EFFICACY OF ANTIOXIDANTS IN HUMAN HEALTH

Mary Khakoni Walingo¹

ABSTRACT

Antioxidants is a classification of several organic compounds including vitamins E, C, and A, transition metals iron and selenium, and plant pigments  β -cryptoxanthin, α-carotene and β-carotene.  Carotenoids, for example, are pigments that add colour while flavonoids add flavour to many fruits and vegetables. Antioxidants abound in nature. Antioxidants serve to deactivate free radicals that result from many metabolic processes and exposure to various environmental factors.  Free radicals promote beneficial oxidation that produces energy and bacterial invaders.  However, free radicals oxidation also damage cell membrane and cell contents such as DNA, proteins, lipids and carbohydrates.  This results in the loss of membrane function, inactivation of enzymes and chemical alteration of the DNA predisposing the body to degenerative diseases such as coronary heart diseases, cancer and also affects the human immunodeficiency.  Antioxidants present in foods at high levels have been reported to delay or even reverse the degenerative processes.  Diets consumed contain antioxidants and phytochemicals that block the oxidative processes that could otherwise lead to diseases like heart disease and cancer.  Consumption of a balanced diet containing antioxidants-rich fruits and vegetables and whole grains, protects the body against degenerative chronic diseases.  Besides the health benefits of fruits and vegetables, they also grow easily in kitchen gardens, add variety to household diets and nutrients, and improve household incomes for improved food security situation. Reduction in coronary artery disease has been reported with increased consumption of plant-based foods high in antioxidants, phytochemicals, fiber, mono- and poly-unsaturated fatty acids.  However there seems to be very little or none preventive effects of α-tocopherol and β -carotene on coronary diseases.  Oxidative stress is an important factor in the progression of aging and chronic diseases.

KEY WORDS:Antioxidants, cancer, cardiovascular, immunodeficiency,  aging. 

FRENCH

EFFICACITE DES ANTIOXYDANTS POUR LA SANTE HUMAINE

NOTE DE SYNTHESE

Les antioxydants sont constitués de plusieurs composés organiques, tels que les vitamines E, C et A, de métaux de transition tels que le fer et le sélénium et de pigments végétaux, tels que β - cryptoxanthine, α-carotène et β -carotène. Par exemple, les caroténoïdes sont des pigments qui ajoutent la couleur et les flavonoïdes ajoutent la saveur à bon nombre de fruits et de légumes. Les antioxydants abondent dans la nature. Les antioxydants participent dans la désactivation des radicaux libres résultant de plusieurs processus métaboliques et à l'exposition à divers facteurs exogènes.  Les radicaux libres promeuvent l'oxydation bonne pour la production de l'énergie et des envahisseurs bactériens. Cependant l'oxydation de radicaux libres endommage aussi la membrane et le contenu de la cellule tels que l'ADN, les protéines, les lipides et les hydrates de carbone. Cela aboutit à la perte de fonction de membrane, à l'inactivation des enzymes et à la modification chimique de l'ADN, prédisposant ainsi le corps aux maladies dégénératives telles que les maladies coronariennes, le cancer et affectant aussi l'immunodéficience humaine.  Cependant, lorsqu'ils sont consommés en grandes quantités, les antioxydants contenus dans les produits alimentaires retardent ou transforment complètement les processus dégénératifs. Les régimes consommés contiennent des antioxydants et des produits phytochimiques qui bloquent les processus d'oxydation qui pourraient autrement mener aux maladies telles que les maladies cardiaques et le cancer.  Un régime équilibré de fruits, de légumes et de graines entières riches en antioxydants, protège contre les maladies dégénératives chroniques.  En plus, les fruits et les légumes poussent facilement dans les jardins potagers.  Ils ajoutent la variété aux régimes du ménage et des substances nutritives. Ils améliorent aussi les revenus du ménage en assurant une sécurité d'alimentation enrichie. La réduction de la coronaropathie a été annoncée avec La consommation accrue de produits alimentaires à base végétale, riches en antioxydants et de produits phyto-chimiques, de fibre, d'acide gras mono et polyinsaturé.  Cependant, il semble y avoir très peu ou aucun effet préventif de α-tocophérol et β-carotène sur les incidents coronaires. La mortalité est associée au régime alimentaire contenant des oxydants, particulièrement chez les fumeurs dont l'alimentation contient beaucoup d'oxydants (régime alimentaire à faible teneur en vitamine C et β-carotène et/ou contenant beaucoup de fer).  Les fumeurs sont fort exposés à tous les risques de cancer, bien que l'effet soit moins prononcé dans les maladies coronaires. Le stress des oxydants est un facteur important dans la progression du vieillissement et des maladies chroniques.

