Reference from the joint report of FAO/WHO expert consultation on Human Vitamins and Minerals verbatim.
3. Thurnham, D,I. 1990. Antioxidants and pro-oxidants in malnourished populations. Proc. Nutr. Soc., 48: 247-259.
29. Thurnham, D.I. 1994. β-Carotene, are we misreading the signals in risk groups? Some analogies with vitamin C. Proc. Nutr. Soc., 53:557-569.
30. Thurnham, D.I. 1997. Impact of disease on markers of micronutrient status. Proc. Nutr. Soc., 56: 421-431.
Pro-oxidant activity of biologic antioxidants
Most biologic antioxidants are antioxidants because when they accept an unpaired electron, the free radical intermediate formed has a relatively long half-life in the normal biologic environment. The long half-life means that these intermediates remain stable for long enough to interact in a controlled fashion with intermediates which prevent autoxidation, and the excess energy of the surplus electron is dissipated without damage to the tissues.
31. Packer, J.E., Slater, T.F. & Willson, R.L. 1979. Direct observations of a free radical interaction between vitamin E and vitamin C. Nature, 278: 737-738.
32. Niki, E., Tsuchiya, J., Tanimura, R. & Kamiya, Y. 1982. Regeneration of vitamin E from α-chromanoxyl radical by glutathione and vitamin C. Chem. Lett., 27: 798-792.
13. Diplock, A.T., Charleux, J-L. & Crozier-Willi, G. 1998. Functional food science and defence against reactive oxidative species. Br. J. Nutr., 80: S77-S112.
Thus it is believed that the tocopheroxyl radical formed by oxidation of α-tocopherol is sufficiently stable to enable its reduction by vitamin C or GSH to regenerate the quinol (31, 32) rather than oxidizing surrounding PUFAs. Likewise the oxidized forms of vitamin C, the ascorbyl free radical and dehydroascorbate, may be recycled back to ascorbate by GSH or the enzyme dehydroascorbate reductase (13).
33. Burton, G.W. & Ingold, K.U. 1984. B-carotene: an unusual type of lipid antioxidant. Science, 224: 569-573.
34. Palozza, P. 1998. Prooxidant actions of carotenoids in biologic systems. Nutr. Rev., 56: 257-265.
The ability to recycle these dietary antioxidants may be an indication of their physiologic essentiality to function as antioxidants. Carotenoids are also biologic antioxidants but their antioxidant properties very much depend on oxygen tension and concentration (33, 34).
At low oxygen tension β-carotene acts as a chain-breaking antioxidant whereas at high oxygen tension it readily autoxidizes and exhibits pro-oxidant behaviour (33). Palozza (34) reviewed much of the evidence and suggests that β-carotene has antioxidant activity between 2 and 20 mmHg of oxygen tension, but at the oxygen tension in air or above (>150 mmHg) it is much less effective as an antioxidant and can show pro-oxidant activity as the oxygen tension increases.
Palozza (34) also suggests that autoxidation reactions of β-carotene may be controlled by the presence of other antioxidants (e.g., vitamins E and C) or other carotenoids. There is some evidence that large supplements of fat-soluble nutrients such as β-carotene and other carotenoids may compete with each other during absorption and lower plasma concentrations of other nutrients derived from the diet.
35. Heinonen, O.P., Huttunen, J.K., Albanes, D. & ATBC cancer prevention study group. 1994. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med., 330: 1029-1035.
However, a lack of other antioxidants is unlikely to explain the increased incidence of lung cancer in the α-tocopherol β-carotene intervention study, because there was no difference in cancer incidence between the group which received both β-carotene and α-tocopherol and the groups which received one treatment only (35).
36. Halliwell, B., Gutteridge, J.M.C. & Cross, C.E. 1992. Free radicals, antioxidants, and Human disease: where are we now? J. Lab. Clin. Med., 119: 598-620.
The free radical formed from a dietary antioxidant is potentially a pro-oxidant as is any other free radical. In biologic conditions which might deviate from the norm, there is always the potential for an antioxidant free radical to become a pro-oxidant if a suitable receptor molecule is present to accept the electron and promote the autoxidation (36).
29. Thurnham, D.I. 1994. β-Carotene, are we misreading the signals in risk groups? Some analogies with vitamin C. Proc. Nutr. Soc., 53:557-569.
37. Stadtman, E.R. 1991. Ascorbic acid and oxidative inactivation of proteins. Am. J. Clin. Nutr., 54: 1125S-1128S.
Mineral ions are particularly important pro-oxidants. For example, vitamin C will interact with both copper and iron to generate cuprous or ferrous ions, respectively, both of which are potent pro-oxidants (29, 37).
