmacological context, antioxidants are commonly divided into two groups depending on their...

Proapoptotic Properties Of Antioxidants

Apart from ROS-detoxifying effects, antioxidant molecules may function as regulators of signal transduction pathways. For example, the possibility that N-acetylcysteine, unlike other antioxidants, suppresses neuronal apoptosis by regulating cell cycle progression has been proposed (Ferrari et al., 1995). In several other cases, however, potentiation of apoptosis by antioxidants has been reported to occur by pathways that are apparently independent of ROS detoxification. N-Acetylcysteine has been shown to elevate p53 expression posttranscriptionally by increasing the rate of p53 mRNA translation. In this way, N-acetylcysteine induced apoptosis in several transformed cell lines and transformed primary cultures but not in normal cells (Liu et al., 1998). NF-kB induction has been shown to play a role in protecting cells from programmed cell death (see Chapter 9, this volume). HIV-1 infection of primary monocytic cells and myeloid cell lines results in sustained NF-kB activation....

Antioxidants from herbs and spices

The presence of glycosides of kaempferol, rhamnetin and quercetin and phenolic amides are believed to confer antioxidant activity to pepper (Nakatani et al., 1986). In oregano, among the active components, four flavonoids were identified (Lagouri and Boskou, 1996) while in thyme, compounds have been isolated and identified as dimers of thymol and flavonoids. Similarly, the phenolic antioxidants, -coumaric acid, ferulic acid, curcumin and caffeic acid, which are found in coriander, turmeric, liquorice, oregano, sesame and rosemary, inhibit the formation of 3-nitrotyrosine in vitro and may prevent lipid peroxidation in vivo (Aruoma et al., 1992, 1996). Caffeic acid and other hydroxycinnamic acids have also been found to have an inhibitory effect on LDL oxidation (Abu-Amsha et al., 1996). Rosmarinic acid also fulfils the requirements for being considered as a potent antioxidant since it is not only capable of scavenging superoxide anions but is also able to chelate...

Antioxidants In Neuroprotection In Vitro

Antioxidant therapies are discussed for a variety of neurodegenerative disorders such as Parkinson's disease, ischemia, and other age-related disorders in general (3,37,38). Numerous free radical scavengers have been tested for their neuropro- tective potential in vitro and in vivo. The most prominent lipophilic antioxidant is vitamin E which has not only a protective activity against Ap toxicity, but also against other oxidative challenges such as glutamate (33). On the other hand, it is known that vitamin E does not easily pass the blood-brain barrier, which makes it hard to enrich a powerful antioxidant in brain tissue in general (39). Therefore, the search for antioxidants with an increased permeability for endothelial tissues is very important and may lead to more effective antioxidant neuroprotection. Among the various other compounds that have been tested for an antioxidant activity against Ap toxicity or glutamate toxicity in vitro is also the pineal hormone melatonin, the...

Oxidative Stress And Antioxidant Treatment Effects On Neurovascular Function In Experimental Diabetes

Antioxidant protection mechanisms are compromised in nerves of diabetic rats lipid peroxidation is increased, and the levels of superoxide dismutase and reduced glutathione (GSH) are decreased, although glutathione peroxidase and reductase remain unchanged (34-37). Long-term exposure to elevated ROS, coupled with diminished endogenous antioxidant protection, could lead to cumulative neurodegenerative changes involving axonopathy and demye-lination, and damage to dorsal root ganglion cell bodies and their mitochondria has been observed (37,38). However, in the short term, ROS effects on vasa nervorum are more important, being responsible for the earliest defects in nerve function in diabetic rats. A. Antioxidant Treatment, Vascular Endothelium, and Nerve Function Defective endothelium-dependent relaxation has been found in diabetic animals and in type 1 and type 2 patients (39-47) and is an important target for antioxidant treatment. An example is shown in Figure 2, where the...

Defining Free Radicals Antioxidants and Related Terms

The terms reactive oxygen species (ROS) and reactive nitrogen species (RNS) describe both radicals and nonradical reactive oxygen and nitrogen-containing molecules. These molecules can enter reactions that can result in production of free radicals or directly damage organic biochemical substrates. The nomenclature used within the field of free radical biology has not been established by any one organization. However, there is a consensus within the field from several sources, including the International Union of Pure and Applied Chemistry (IUPAC),10 the Commission on the Nomenclature of Inorganic Chemistry,11 and by recommendations of authors in the field.12 Current convention denotes a free radical in text by a superscript dot to the right preceding any charge that the molecule may have, for example H*, HO, NO, O2 -, CO -, and H3C. O22* denotes the radical notation for dioxy-gen in its ground state or, in other words, the lowest allowed energy state for this molecule. A molecule is...