Mots-clés: Antioxydants, cancer, cardiovasculaire, immunodéficience,  vieillissement. 

INTRODUCTION

‘Antioxidants' is a classification of several organic substances such as vitamins C, E and A (β -carotene), transition metals (iron, copper, selenium) and plant pigments (β -carotene, α-carotene, β –cryptoxanthin) found in fruits and vegetables. Antioxidants are thought to be effective in helping prevent certain chronic diseases and boost the immune system.  Antioxidants serve to deactivate free radicals that result from many processes within and among the cells, and also by exposure to various environmental factors such as tobacco smoke and radiation.  Free radicals generated are capable of damaging the DNA, proteins, carbohydrates and lipids.  This results in the loss of membrane function, inactivation of enzymes and chemical alteration of the DNA.  Oxidative damages contribute to aging and degenerative processes such as heart diseases and cancer. They also affect human immunodeficiency cataract and cognitive dysfunction.  Oxidative damage to molecules can be delayed or inhibited by antioxidants [1-4].  Oxidative damage results in lesions, which are not completely repaired and are common among individuals with low vitamin C intake [5]. In fact, pregnant women with low intake of vitamin C have been reported to have a significantly increased risk of having children with brain tumors [5,6].  Antioxidants scavenge free radicals in the body system.  Therefore, the body must have continuous and abundant antioxidants and free radical scavenging capability in order to block the oxidative processes.   

Each antioxidant has its role to play in the body system.  Vitamin E is the major lipid soluble antioxidant found in fish liver oils, oilseeds and nuts.  It is a well-known biological antioxidant that can function as a protective agent against peroxidative cellular damage [7,8].  Tocopherols are known to be highly reactive radicals.  In membranes such high reactivity is of considerable importance because tocopherols react with peroxyl radicals to yield a relatively stable lipid hydroperoxide and tocopheroxyl radical chain reaction, thereby affording protection against lipid peroxidation. 

Vitamin C is present in most biological settings.  In studies with human plasma lipids, it was shown that ascorbate was far more effective in inhibiting lipid peroxidation initiated by a peroxyl radical initiator than other plasma components, such as protein thiols, urate, bilirubin, and α–tocopherol.  Thus, by efficiently trapping peroxyl radicals in the aqueous phase before they can initiate lipid peroxidation, ascorbate can protect biomembranes against peroxidative damage.  Dietary ascorbate protects human sperms from endogenous oxidative DNA damage that affect sperm quality and increase the risk of genetic defects, particularly in populations with low ascorbate seen in smokers [9].  In addition, ascorbate protects membranes against peroxidation by enhancing the activity of tocopherols. 

Epidemiological studies in humans have suggested that β-carotene aids in cancer prevention, and may also exert this effect, independent of its role as a precursor of vitamin A.  β-carotene inhibit neoplastic transformation induced physically or chemically in class in vitro.  The mechanism by which carotenoids protect biological systems against singlet-oxygen–mediated damage appears to depend largely on physical quenching.  Among the biologically occurring carotenoids, lycopene is an efficient singlet oxygen quencher. 

Phenolics are found virtually in all plant foods at very high concentrations and influence the quality, acceptability and stability of foods by acting as flavourants, colourants and antioxidants.  Phenolics inhibit the pro-oxidant enzymes [10], inhibit lipid peroxidation in biological systems and oxidative reactions in processed foods [11].  The use of phenolic compounds in food products is limited because of their unacceptable flavour [12].  Phenolics are anticarcinogenic as they reduce the bioavailability of carcinogens and inhibit the metabolic activation of carcinogens [13]. 

