Reference from the joint report of FAO/WHO expert consultation on Human Vitamins and Minerals verbatim.
28. Koj., A. 1985. Biological functions of acute phase proteins. In: Gordon AH, Koj A, eds. The acute phase response to injury and infection. p.145-160. London: Elsevier.
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.
Nutrients with an antioxidant role
1. Young, V.R., Erdman, J.W.J. & King, J.C. 1998. Dietary reference intakes. Proposed definition and plan for review of dietary antioxidant and related compounds. Washington D.C. National Academy Press.
2. Dormandy, T.L. 1983. An approach to free radicals. Lancet, ii:1010-1014.
3. Thurnham, D,I. 1990. Antioxidants and pro-oxidants in malnourished populations. Proc. Nutr. Soc., 48: 247-259.
4. Shankar, A.H. & Prasad, A.S. 1998. Zinc and immune function: the biological basis of
altered resistance to infection. Am. J. Clin. Nutr., 68: 447S-463S.
The potential beneficial effects from antioxidants in protecting against disease have been used as an argument for recommending increasing intakes of several nutrients above those derived by conventional methods. If it is possible to quantify such claims, antioxidant properties should be considered in decisions concerning the daily requirements of these nutrients.
This section examines metabolic aspects of the most important dietary antioxidants – vitamins C and E, the carotenoids, and several minerals – and tries to define the populations which may be at risk of inadequacy to determine whether antioxidant properties per se should be and can be considered in setting a requirement.
In addition, pro-oxidant metabolism and the importance of iron are also considered. Members of the Food and Nutrition Board of the National Research Council in the United States, recently defined a dietary antioxidant as a substance in foods which significantly decreases the adverse effects of reactive oxygen species, reactive nitrogen species, or both on normal physiologic function in humans (1).
It is recognised that this definition is somewhat narrow because maintenance of membrane stability is also a feature of antioxidant function (2) and an important antioxidant function of both vitamin A (3) and zinc (4). However, it was decided to restrict consideration of antioxidant function in this document to nutrients which were likely to interact more directly with reactive species.
The need for biologic antioxidants
5. Halliwell, B. & Gutteridgem J.M.C. 1989. Free radicals in biology and medicine. 2nd ed. Oxford: Clarendon Press.
6. Ames, B.N. 1983. Dietary carcinogens and anticarcinogens, oxygen radicals and degenerative diseases. Science, 221: 1256-1264.
7. Moncada, S. & Higgs, E.A. 1993. Mechanisms of disease: the L-arginine-nitric oxide pathway. N. Engl. J. Med., 329: 2002-2012.
It is now well established that free radicals, especially superoxide (O2·- ), nitric oxide (NO·), and other reactive species such as H2O2, are continuously produced in vivo (5-7).
8. Fridovich, I. 1983. Superoxide radical: an endogenous toxicant. Annu. Rev. Pharmacol Toxicol., 23: 239-257.
9. Baboire, M.B. 1973. Oxygen microbial killing of phagocytes. N. Engl. J. Med., 298:659-680.
Superoxide in particular is produced by leakage from the electron transport chains within the mitochondria and microsomal P450 systems (8) or formed more deliberately, for example, by activated phagocytes as part of the primary immune defence in response to foreign substances or to combat infection by micro-organisms (9).
7. Moncada, S. & Higgs, E.A. 1993. Mechanisms of disease: the L-arginine-nitric oxide pathway. N. Engl. J. Med., 329: 2002-2012.
10. Hogg, N., Kalyanaraman. B., Joseph. J., Struck. A. & Parthasarthy, S. 1993. Inhibition of low density lipoprotein oxidation by nitric oxide. FEBS Lett, 334:170-174.
Nitric oxide is produced from L-arginine by nitric oxide synthases, and these enzymes are found in virtually every tissue of the mammalian body, albeit at widely different levels (7). Nitric oxide is a free radical but is believed to be essentially a beneficial metabolite and indeed it may react with lipid peroxides and function as an antioxidant (10).
11. Hibbs, J.B.J., Taintor, R.R., Vavrin, Z. & Rachlin, E.M. 1988. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem. Biophys. Res. Comm., 157:87-94.
12. Koppenol, W.H., Moreno, J.J., Pryor, W.A., Ischiropoulos, H. & Beckman, J.S. 1992. Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. Chem. Res. Toxicol., 5: 834-842.
Nitric oxide also serves as a mediator whereby macrophages express cytotoxic activity against micro-organisms and neoplastic cells (11). If nitric oxide is at a sufficiently high concentration, it can react rapidly with superoxide in the absence of a catalyst to form peroxynitrite. Peroxynitrite is a potentially damaging nitrogen species which can react through several different mechanisms, including the formation of an intermediate with the reactivity of the hydroxyl radical (12).
13. Diplock, A.T., Charleux, J-L. & Crozier-Willi, G. 1998. Functional food science anddefence against reactive oxidative species. Br. J. Nutr., 80: S77-S112.
14. Meister A. 1988. Glutathione metabolism and its selective modification. J. Biol. Chem., 263: 17205-17206.
To cope with potentially damaging reactive oxidant species (ROS), aerobic tissues contain endogenously produced antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase and several exogenously acquired radical scavenging substances such as vitamins E and C and the carotenoids (13).
Under normal conditions the high concentrations of SOD maintains superoxide concentrations too low to allow the formation of peroxynitrite. It is also important to mention the antioxidant reduced glutathione (GSH). GSH is ubiquitous in aerobic tissues, and although it is not a nutrient, it is synthesised from sulfhydryl-containing amino acids and is highly important in intermediaryantioxidant metabolism (14).