Antioxidant Supply

Finally, the process of phagocytosis by the RPE is itself an oxidative stress, and results in the generation of reactive oxygen species. Oxidative damage in the retina is thought to be involved in retinal diseases, such as diabetic retinopathy (29) and age-related macular degeneration (28). It has been shown that transporters at the inner BRB protect the retina by supplying antioxidants.

Antioxidant Defenses

As discussed, the most significant sources of oxygen radicals in aerobic plant and animal cells come from the electron-transport chains of the chloroplasts (in plants) and mitochondria (in both plants and animals). Uncoupling proteins exist in the inner mitochondrial membranes of plants and animals that have been proposed as initial antioxidants, acting as an engine vent and permitting increased proton leakage into the mitochondria. This in turn minimizes the accumulation of excessive electrons in the chain that could escape to O2 and result in oxygen radical formation.47 The product of the action of GPx, oxidized glutathione (GSSG), can be converted back to GSH by glutathione reductase enzymes. There are four types of GPx in animal tissues and they all require selenium for activity. This has led to the misconception that selenium is an antioxidant. Selenium, in reality, is a cofactor. Because of this incorporation of selenium, GPx are referred to as selenoproteins. Plant GPx are not...

Free Radicals

A free radical is a species containing one or more unpaired electrons. The highly reactive nature of free radicals makes them potentially dangerous particularly if they are not tightly controlled. Pine33 (1987) suggested that free radicals can be formed in three general ways Free radicals are typically short-lived, but one radical can generate other free radicals until a termination reaction occurs (e.g., combination of two free radicals). Targets of free radicals include proteins, DNA,35 37 carbohydrates and the phospholipid component of cellular membranes.34' 38 39 Depending upon the cellular or extracellular target, free radical damage can result in 1) modified ion transport 2) modified enzyme activity 3) mutations and translational errors and, 4) modification of the structural and functional integrity of the membrane. Most free radicals have a chronic effect on cells. Antioxidant is a term given to a compound that scavenges free radicals. All radical scavengers are electron donors...

Antioxidants

Many pharmaceutical products undergo oxidative deterioration upon storage because the therapeutic ingredients or adjuvants oxidize in the presence of atmospheric oxygen. Vitamins, essential oils, and almost all fats and oils can be oxidized readily. The decomposition can be particularly significant in disperse systems, such as emulsions, because of the large area of interfacial contact and because the manufacturing process may introduce air into the product. Many drugs commonly incorporated into emulsions are subjected to autoxidation and subsequent decomposition. Traces of oxidation products are undesirable as they are generally easily noticed by their smell and or taste. The term autoxidation is used when the ingredient(s) in the product react(s) with oxygen without drastic external interference. Series of autoxidative reactions involve the initiation step or the formation of a free radical, the propagation step where the free radical is regenerated and reacts with more oxygen,...

Antioxidant effect

Uncontrolled production of free radicals that attack macromolecules such as membrane lipids, proteins, and DNA is leading to many health disorders such as cancer, diabetes mellitus, and neurodegenerative and inflammatory diseases with severe tissue injuries (Butterfield et al., 2002 Frlich and Riederer, 1995 Yang et al., 2001). Antioxidants may have a positive effect on human health as they can protect human body against damage by reactive oxygen species (ROS), which attack macromolecules. Moreover, deterioration of some foods has been identified due to oxidation of lipids or rancidity and formation of undesirable secondary lipid peroxidation products. Lipid oxidation by ROS such as superoxide anion, hydroxyl radicals, and H2O2 also causes a decrease in nutritional value of lipid foods and affects their safety and appearance. Therefore, in food and pharmaceutical industries, many synthetic commercial antioxidants such as butylated hydroxytoluene, butylated hydroxyanisole (BHA),...

Materials and Methods

CVD, including end points likely to be affected by antioxidant mechanisms (e.g., ischemic heart disease, cerebrovascular disease, sudden death, and diseases of arterioles). Adjustment for potential confounders in multivariate analyses from all three studies were generally comparable however, the first two studies used smoking status (i.e., current, past, never) whereas the last study used average number of cigarettes smoked per day. Findings also tended to be positive when a wider definition of CVD was used this pattern was observed in studies using both serum concentrations and intake data. Studies that examined CHD, either fatal or nonfatal, as an end point yielded inconsistent findings, although those using serum ascorbate concentrations tended to be positive compared with those using vitamin C intake. The evidence for a relationship between stroke and vitamin C status was also weak. No studies examined the association of vitamin C on morbidity alone it is possible that vitamin C...