Epidemiological evidence abounds on the effect of antioxidants, in combination or singly on human health.  Some studies have shown that smokers with diets high in carotenoids have a lower rate of lung cancer development than smokers on a low β-carotene diet.  There are also studies that indicate to the contrary, that smokers taking β-carotene had higher death rates.  Vitamin C, on the other hand, has been found to prevent the formation of N-nitroso compounds, the cancer causing substances from nitrates and nitrites found in preserved meats and in some drinking water.  Elderly people with impaired immune system, who may suffer reduced food intake, and who are heavy drinkers, smokers and use aspirins, may benefit from taking antioxidant supplements daily.  For cardiovascular diseases, it is possible that higher levels of antioxidants slow or even prevent the development of arterial blockages and also the collection of plaque of arterial walls.  There are conflicting reports on the health benefits of antioxidants and β-carotene.  

 Randomized trials, prospective cohort studies, and case-control studies conducted in the context of prospective cohort studies, in this case nested case-control studies have been reviewed. These include studies of supplementation with vitamin A, C and E, β-carotene, α-carotene, selenium, β-cryptoxanthin combinations of these substances and diet rich in these substances. This review has concentrated on studies that have reported on the preventive, control or curative role of antioxidants on cardiovascular diseases, cancer, aging and human immunodeficiency.  

Cardiovascular Disease

Cardiovascular disease is a current public health problem.  Considerable evidence now suggests that antioxidants may contribute to disease resistance.  Epidemiological evidence abounds stating the contribution of antioxidants to prevention of cardiovascular disease.  Oxidized low-density lipoprotein is involved in the pathogenesis of atheroscelerosis. In some epidemiological studies, antioxidants have been inversely related with coronary disease.  Evidence from prospective cohort studies have shown that a high consumption of plant-based foods especially fruits, vegetables, whole grains and nuts, is associated with lower risk of coronary artery disease and stroke [14].  Protective effects of these foods are probably mediated through multiple beneficial nutrients contained in these foods including antioxidants, vitamins, minerals, phytochemicals, fiber, plant protein, mono- and polyunsaturated fatty acids.  These diets deserve more emphasis in dietary recommendations to prevent chronic disease. 

Baseline consumption of carotenoids and other nutrients of 73,286 female nurses were recorded and the sample population followed for 12 years for the development of coronary artery disease (CAD), nonfatal myocardial infarction and fatal coronary artery disease.  A total of 998 nurses developed coronary artery disease.  There was a significant inverse association between the highest quintiles of intake of β-carotene and α-carotene and risk of coronary artery disease (CAD) [15].  Higher intakes of foods rich in α-carotene or β-carotene are associated with a reduction in coronary artery disease. On the contrary, a prospective nested case-control analysis of male physicians without prior history of cardiovascular disease were followed up for 13 years to assess the effect of plasma carotenoids and tocopherols on myocardial infarction. In this study, there was no protective relation between plasma carotenoids or tocopherols and future myocardial infarction in the study group [16]. Other factors besides diet also have an influence on the development of heart disease. 

Vitamin E, an α-tocopherol appears to have more protective effects on nonfatal coronary heart disease than β-carotene. Preventive effects of α-tocopherol and β-carotene supplementation in coronary events of 27,271 Finish male smokers (50-69years) with no history of myocardial infarction revealed a reduction on the incidence of primary major coronary events by 4% among recipients of β-carotene compared with the respective non-recipients.  None of the agents affected incidence of nonfatal myocardial infarction.  Supplementation with vitamin E reduced incidence of fatal coronary heart disease by 8% whereas β-carotene had no effect [17]. 

Other dietary factors seem to be more effective in heart diseases than antioxidant supplements. Antioxidant supplements were given to 28 male myocardial infarction survivors and 57 rural male controls to see its effect on chromosome damage.  There was a decrease in the percentage of cells with chromosome aberrations in the group of rural controls.  The largest effect was seen in smokers in this group [18].  The reducing effect of  dietary intake on heart disease, especially fruits and vegetables, can be attributed to the change in form of supplements, mechanisms of their preparation, and absence or low levels of other plant factors that possibly have influence on heart disease. 

