Reference from the joint report of FAO/WHO expert consultation on Human Vitamins and Minerals verbatim.
Vitamin C
51. Myllyla, R., Kuutti-Savolainen, E. & Kivirikko, K.I. 1978. The role of ascorbate in the prolyl hydroxylase reaction. Biochem. Biophys. Res. Comm., 83: 441-448.
52. Hulse, J.D., Ellis, S.R. & Henderson, L.M. 1978. β-Hydroxylation of trimethyllysine by an α-ketoglutarate-dependent mitochondrial dioxygenase. J. Biol. Chem., 253:1654-1659.
53. Bates, C.J. 1981. The function and metabolism of vitamin C in man. In: Counsell JN, Hornig DH, eds. Vitamin C - ascorbic acid. p.1-22. London: Applied Science Publishers.
54. Zannoni, V.G. & Lynch, M.M. 1973. The role of ascorbic acid in drug metabolism. Drug Metab. Rev., 2: 57-69.
Many, if not all of the biologic properties of vitamin C are linked to its redox properties (see Chapter 6). For example, essential defects in scurvy such as the breakdown of connective tissue fibres (51) and muscular weakness (52) are both linked to hydroxylation reactions in which ascorbate maintains loosely bound iron in the ferrous form to prevent its oxidation to the ferric form, which makes the hydroxylase enzymes inactive (53). Ascorbate exhibits similar redox functions in catecholamine biosynthesis (53) and in microsomal cytochrome P450 enzyme activity, although the latter may only be important in young animals (54).
55. Koskela, T.K., Reiss, G.R., Brubacher, R.F. & Ellefson, R.D. 1989. Is the high concentrations of ascorbic acid in the eye an adaptation to intense solar irradiation? Invest. Ophthalmol. Vis. Sci., 30: 2265-2267.
56. Hornig, D.H. 1975. Distribution of ascorbic acid, metabolites and analogues in man and animals. Ann. N Y Acad. Sci., 258: 103-118.
57. Fraga, C.G., Motchnik, P.A., Shigenaga, M.K., Helbock, H.J., Jacob, R.A. & Ames, B.N. 1991. Ascorbic acid protects against endogenous oxidative DNA damage in Human sperm. Proc. Natl. Acad. Sci. USA, 88: 11003-11006.
58. Frei, B. 1991. Ascorbic acid protects lipids in Human plasma and low-density lipoprotein against oxidative damage. Am. J. Clin. Nutr., 54: 1113S-1118S.
In the eye, vitamin C concentrations may be 50 times higher than in the plasma and may protect against the oxidative damage of light (55). Vitamin C is also present in the gonads, where it may play a critical role in sperm maturation (56). Spermatogenesis involves many more cell divisions than does oogenesis, resulting in an increased risk of mutation. Fraga et al. (57) reported that levels of sperm oxidized nucleoside 8-OH-2’-deoxyguanosine (an indicator of oxidative damage to DNA) varied inversely with the intake of vitamin C (5-250 mg/day). No apparent effects on sperm quality were noted. Frei (58) also showed that vitamin C was superior to all other biologic antioxidants in plasma in protecting lipids exposed ex vivo to a variety of sources of oxidative stress.
The importance of vitamin C in stabilising various plasma components such as folate, homo-cysteine, proteins, other micronutrients, etc. has not been properly evaluated. When blood plasma is separated from erythrocytes, vitamin C is the first antioxidant to disappear. Vitamin C is a powerful antioxidant because it can donate a hydrogen atom and form a relatively stable ascorbyl free radical (Figure 27).
59. Rose, R.C. 1989. The ascorbate redox potential of tissues: a determinant or indicator of disease? NIPS, 4: 190-195.
60. Weber, P., Bendich, A. & Schalch, W. 1996. Vitamin C and Human health - a review of recent data relevant to Human requirments. Int. J. Vit. Nutr. Res., 66: 19-30.
61. Tannenbaum, S.R., Wishnok, J.S. & Leaf, C.D. 1991. Inhibition of nitrosamine formation by ascorbic acid. Am. J. Clin. Nutr., 53: 247S-250S.