Integrated antioxidant defences protect tissues and are presumably in equilibrium with continuously generated ROS to maintain tissues metabolically intact most of the time. Disturbances to the system occur when production of ROS is rapidly increased, for example, by excessive exercise, high exposure to a xenobiotic compounds (such as an anaesthetic, pollutants, or unusual food), infection, or trauma. Superoxide production is increased by activation of NADPH oxidases in inflammatory cells or after the production of xanthine oxidase, which follows ischaemia.
15. Hennekens, C.H. 1986. Micronutrients and cancer prevention. N. Engl. J. Med., 315:1288-1289.
16. Van Poppel, G., Kardinaal, A.F.M., Princen, H.M.G. & Kok, F.J. 1994. Antioxidants and coronary heart disease. Ann. Med., 26:429-434.
The degree of damage resulting from the temporary imbalance depends on the ability of the antioxidant systems to respond to the oxidant or pro-oxidant load. Fruits and vegetables are good sources of many antioxidants, and it is reported that diets rich in these foods are associated with a lower risk of the chronic diseases of cancer (15) and heart disease (16).
17. Thurnham, D.I. 1994. Carotenoids: functions and fallacies. Proc. Nutr. Soc., 53: 77-87.
18. Rock, C.L., Jacob, R.A. & Bowen, P.E. 1996. Update on the biological characteristics of the antioxidant micronutrients: vitamin C, vitamin E and the carotenoids. J. Am. Diet. Assoc., 96:693-702.
19. Hertog, M.G.L., Feskens, E.J.M., Hollman, P.C.H., Katan, M.B. & Kromhout, D. 1993. Dietary antioxdant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet, 342:1007-1011.
Hence, it is believed that a healthful diet maintains the exogenous antioxidants at or near optimal levels thus reducing the risk of tissue damage. The most prominent representatives of dietary antioxidants are vitamin C, tocopherols, carotenoids, and flavonoids (17-19).
Requirements for flavonoids are not being considered at this time and work on this subject is still very much in its infancy. In contrast, several intervention studies have been carried out to determine whether supplements of the other nutrients can provide additional benefits against such diseases.
20. Chevion, M., Jiang, Y., Har-El, R., Berenshtein, E., Uretzky, G. & Kitrossky, N. 1993. Copper and iron are mobilised following myocardial ischemia: Possible predictive criteria for tissue injury. Proc. Natl. Acad. Sci. USA, 90: 1102-1106.
21. Beare, S. & Steward, W.P. 1996. Plasma free iron and chemotherapy toxicity. Lancet
347:342-343.
The components in biologic tissues make an ideal mixture of substrates for oxidation. Polyunsaturated fatty acids (PUFAs), oxygen, and transition metals are present in abundance but are prevented from reaction by cellular organisation and structure. PUFAs are present in membranes but are always found with vitamin E. Transition metals, particularly iron, are bound to both transport and storage proteins; abundant binding sites on such proteins prevent overloading the protein molecule with metal ions. Tissue structures, however, break down during inflammation and disease, and free iron and other transition metals have been detected (20, 21).
22. Halliwell. B. & Gutteridge. J.M.C. 1992. Biologically relevant metal ion-dependent hydroxyl radical generation. An update. FEBS, 307: 108-112.
12. Koppenol, W.H., Moreno, J.J., Pryor, W.A., Ischiropoulos, H. & Beckman, J.S. 1992. Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. Chem. Res. Toxicol., 5: 834-842.
23. Carreras, M.C., Pargament, G.A., Catz, S.D., Poderoso, J.J. & Boveris, A. 1994. Kinetics of nitric oxide and hydrogen peroxide production and formation of peroxynitrite during the respirtory burst of Human neutrophils. FEBS Lett., 341:65-68.
Potentially damaging metabolites can arise from interactions between transition metals and the ROS described above. In particular the highly reactive hydroxyl radical can be formed by the Fenton (reaction 1) and Haber-Weiss reactions (reaction 2; with an iron-salt catalyst) (22).
Pathologic conditions greatly increase the concentrations of both superoxide and nitric oxide, and the formation of peroxynitrite has been demonstrated in macrophages, neutrophils, and cultured endothelium (reaction 3) (12, 23). Peroxynitrite can react through several different mechanisms, including the formation of an intermediate with the reactivity of the hydroxyl radical (12).
3. Thurnham, D,I. 1990. Antioxidants and pro-oxidants in malnourished populations. Proc. Nutr. Soc., 48: 247-259.
24. Thurnham, D.I. 1995. Iron as a pro-oxidant. In: Wharton BA, Ashwell M, eds. Iron, nutritional and physiological significance. p.31-41.London: Chapmann & Hall.
25. Weiss, G., Wachter, H. & Fuchs, D. 1995. Linkage of cell-mediated immunity to iron metabolism. Immunol. Today, 16: 495-500.
During inflammation or other forms of stress and disease, new measures are adopted by the body to counter potential pro-oxidant damage. The body alters the transport and distribution of iron by blocking iron mobilisation and absorption and stimulating iron uptake from plasma by liver, spleen, and macrophages (3, 24, 25).
26. Pantopoulos, K., Weiss, G. & Hentze, M.W. 1994. Nitric oxide and the post-transcriptional control of cellular iron traffic. Trends Cell. Biol., 4: 82-86.
27. Thompson, D., Milford-Ward, A. & Whicher, J.T. 1992. The value of acute phase protein measurements in clinical practice. Ann. Clin. Biochem., 29: 123-131.
Nitric oxide has been shown to play a role in the coordination of iron traffic by mimicking the consequences of iron starvation and leading to the cellular uptake of iron (26). The changes accompanying disease are generally termed the acute-phase response and are, generally, protective (27). Some of the changes in plasma acute-phase reactants which affect iron at the onset of disease or trauma are shown in Table 57.
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