Humans with increased dietary intake of vitamins E, C and carotenoids have decreased risk of coronary heart disease [19] and so are diets high in phenolic compounds [20-22].  Drinking tea provides a degree of protection against cardiovascular disease.  There is epidemiological evidence of an inverse relationship between tea drinking and plasma cholesterol levels.  There is evidence of reduction in cholesterol levels and blood pressure with intakes of over nine cups of green tea and over 5 cups of black tea [21-23].  Tea and proper diet trend has a reduction effect on coronary disease mortality [24].  Tea polyphenols reduce both blood cholesterol levels and blood pressure.  Possibly tea catechins and gallate esters reduce the solubility of cholesterol absorption from intestine and also lower blood coagulability, conferring protection against coronary disease and blood pressure. 

Oxidative damage accelerates the process of atherogenesis and oxidative modification of low-density lipoprotein (LDL), a key step in atherosclerotic lesion.  Antioxidants prevent oxidation of LDL and potentially slow down the rate of atherogenesis [25]. Phenolic compounds, especially in the form of red wine,  helps to prevent the manifestations of cardiovascular diseases and inhibit atheroscelerosis [26]. A three-year double blind controlled study of 160 patients with significant coronary artery disease and low HDL levels reported fewer attacks and slight regression of lesions in those who received niacin and simvastatin. However, in this study those who received  antioxidants only (vitamin C, E, β-carotene and selenium) had no benefit and the case was worse for those who received antioxidants in addition to niacin and simvastatin [25, 27, 28].  The researchers believe that the negative effect resulted from blocking an increase in HDL₂ that would have had a cardioprotective effect.  Other combinations of antioxidant treatments are useful in distinct populations. 

Carcinogenesis

The basic mechanism for carcinogenesis is cell differentiation.  Vitamins E, C and β- carotene have a profound influence on cell growth and differentiation.  Many chemical carcinogens are blocked through antioxidants that convert them into less harmful compounds.  In the human tissue, in foods and cigarette smoke are animal carcinogens such as nitrosamines and nitrosamides antioxidants that inhibit carcinogenesis by blocking nitrosation.  High-density dosage of vitamin C and carotenoids are necessary for reduced cancer risk.  Since the generation of reactive oxygen species is linked to activation of carcinogens in the phase of initiation as well as to alterations in cellular activities in the phases of both promotion and progression, it is conceivable that their inactivation may result in protection against carcinogenesis. 

Epidemiological studies have provided strong evidence for a protective effect of various antioxidative and singlet oxygen-quenching nutrients against the development of cancer.  Most of the studies determining dietary intake or analysis of serum concentrations of carotenoids, in particular β-carotene, in relation to cancer incidence have a significant inverse association [29].  Corresponding findings have been obtained for vitamin C  [4] and vitamin E [30, 31].  Epidemiological evidence is strongest for β–carotene, followed by vitamin C and is comparatively weaker for vitamin E.  Though enzymatic and metal sequestrant antioxidants play an important role in quenching free radicals, they are difficult to be modulated by dietary or pharmacological interventions.  Therefore, dietary antioxidants such as β-carotene, vitamin E and C offer promising possibilities in preventing initiation, promotion and progression of carcinogenesis in humans.  Epidemiological evidence has suggested that vitamin A, E and potent cell regulation factors, can profoundly modulate cancer cell growth, differentiation and regression or even reverse cancer cells to normal phenotype in vitro [32] as well as in vivo [33, 34].  These vitamins can reduce the incidence and delay the progression of various cancers [35].   

In vivo mutagenic effects of several dietary items and smoking habits were assessed using hypoxanthine-guanine phosphoribosyl transferase (HPRT) gene essay with T-lymphocytes from 158 lung cancer cases and 154 population control.  HPRT mutant frequency was significantly decreased in relation to intake of vegetables, citrus fruits and berries respectively.  Lowest mutagenic frequency was also associated with carotenoid intake.  Vegetables and fruits have a cancer-protective effect by modulation of somatic mutagenesis [36].  There is an increased risk of lung cancer in smokers with β-carotene supplementation and thus it should not be recommended for smokers. 