As a scavenger of ROS, ascorbate has been shown to be effective against the superoxide radical anion, hydrogen peroxide, the hydroxyl radical, and singlet oxygen (59, 60). Vitamin C also scavenges reactive nitrogen oxide species to prevent nitrosation of target molecules (61).
56. Hornig, D.H. 1975. Distribution of ascorbic acid, metabolites and analogues in man and animals. Ann. N Y Acad. Sci., 258: 103-118.
The ascorbyl free radical can be converted back to reduced ascorbate by accepting another hydrogen atom or it can undergo further oxidation to dehydroascorbate. Dehydroascorbate is unstable but is more fat soluble than ascorbate and is taken up 10–20 times more rapidly by erythrocytes, where it will be reduced back to ascorbate by GSH or NADPH from the hexose monophosphate shunt (56).
62. Moser, U. & Weber, F. 1984. Uptake of ascorbic acid by Human granulocytes. Int. J. Vit. Nutr. Res., 54: 47-53.
63. McGowen, E., Parenti, C.M., Hoidal, J.R. & Niewoehner, D.E. 1984. Ascorbic acid content and accumulation by alveolar macrophages from cigarette smokers and nonsmokers. J. Lab. Clin. Med., 104: 127-134.
Thus, mechanisms exist to recycle vitamin C similarly to those for vitamin E. The existence of a mechanism to maintain plasma ascorbate in the reduced state means that the level of vitamin C necessary for optimal antioxidant activity is not absolute because the turnover will change in response to oxidant pressure. Recycling of vitamin C will depend on the reducing environment which exists in metabolically active cells.
In atrophic tissues or tissues exposed to inflammation, cell viability may fail and with it the ability to recycle vitamin C. In such an environment, the ability of newly released granulocytes (62) or macrophages (63) to scavenge vitamin C from the surrounding fluid may be invaluable for conservation of an essential nutrient as well as reducing the risk of ascorbate becoming a pro-oxidant through its ability to reduce iron (37).
β-Carotene and other carotenoids
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.
64. Bendich, A. & Olson, J.A. 1989. Biological action of carotenoids. FASEB J., 3: 1927-1932.
Many hundreds of carotenoids are found in nature but relatively few are found in human tissues, the five main ones being β-carotene, lutein, lycopene, β-cryptoxanthin, andα-carotene (17, 18, 64).
β-Carotene is the main source of pro-vitamin A in the diet. There are approximately 50 carotenoids with pro-vitamin A activity, but β-carotene is the most important and is one of the most widely distributed carotenoids in plant species (64).
65. Gregory, J.R., Foster, K., Tyler, H. & Wiseman, M. 1990. The dietary and nutritional survey of British adults. London: HMSO.
66. Chug-ahuja, J.K., Holden, J.M., Forman, M.R., Mangels, A.R., Beecher, G.R. & Lanza, E. 1993. The development and application of a carotenoid database for fruits, vegetables, and selected multicomponent foods. J. Am. Diet. Assoc., 93: 318-323.
67. Heinonen, M.I., Ollilainen, V., Linkola, E.K., Varo, P.T. & Koivistoinen, P.E. 1989. Carotenoids in Finnish Foods: Vegetables, fruits, and berries. .J Agric. Food Chem., 37: 655-659.
68. de Pee, S. & West, C. 1996. Dietary carotenoids and their role in combatting vitamin A deficiency: a review of the literature. Eur. J. Clin. Nutr., 50: 38-53.
69. IARC Working Group. 1998. Carotenoids. Lyon: WHO International Agency for Research on Cancer.
Approximately 2–6 mg β-carotene is consumed by adults daily in developed countries (65,66) and similar amounts of lutein (67) and lycopene (66) are probably also consumed. Smaller amounts may be consumed in the developing world (68, 69). β-Cryptoxanthin is a pro-vitamin A carotenoid which is found mainly in fruits (66).
