Antioxidant nutrients

As mentioned earlier, mutations can occur as a result of oxidative damage to DNA caused by free radicals generated as a damaging side-effect of aerobic metabolism.28 Superoxide radicals are formed by the addition of an electron to molecular oxygen. These highly reactive species can then acquire a further electron and combine with protons to form hydrogen peroxide. In the presence of transition metal ions such as Fe2+ and Cu2+, hydrogen peroxide can break down to give even more highly reactive hydroxy radicals which can damage DNA directly, or participate in self-propagating chain reactions with membrane lipids. Plant and animal cells defend themselves against these effects by deploying so-called antioxidant compounds to trap or quench free radicals and hence arrest their damaging reactions. A variety of defence systems based on both water- and lipid-soluble antioxidant species and on antioxidant enzymes are deployed throughout the intra- and extracellular environment, at the sites most vulnerable to pro-oxidant damage. Many of those in the human body are dependent upon antioxidants derived from the diet. The theory that free radicals are a major cause of human cancer and that the risk of disease can be reduced by increased consumption of food-borne antioxidants has prompted an enormous growth of interest in antioxidant nutrients and other antioxidant substances in food.29 It is worth noting, however, that the role of mutagenesis due to oxygen free radicals in the pathogenesis of human cancers remains largely hypothetical,28 and attempts to prevent cancer by intervention with high doses of antioxidant vitamins have been largely unsuccessful.30'31 Vitamin E

The major lipid-soluble antioxidant is vitamin E, first isolated from wheat-germ oil and obtained principally from nuts, seed oils and cereals. Vitamin E is actually a collective term for eight compounds: a-, b-, g- and S- tocopherol, and a-, b-, g- and S- tocotrienol, but RRR-a-tocopherol, accounts for 90 % of endogenous vitamin E activity in humans. All the tocopherols and tocotrienols contain a hydroxyl-bearing aromatic ring structure, which enables them to donate hydrogen to free radicals, and thus act as biological antioxidants. The unpaired electron which results from hydrogen donation is delocalised into the ring structure of the tocopherol, rendering it relatively stable and unreactive. Chain reactions initiated by hydroxy radicals can be broken by the formation of a stable radical as a result of interaction with vitamin E.32 Vitamin E is readily incorporated into cell membranes, which, being rich in polyunsaturated fatty acids, are highly susceptible to damage by free radicals derived from metabolic activity. In humans, frank symptoms of vitamin E deficiency are only seen in premature infants or malabsorption states, but intakes higher than are required to protect against deficiency may provide additional protection against free-radical mediated DNA damage. Epidemiological studies show a strong inverse correlation between risk of cancer and vitamin E intake at the population level, but the association is not corroborated by studies of individuals taking supplements.33 Moreover, a well-controlled investigation designed to test the hypothesis that dietary supplementation with vitamins

C and E would reduce the recurrence of adenomas in patients who had undergone polypectomy showed no evidence of a protective effect.31 Similarly, a prolonged placebo-controlled intervention with vitamin E or vitamin E and beta-carotene failed to prevent the development of lung cancer in smokers.30 Carotenoids

Approximately 500 carotenoids have been identified in vegetables and fruits used as human foods, but the vast majority of these compounds occur at low concentrations and are probably of little nutritional importance. By far the most well-known and intensively studied of the carotenoids is beta-carotene,34 which is a precursor for vitamin A, but the increased interest in dietary antioxidants in recent years has focused attention on other carotenoids such as lycopene and lutein which are abundant in tomatoes and coloured vegetables.3536 The molecular structure of the carotenoids includes an extended chain of double bonds which enables them to function as antioxidants. Carotenoids are released from plant foods in the small intestine and absorbed in conjunction with dietary fat. Beta-carotene is converted into vitamin A by enzymes in the intestinal mucosa but it is detectable in human plasma, at levels that are related positively to the dietary intake of fruits and vegetables, and at least ten other carotenoids have also been recorded in human blood.

There is good epidemiological evidence for an inverse association between intake of carotenoids and lung cancer, and weaker evidence for protective effects against cancers of the alimentary tract.37 The possibility that carotenoids might express antioxidant activity in human tissues, thereby protecting cell membranes, proteins and DNA against damage by free radicals, provides a plausible rationale for these associations, but once again the causal link has not been proven and the possibility remains that carotenoids are acting as markers for fruit and vegetable intake which may be beneficial for other reasons.36 Intervention trials with beta-carotene have proved disappointing. The alpha-tocopherol beta-carotene (ATBC) study, which involved over 29000 male smokers, and included a cohort given 20 mg betacarotene daily for up to eight years, produced no evidence for a protective effect against cancer at any site. On the contrary, there was a higher incidence of lung, prostate and stomach cancer in the beta-carotene group.30 Similarly, the CARET study, in which subjects received 30mg beta-carotene and 25 000 international units of retinol per day, was terminated because of an increase in deaths from lung cancer in the treatment group.38 There is no suggestion that beta-carotene is toxic in any other circumstances, even when given at pharmacological doses for long periods to treat photosensitivity disorders,39 but the evidence suggests that it may act as a tumour promoter when taken by subjects already harbouring pre-cancerous lesions induced by chronic exposure to tobacco smoke. Under these circumstances it is obviously inappropriate to encourage the devel opment and consumption of functional foods designed to provide consumers with high doses of carotenoids, but the general advice to increase fruit and vegetable consumption remains valid. Vitamin C