Beta-carotene may affect cell growth, by redox mechanism.  Human leukemic cells and color adenocarcinoma cells were treated with β-carotene, alone or in combination with α-tocopherol or N-acetylsteine, and changes in cell oxidative status and cell growth and apoptosis were assessed [39].  Colon adenocarcinoma cells displayed substantial differences in their sensitivity to β-carotene. Alpha-tocopherol and N-acetylcysteine inhibited the effects of β-carotene on NF-K^B  (redox-sensitive transcription factor nuclear factor) cell growth and apoptosis, and normalized increased expression of c-myc induced by carotenoids.  Thus redox regulation of NF-K^B  induced by β-carotene is involved in the growth-inhibitory and proapoptic effects of the carotenoids in tumor cells [37]. 

In a randomized placebo-controlled study to evaluate the effect of lycopene supplementation on DNA damage, 33 patients with localized prostrate adenocarcinoma, were fed on tomato sauce based pasta dishes for 3 weeks (each received 30 mg lycopene per day) before their scheduled radical prostratectomy.  There was significant uptake of lycopene into prostrate tissue and a reduction in DNA damage in both leukocyte and prostrate tissue [38].  It is, however, not clear whether reduction in DNA damage to prostrate cancer cells is beneficial. Evidence from a prospective nested case-control study of the association between serum carotenoids, retinoids and tocopherols on both lung cancer and prostrate cancer incidence revealed a significant association between tobacco use and serum micronutrient concentration.  Physiological levels of dietary micronutrients have an influence on cancer incidence [39]. 

Evaluation of the association between plasma β-carotene, lycopene, lutein/zeaxanthin, total carotenoids, retinal α-tocopherol and subsequent mortality was conducted among 259 participants in a chemoprevention trial aimed at the prevention of cancers of larynx, pharynx and oral cavity [40].  Lycopene was significantly inversely associated with total mortality in the study population while retinal was positively associated with cardiovascular death.  Lycopene, α-carotene and total carotenoids were inversely associated with mortality in non-smokers while plasma retinal and α-tocopherol were positively associated with mortality in smokers. 

Dietary factors have been found to have more protective effects against lung cancer than antioxidant supplements. The association of diet and lung cancer risk was examined in 14,120 Carotene Retinol Efficacy Trial (CARET) participants who completed food frequency questionnaire and were followed up for 12 years.  A total of 742 (5.25%) participants developed lung cancer [41]. Fruits and vegetables were significantly associated with lower lung cancer risk.  Though plant foods have important preventive influence in a population at high risk for lung cancer, smokers who use β-carotene supplements do not benefit from their protective effects [42].  Greater intake of foods high in β-cryptoxanthin, for example citrus fruits may modestly lower lung cancer risk. High prediagnostic serum β-cryptoxanthin levels have been found to be associated with reduced risk of lung cancer [43].  β-cryptoxanthin is a chemopreventive agent for lung cancer in humans.  Fruit and vegetable consumption or diet rich in carotenoids, tomatoes and tomato-based products may reduce the risk of lung cancer [36,41]. 

The effect of diet on the influence of disease onset is related to its oxidative balance, and is associated with mortality. Evaluation of the oxidative balance of the dietary pattern of smokers was classified into two groups.  High oxidative balance group included those with a diet low in vitamin C and β-carotene and/or high in iron.  Low oxidative balance group included smokers with a diet high in vitamin C and β-carotene and/low in iron.  Individuals with high oxidative balance score group had a high relative risk total cancer mortality compared with those in the lowest group [44].  This association was less pronounced for coronary disease mortality risk and was not significant [45].  Smokers whose diet is unbalanced in terms of antioxidants and prooxidants may benefit from increased consumption of fruits and vegetables and reduced consumption of meat. 

Human Immunodeficiency

There is a close relationship between susceptibility to infectious diseases and nutritional state, in the sense that an adequate diet and good general condition make the subject more resistant to infections. A well-nourished individual can resist infections better than a malnourished individual.  Malnutrition, in all its forms, is one of the most common and striking phenomena of Acquired Immune Deficiency Syndrome.  It is well known that the normal development or repair of the damaged immunocompetent system needs adequate levels of vitamins, especially A, E and folic acid.  Supplementation of high doses of β-carotene, use of multivitamins and/or single vitamins could delay the progression of HIV-infection. 