33. Burton, G.W. & Ingold, K.U. 1984. B-carotene: an unusual type of lipid antioxidant. Science, 224: 569-573.
70. Stryker, W.S., Kaplan, L.A., Stein, E.A., Stampfer, M.J., Sober, A. & Willett, W.C. 1988. The relation of diet, cigarette smoking, and alcohol consumption to plasma beta-carotene and alpha-tocopherol levels. Am. J. Epidemiol., 127: 283-296.
71. Mathews-Roth, M.M., Wilson, T., Fujimore, E. & Krinsky, N.I. 1974. Carotenoid chromophore length and protection against photosensitization. Photochem Photobiol 19: 217-222.
70. Stryker, W.S., Kaplan, L.A., Stein, E.A., Stampfer, M.J., Sober, A. & Willett, W.C. 1988. The relation of diet, cigarette smoking, and alcohol consumption to plasma beta-carotene and alpha-tocopherol levels. Am. J. Epidemiol., 127: 283-296.
71. Mathews-Roth, M.M., Wilson, T., Fujimore, E. & Krinsky, N.I. 1974. Carotenoid chromophore length and protection against photosensitization. Photochem Photobiol 19: 217-222.
Consumption is small but bio-availability of carotenoids may be greater from fruit than vegetable, so its contribution to dietary intake and vitamin A status may be higher than the amount in the diet would predict. β-Carotene has the general structure of this group of compounds and has two6-membered carbon rings (β-ionone rings) separated by 18 carbon atoms in the form of a conjugated chain of double bonds. The latter is responsible for the antioxidant properties of the molecule (33, 70, 71).
33. Burton, G.W. & Ingold, K.U. 1984. B-carotene: an unusual type of lipid antioxidant. Science, 224: 569-573.
72. Foote, C.S. & Denny, R.W. 1968. Chemistry of singlet oxygen. VII. Quenching by
β-carotene. Am. Chem. Soc. J., 90: 6233-6235.
74. Palozza, P. & Krinsky, N.I. 1992. β-carotene and α-tocopherol are synergistic
antioxidants. Arch. Biochem. Biophys., 297: 184-187.
β-Carotene is unique in possessing two β-ionone rings in its molecule which are essential for vitamin A activity. The chemical properties of the carotenoids closely relate to the extended system of conjugated double bonds, which occupies the central part of carotenoid molecules, and various functional groups on the terminal ring structures. The ROS scavenged by carotenoids are singlet oxygen and peroxyl radicals (33,72-74).
72. Foote, C.S. & Denny, R.W. 1968. Chemistry of singlet oxygen. VII. Quenching by β-carotene. Am. Chem. Soc. J., 90: 6233-6235.
73. Di Mascio, P., Kaiser, S. & Sies, H. 1989. Lycopene as the most efficient biological carotenoid singlet-oxygen quencher. Arch. Biochem. Biophys., 274: 532-538.
Carotenoids in general and lycopene specifically are very efficient at quenching singlet oxygen (72, 73). In this process the carotene absorbs the excess energy from singlet oxygen and then releases it as heat. Singlet oxygen is generated during photosynthesis;therefore, carotenoids are important for protecting plant tissues, but there is limited evidencefor this role in humans.
75. Mathews-Roth, M.M. 1986. Systemic photoprotection. Derm. Clin., 4: 335-339.
76. Mathews-Roth, M.M., Pathak, M.A., Fitzpatrick, T.B., Harber, L.C. & Kass, E.H. 1977. Beta-carotene therapy for erythropoietic protoporphyria and other photosensitive diseases. Arch. Dermatol., 113: 1229-1232.
77. Greenberg, E.R., Baron, J.A. & Stukel, T.A. 1990. A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin. N. Engl. J. Med., 323: 789-795.
However, ß-carotene has been used in the treatment of erythropoieticprotoporphyria (75), which is a light-sensitive condition which in some persons respond to treatment with amounts of β-carotene (in excess of 180 mg/day) (76). It has been suggested that large amounts of dietary carotenes may provide some protection against solar radiation but results are equivocal. No benefit was reported when large amounts of β-carotene were used to treat persons with a high risk of non-melanomatous skin cancer (77).