Fortunately, mineral ions are tightly bound to proteins and are usually unable to react with tissue components unless there is a breakdown in tissue integrity. Such circumstances can occur in association with disease and excessive phagocyte activation, buteven under these circumstances there is rapid metabolic accommodation in the form of the acute-phase response to minimise the potentially damaging effects of an increase in free mineral ions in extra-cellular fluids (Table 57).
Nutrients associated with endogenous antioxidant mechanisms Both zinc and selenium are intimately involved in protecting the body against oxidant stress.Zinc combined with copper is found in the cytoplasmic form of SOD whereas zinc and magnesium occur in the mitochondrial enzyme. SOD occurs in all aerobic cells and is responsible for the dismutation of superoxide (reaction 4):
Hydrogen peroxide produced as a product of dismutation reaction is removed by GPx of which selenium is an integral component (reaction 5). To function effectively, this enzyme also needs a supply of hydrogen, which it obtains from GSH. Cellular concentrations of GSH are maintained by the riboflavin-dependent enzyme glutathione reductase.
38. Arthur, J.R., Bermano, G., Mitchell, J.H. & Hesketh, J.E. 1996. Regulation of selenoprotein gene expression and thyroid hormone metabolism. Trans. Biochem. Soc., 24: 384-388.
39. Howie, A.F., Arthur, J.R., Nicol, F., Walker, S.W., Beech, S.G. & Beckett, G.J. 1998. Identification of a 57-kilodalton selenoprotein in Human thyrocytes as thioredoxin redctase and evidence that its expression is regulated through the calcium phosphoinositol-signalling pathway. J. Clin. Endocrinol. Metab., 83: in press.
Four forms of selenium-dependent GPx have been described which have different activities in different parts of the cell (38). In addition, a selenium-dependent thyrodoxin reductase was recently characterised in human thyrocytes. Thyrodoxin reductase may be particularly important to the thyroid gland because it can cope with higher concentrations of peroxide and hydroperoxides generated in the course of thyroid hormone synthesis better than can GPx (39).
It is suggested that in combination with iodine deficiency, the inability to remove high concentrations of hydrogen peroxide may cause atrophy in the thyroid gland, resulting in myxedematous cretinism (39).
36. Halliwell, B., Gutteridge, J.M.C. & Cross, C.E. 1992. Free radicals, antioxidants, and Human disease: where are we now? J. Lab. Clin. Med., 119: 598-620.
SOD and GPx are widely distributed in aerobic tissues and, if no catalytic metal ions are available, endogenously produced superoxide and hydrogen peroxide at physiologic concentrations may have limited, if any, damaging effects (36).
40. Chow, C.K. 1976. Biochemical responses in lungs of ozone-tolerant rats. Nature, 260: 721-722.
SOD and GPx are of fundamental importance to the life of the cell, and their activity is not readily reduced by deficiencies in dietary intake of these nutrients. In contrast, enzyme activity can be stimulated by increased oxidant stress (e.g., ozone) (40).
41. Aggett, P.J. & Favier, A. 1993. Zinc. Int. J. Vit. Nutr. Res., 63: 301-307.
42. Alfthan, G., Aro, A., Arvilommi, H. & Huttunen, J.K. 1991. Selenium metabolism and platelet glutathione peroxidase activity in healthy Finnish men: effects of selenium yeast, selenite and selenate. Am. J. Clin. Nutr., 53: 120-125.
Activities of zinc-dependent enzymes have been shown to be particularly resistant to the influence of dietary zinc (41), and although erythrocyte GPx activity correlates with selenium when the intake is below 60–80 μg/day (42), there is no evidence of impaired clinical function at low GPx activities found in humans.
43. Clark, L.C., Combs, G.F.J. & Turnbull, B.W. 1996. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomised controlled trial. J. Am. Med. Assoc., 276: 1957-1963.
Nevertheless, one selenium intervention study reported remarkably lower risks of several cancers after 4.5 years of selenium at 200 μg/day (43). The effects were so strong on total cancer mortality that the study was stopped prematurely. However, the subjects were patients with a history of basal or squamous cell carcinomas and were not typical of the general population.
44. Willett, W.C., Polk, B.F. & Morris, J.S. 1983. Prediagnostic serum selenium and risk of cancer. Lancet, ii:130-134.
45. Willett, W.C., Stampfer, M.J., Underwood, B.A., Taylor, J.O. & Hennekens, C.H. 1983. Vitamins A, E and carotene: effects of supplementation on their plasma levels. Am. J. Clin. Nutr., 38: 559-566.
In addition, a prospective analysis of serum selenium in cancer patients (44) (1.72 μmol/L) found very little difference from concentrations in matched controls (1.63 μmol/L) although the difference was significant (45). Furthermore, areas with high selenium intakes have a lower cancer incidence than do those with low intakes, but the high selenium areas were the least industrialized (45).
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