There is evidence that the presence of antioxidants, such as glutathione and ascorbic acid in the cell culture medium affects the HIV activity.  Cellular antioxidant status is possibly an important factor determining the latency period of HIV infection.  HIV–seropositive individuals have been reported to decrease levels of total acid-soluble thiols, cysteine, and glutathione in their blood plasma, lung-epithelial lining fluids, and peripheral blood monocyte [46-48].  The thiols of glutathione, glutathione monoester, and N-acetylcysteine alter HIV expression in vitro.  These thiols possibly have therapeutic value. 

An intracellular protein called nuclear factor -k^B (NF-K^B), an important cellular transcription factor that can trigger HIV replication, is inhibited by N-acetylcysteine  [49].  This protein is likely to be activated by free radical peroxide.  It has been shown in rats and chicks that dietary cysteine deficiency leads to depressed levels of hepatic glutathione [50, 51].  Cysteine as well as glutathione is found in certain vegetables. It occurs in relatively low amounts in most foods.  Enteral nutrition products used in hospitals are also low in cysteine.  This product is made extensively of casein, which is very low in cysteine. 

Vitamin C though not directly used for glutathione synthesis, affects HIV replication in acute or chronic in vitro systems [52].  The presence of ascorbic acid caused a time- and dose-dependent decrease in HIV activity in acutely infected CD4 + T. lymphocytes.   A nutritionally adequate diet is important in the maintenance of a fairly healthy status in people living with HIV/AIDS.  Observations have shown comparatively longer life in individuals on a good diet than those on a poor diet. 

Aging

Though the physiological aspects of aging are more complex, comparative and evolutionary studies have indicated that aging may be the result of pleiotropic effects of two major biological processes: differentiation and development.  Aging rate is generally correlated to metabolic rate or the rate of oxygen utilized per unit of tissue.  The rate of oxygen metabolism is positively correlated with the rate of oxygen radical production, which is a primary causative factor in the aging process.  Accordingly, there is greater need for antioxidants to suppress the toxic effects of active oxygen species.  The importance of tissue concentration of some endogenous antioxidants (carotenoids, α- tocopherol, uric) in giving protection against oxyradical formed in tissues was examined [53].  The tissue concentration of these antioxidants showed positive correlation with lifespan of mammalian species by giving protection against the active oxygen radical damage.  Though the mechanism through which active oxygen species cause aging is not well understood, a commonly accepted concept is that oxy-radicals destroy cells and/or enzymes so that older animals simply run out of enough cells or enzymes to maintain optimum health status [46,48] 

Oxidative stress is thought to be a factor in the progression of chronic diseases and even aging.  The effect of two moderate vitamin, mineral and phytochemicals supplements and a dietary intervention on markers of oxidative stress and antioxidant status was examined in human subjects by randomly assigning them to a group with one of the four intervention: antioxidant supplement capsule, antioxidant supplement tablet, high carotenoids diet and a placebo.  Post intervention serum levels of some of the supplemented carotenoids and α-tocopherol were higher in all treatment groups compared with placebo group and with preintervention levels within groups [54].  Both moderate antioxidant supplements and a diet rich in carotenoids elevate serum carotenoids and antioxidant level among old population.

CONCLUSION

Antioxidants play a great role in scavenging free radicals in the body, which would otherwise damage the DNA, proteins, carbohydrates and lipids.  The body, therefore, needs a continuous supply of antioxidants, which are essential components of foods.  This review indicates that antioxidants play a great role in human health.  Increased dietary intake of antioxidants showed less risk for coronary heart diseases and also offered promising possibilities in preventing initiation, promotion and progression of carcinogenesis. For normal development or repair of the damaged immunocompetent system, the importance of adequate levels of antioxidants is highly imperative.  Antioxidants also play an important role in aging.   Epidemiological evidence has revealed a relationship between the body levels of antioxidant vitamins and certain health problems. It is essential to have a dietary intake of these vitamins to enjoy good health.  Fruits and vegetables have been reported to have preventive effect on degenerative chronic diseases and aging.  They contain antioxidants and other phytochemicals that have preventive effects.  Fruits and vegetables grow easily and are accessible to most of the human population, who should be encouraged to expand kitchen gardens to promote the consumption of these foods.

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Department of Home Science & Technology, Maseno University, Box 333 Maseno, Kenya. E-Mail:khakoni@yahoo.com