Vitamin C occurs as L-ascorbic acid and dehydroascorbic acid in fruits, vegetables and potatoes, as well as processed foods to which it has been added as an antioxidant. The only wholly undisputed function of vitamin C is the prevention of scurvy. Although this is the physiological rationale for the currently recommended intake levels, there is growing evidence that vitamin C may provide additional protective effects against other diseases including cancer, and the RDA may be increased in the near future. Scurvy develops in adults whose habitual intake of vitamin C falls below 1 mg per day, and under experimental conditions 10 mg per day is sufficient to prevent or alleviate symptoms.40 The recommended dietary allowance (RDA) is 60mg per day in the USA, but plasma levels of ascorbate do not achieve saturation until daily intakes reach around 100mg.41 Ascorbate is probably the most effective water-soluble antioxidant in the plasma. It scavenges and reduces nitrite, thus inhibiting the formation of carcinogenic N-nitroso compounds in the stomach, and in vitro studies suggest that it plays a protective role against oxidative damage to cell constituents and circulating lipoproteins.42 The epidemiological evidence is consistent with a protective effect of vitamin C against cancers of the stomach, pharynx and oesophagus in particular,43 but the evidence for causality remains inconclusive because of the sheer complexity of the composition of fruits and vegetables, which are the main source of the vitamin in the unsupplemented diet. Byers and Guerrero33 considered the collective evidence from a large series of case-control and cohort studies in which intakes of fruits and vegetables, and of vitamins C and E from food or from supplements, were determined. There was a strong and consistent protective effect of fruits and vegetables against cancers of the alimentary tract and lung and a correlation with estimated vitamin C intake based on fruit and vegetable composition. However, there were considerable confounding effects of other dietary constituents and the evidence for a protective effect of vitamin C from supplements was less convincing. Most of the ascorbate in human diets is derived from natural sources, and consumers who eat five portions, or about 400-500g, of fruits and vegetables per day could obtain as much as 200mg of ascorbate. Nevertheless, given the low cost and toxicity of ascor-bate, it seems likely that there will be a continuing trend towards supplementation of foods. Selenium

Selenium is a trace mineral, widely distributed at relatively low concentrations in the human food chain. It is essential to human nutrition because of the role played by the amino acid selenocysteine as a component of the mammalian selenoproteins. Over 30 of these have now been identified,44 the best characterised and widely studied of which are the glutathione peroxidases. Cytosolic glutathione peroxidase was the first of the seleno-proteins to be identified,45 but three other tissue-specific glutathione peroxidases have been identified more recently. All of the glutathione peroxidases catalyse the reduction of hydrogen peroxide and other reactive oxygen species, including lipid peroxides, at the expense of the tripeptide glutathione, which is synthesised within the cell. This system is the major regulator of intracellular redox status throughout the body, but tissue-specific glutathione peroxidases such as that of the gastrointestinal mucosa probably play a more particular role in the detoxification of dietary lipid peroxides.46 Biosynthesis of the selenoproteins is rate-limited by the supply of selenium in the diet, and selenium is therefore classed as an antioxidant nutrient. It is interesting to note that when the supply of dietary selenium is limited, the mineral is preferentially used for the biosynthesis of certain glutathione peroxidases at the expense of others. This hierarchy is thought to reflect their relative importance in the maintenance of antioxidant defences in key tissues.44

Selenium supplementation has been reported to have a variety of positive effects on the cardiovascular system, the immune system, and on general health, not all of which necessarily reflect its antioxidant role.47 However, it is reasonable to propose that adequate selenium status is required to minimise the risk of cancer because maintenance of cellular redox balance is probably crucial to the prevention of free-radical mediated DNA damage. The design of epidemiological studies to test this hypothesis has been complicated by the difficulty of assessing accurately the exposure of individuals to dietary selenium, but there is evidence of an inverse relationship between risk of cancer and dietary intake of selenium at the population level.48 Prospective studies in which the incidence of cancer has been correlated with selenium status assessed by analysis of toenails have provided evidence of protective effects against a variety of cancers, but such studies have usually been relatively small. In one recent study, however, a significant three-fold inverse association between prostate cancer and toenail selenium was observed in a cohort of 33737 men.49 Perhaps the strongest evidence for the protective effect of selenium comes from the Nutritional Prevention of Cancer Trial, an intervention study in which a selenium-rich yeast product was used in an attempt to reduce the recurrence of non-melanoma skin cancer. Although there was no effect of supplementation on the primary endpoint, there were significant reductions of around 50 % in the incidence of other cancers, including those of the lung, colon and prostate.50 Further intervention trials with large cohorts designed to explore the implications of these findings are planned for both Europe and the USA.47

Dietary provision of selenium is problematic in a number of countries, including many in Europe, because of the low availability of soil selenium to plants used as human food. Although there are a few rich sources of selenium in the human food chain, notably Brazil nuts and some types of offal, these are usually only eaten in small quantities. Wheat is one of the most important sources of selenium in western diets, but European cereals are relatively low in selenium compared to North American wheat, and this has led to fears that populations may be at increased risk of cancer because of sub-optimal selenium intakes.51 Unfortunately, selenium is potentially toxic at relatively low levels of intake, and food fortification carries a real risk of harm to individuals who might be tempted to overconsume. Another strategy is the addition of selenium to agricultural fertilisers, so as to raise the selenium content of staple crops. This approach has been pursued successfully in Finland. Both public health policy in relation to selenium, and the commercial development of selenium-enriched products seem likely to continue to evolve as further information about the potential health benefits of selenium becomes available.

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