Vitamin E Supplement

Hence, intervention trials to date do not support a regimen of high-dose vitamin E ingestion for reducing risk of cardiovascular and or cancer death in high-risk populations. Furthermore, there is some evidence indicating a potential adverse effect on risk for hemorrhagic stroke in users of vitamin E supplements. Hemorrhagic stroke is classified as subarachnoid hemorrhage or intracerebral hemorrhage, and the risk profiles of these two subtypes are distinct. Subarachnoid hemorrhage is typically caused by rupture of an arterial aneurysm and has been related to a smoking-induced elastase a-antitrypsin imbalance (17), whereas intracerebral hemorrhage may be related more to hypertension and necrosis of small arterioles (18). The number of cigarettes smoked increased the risk of subarachnoid hemorrhage but not intracerebral hemorrhage (18). In smokers, vitamin E supplementation raised the risk of fatal subarachnoid hemorrhage (+181 , P 0.005) but did not alter risk of fatal intracerebral...

Prooxidant Activity

Brown et al. (85) examined the effect of a wide range of supplemental vitamin E (0, 70, 140, 560, or 1050 mg d for 20 wk) on lipid peroxidation in male smokers and in men who had never smoked. Red blood cell vitamin E concentrations were significantly elevated in all groups ingesting vitamin E. The susceptibility of red blood cells to hydrogen peroxide-induced lipid peroxidation in vitro was reduced substantially (-63 to -73 , P 0.05) in smokers ingesting 70-1050 mg vitamin E. In the non-smokers, lipid peroxidation was decreased in those ingesting 70, 140, or 560 mg vitamin E however, lipid peroxidation was significantly elevated (+36 ) in nonsmokers consuming the highest dosage of vitamin E, 1050 mg d. Moreover, the erythrocyte vitamin E plasma vitamin C ratio was highest in this group, indicating the highest degree of antioxidant imbalance of all groups. Thus, the increased susceptibility to red blood cell peroxidation in this group may reflect a decrease in vitamin C regeneration...

Supplementation and Drug Interactions

P-Hydroxyl-p-methyl glutarate-CoA reductase inhibitors (statins) in combination with niacin are often the initial therapy prescribed for dyslipidemia to reduce LDL cholesterol and raise high density lipoprotein (HDL) cholesterol. A recent clinical trial examining the efficacy of different lipid-altering and or antioxidant strategies on coronary artery disease indices demonstrated that when statin niacin therapy was combined with antioxidant use (p-carotene, 12.5 mg vitamin C, 500 mg vitamin E, 268 mg) the beneficial response of HDL to the statin niacin therapy was markedly attenuated (P 0.057) (93). Although these results must be verified, they demonstrate the importance of investigating interactive effects of popular drug therapies and high-dose vitamin supplementation.

The Challenge to Determine Vitamin E Potency in Humans

Biochemical end points reflecting antioxidant potency such as breath pentane (10) and peroxide-induced hemolysis ex vivo in vitamin E-depleted subjects have been used (11). Data obtained by the latter method were taken by FNB to draw a line between vitamin E deficiency and adequacy at 12 mol L to determine the requirement (4). a-Tocopherol in plasma low density lipoprotein (LDL a bioavailability measure) and the rate and lag time of conjugated diene formation, thiobarbituric acid-reactive substances, and macrophage degradation of LDL (measures of potency) after copper-oxidation in vitro were measured in a study comparing RRR and all-rac at supplement doses of 1600 mg d for 8 wk (12). a-Tocopherol in LDL increased and the susceptibility to oxidation decreased at similar rates for both groups, indicating that either form of a-tocopherol provided equal antioxidant protection at this high dose. However, the sensitivity of this method to detect minor differences in potency is not...

Vitamin E Structures vs Activities

Almost since the discovery of vitamin E in 1922 (1), there have been disagreements concerning the biologic activities of the various tocopherols and tocotrienols. a-Tocopherol is found in highest concentrations in animal plasma and tissues. Currently, only a-tocopherol has been demonstrated to reverse human vitamin E deficiency symptoms it is the only form of vitamin E that meets the year 2000 vitamin E recommended dietary allowance (RDA) (2). However, in the plant kingdom, a variety of compounds that have vitamin E antioxidant activity have been described. The latest of these was described in plankton and cold water fishes that consume plankton (3). The rationale for possible differences in biologic activities between various naturally occurring vitamin E forms has been based on slight differences in antioxidant activities. However, antioxidant activities cannot be the explanation for differences in the biologic activities between naturally occurring and synthetic a-tocopherol. When...