78. Bone, R.A., Landrum, J.T., Fernandez, L. & Tarsis, S.L. 1988. Analysis of macula pigment by HPLC: Retinal distribution and age study. Invest. Ophthalmol. Vis. Sci.
29:843-849
79. Gerster, H. 1991. Antioxidant protection of the ageing macula. Age Ageing, 20: 60-69.
80. Seddon, A.M., Ajani, U.A. & Sperduto, R.D. 1994. Dietary carotenoids, vitamin A, C, and E, and advanced age-related macular degeneration. J. Am. Med. Assoc., 272: 1413-1420.
However, two carotenoids – lutein (3,3’-dihydroxy α-carotene) and zeaxanthin (the 3,3’-dihydroxylated form of β-carotene) – are found specifically associated with the rods and cones in the eye (78)and may protect the retinal pigment epithelium against the oxidative effects of blue light (79,80). Burton and Ingold (33) were the first to draw attention to the radical-trapping properties of β-carotene.
81. Terao, J. 1989. Antioxidant activity of β-carotene-related carotenoids in solution. Lipids 24: 659-661.
82. Chopra, M. & Thurnham, D.I. 1993. In vitro antioxidant activity of lutein. In: Waldron KW, Johnson IT, Fenwick GR, eds. Food and cancer prevention. p.123-129. London: Royal Society of Chemistry.
83. Edge, R., McGarvey, D.J. & Truscott, T.G. 1997. The carotenoids as anti-oxidants. J Photochem. Photobiol. B:Biol., 41: 189-200.
33. Burton, G.W. & Ingold, K.U. 1984. B-carotene: an unusual type of lipid antioxidant.
Science, 224: 569-573.
Using in vitro studies, they showed that β-carotene was effective inreducing the rate of lipid peroxidation at the low oxygen concentrations found in tissues.Because all carotenoids have the same basic structure, they should all have similar properties.Indeed, several authors suggest that the hydroxy-carotenoids are better radical-trapping antioxidants than is β-carotene (81, 82). It has also been suggested that because the carotenoid molecule is long enough to span the bilayer lipid membrane (83), the presence of oxyfunctional groups on the ring structures may facilitate similar reactivation of the carotenoidradical in a manner similar to that of the phenoxyl radical of vitamin E (33).
84. Bendich, A. 1989. Carotenoids and the immune response. J. Nutr., 119: 112-115.
85. Pool-Zobel, B.L., Bub, A., Muller, H., Wollowski, I. & Rechkemmer, G. 1997. Consumption of vegetables reduces genetic damage in Humans: first results of a Human intervention trial with carotenoid-rich foods. Carcinogenesis, 18: 847-1850.
86. van Anterwerpen, V.L., Theron, A.J. & Richards, G.A. 1995. Plasma levels of
beta-carotene are inversely correlated with circulating neutrophil counts in young male
cigarette smokers. Inflammation, 19: 405-414.
87. Daudu, P.A., Kelley, D.S., Taylor,P.C., Burri, B.J. & Wu, M.M. 1994. Effect of low β-carotene diet on the immune functions of adult women. Am. J. Clin. Nutr., 60: 969-972.
88. Krinsky, N.I. 1988. The evidence for the role of carotenoids in preventive health. Clin. Nutr., 7: 107-112.
There is some evidence for an antioxidant role for β-carotene in immune cells. Bendich (84) suggested that β-carotene protects phagocytes from auto-oxidative damage;enhances T and B lymphocyte proliferative responses; stimulates effector T cell function; and enhances macrophage, cytotoxic T cell, and natural killer cell tumoricidal capacity. Some data are in conflict with evidence of protective effects on the immune system (85, 86) and other data have found no effect (87). An explanation for the discrepancy may reside in the type of subjects chosen. Defences may be boosted in those at risk but it may not be possible to demonstrate any benefit in healthy subjects (88).
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