Does vitamin C act as a pro-oxidant under physiological conditions?
Anitra Carr
The Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, 97331 USA
Search for more papers by this authorCorresponding Author
Balz Frei
The Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, 97331 USA
Correspondence: Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis OR 97331-6512, USA. E-mail: [email protected]
Search for more papers by this authorAnitra Carr
The Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, 97331 USA
Search for more papers by this authorCorresponding Author
Balz Frei
The Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, 97331 USA
Correspondence: Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis OR 97331-6512, USA. E-mail: [email protected]
Search for more papers by this authorABSTRACT
Vitamin C readily scavenges reactive oxygen and nitrogen species and may thereby prevent oxidative damage to important biological macromolecules such as DNA, lipids, and proteins. Vitamin C also reduces redox active transition metal ions in the active sites of specific biosynthetic enzymes. The interaction of vitamin C with ‘free’, catalytically active metal ions could contribute to oxidative damage through the production of hydroxyl and alkoxyl radicals; whether these mechanisms occur in vivo, however, is uncertain. To examine this issue, we reviewed studies that investigated the role of vitamin C, both in the presence and absence of metal ions, in oxidative DNA, lipid, and protein damage. We found compelling evidence for antioxidant protection of lipids by vitamin C in biological fluids, animals, and humans, both with and without iron cosupplementation. Although the data on protein oxidation in humans are sparse and inconclusive, the available data in animals consistently show an antioxidant role of vitamin C. The data on vitamin C and DNA oxidation in vivo are inconsistent and conflicting, but some of the discrepancies can be explained by flaws in experimental design and methodology. These and other important issues discussed here need to be addressed in future studies of the role of vitamin C in oxidative damage.—Carr, A., Frei, B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J. 13, 1007–1024 (1999)
REFERENCES
- 1Frei, B., England, L., and Ames, B. N. (1989) Ascorbate is an outstanding antioxidant in human blood plasma. Proc. Natl. Acad. Sci. U. S. A. 86, 6377–6381
- 2Frei, B., Stocker, R., England, L., and Ames, B. N. (1990) Ascorbate: the most effective antioxidant in human blood plasma. Adv. Exp. Med. Biol. 264, 155–163
- 3Halliwell, B. (1996) Vitamin C: antioxidant or pro-oxidant in vivo? Free Rad. Res. 25, 439–454
- 4Buettner, G. R., and Jurkiewicz, B. A. (1996) Catalytic metals, ascorbate and free radicals: combinations to avoid. Radiat. Res. 145, 532–541
- 5Chesney, J. A., Mahoney, J. R., and Eaton, J. W. (1991) A spectrophotometric assay for chlorine-containing compounds. Anal. Biochem. 196, 262–266
- 6Menzel, D. B. (1971) Oxidation of biologically active reducing substances by ozone. Arch. Environ. Health 23, 149–153
- 7Chou, P. T., and Khan, A. U. (1983) L-Ascorbic acid quenching of singlet delta molecular oxygen in aqueous media: generalized antioxidant property of vitamin C. Biochem. Biophys. Res. Commun. 115, 932–937
- 8Cooney, R. V., Ross, P. D., and Bartolini, G. L. (1986) N-Nitrosation and N-nitration of morpholine by nitrogen dioxide: inhibition by ascorbate, glutathione and α-tocopherol. Cancer Lett. 32, 83–90
- 9Licht, W. R., Tannenbaum, S. R., and Deen, W. M. (1988) Use of ascorbic acid to inhibit nitrosation: kinetic and mass transfer considerations for an in vitro system. Carcinogenesis 9, 365–372
- 10Kveder, M., Pifat, G., Pecar, S., Schara, M., Ramos, P., and Esterbauer, H. (1997) Nitroxide reduction with ascorbic acid in spin labeled human plasma LDL and VLDL. Chem. Phys. Lipids 85, 1–12
- 11Bartlett, D., Church, D. F., Bounds, P. L., and Koppenol, W. H. (1995) The kinetics of the oxidation of L-ascorbic acid by peroxynitrite. Free Rad. Biol. Med. 18, 85–92
- 12Edge, R., and Truscott, T. G. (1997) Prooxidant and antioxidant reaction mechanisms of carotene and radical interactions with vitamins E and C. Nutrition 13, 992–994
- 13Cross, C. E., van der Vliet, A., O'Neill, C. A., Louie, S., and Halliwell, B. (1994) Oxidants, antioxidants and respiratory tract lining fluids. Environ. Health Perspect. 102, 185–191
- 14Lykkesfeldt, J., Loft, S., Nielsen, J. B., and Poulsen, H. E. (1997) Ascorbic acid and dehydroascorbic acid as biomarkers of oxidative stress caused by smoking. Am. J. Clin. Nutr. 65, 959–963
- 15Neuzil, J., Thomas, S. R., and Stocker, R. (1997) Requirement for, promotion, or inhibition by a-tocopherol of radical-induced initiation of plasma lipoprotein lipid peroxidation. Free Rad. Biol. Med. 22, 57–71
- 16Bowry, V. W., Mohr, D., Cleary, J., and Stocker, R. (1995) Prevention of tocopherol-mediated peroxidation in ubiquinol-10-free human low density lipoprotein. J. Biol. Chem. 270, 5756–5763
- 17May, J. M., Qu, Z. C., and Mendiratta, S. (1998) Protection and recycling of alpha-tocopherol in human erythrocytes by intracellular ascorbic acid. Arch. Biochem. Biophys. 349, 281–289
- 18Jacob, R. A., Kutnink, M. A., Csallany, A. S., Daroszewska, M., and Burton, G. W. (1996) Vitamin C nutriture has little short-term effect on vitamin E concentrations in healthy women. J. Nutr. 126, 2268–2277
- 19Burton, G. W., Wronska, U., Stone, L., Foster, D. O., and Ingold, K. U. (1990) Biokinetics of dietary RRR-α-tocopherol in the male guinea pig at three dietary levels of vitamin C and two levels of vitamin E. Evidence that vitamin C does not ‘spare’ vitamin E in vivo. Lipids 25, 199–210
- 20Meister, A. (1994) Glutathione-ascorbic acid antioxidant system in animals. J. Biol. Chem. 269, 9397–9400
- 21Buettner, G. R. (1993) The pecking order of free radicals and antioxidants: lipid peroxidation, α-tocopherol, and ascorbate. Arch. Biochem. Biophys. 300, 535–543
- 22Wells, W. W., and Jung, C. (1997) Regeneration of vitamin C. In Vitamin C in Health and Disease ( L. Packer, and J. Fuchs, eds) pp. 109–121, Marcel Dekker, Inc., New York
- 23May, J. M., Cobb, C. E., Mendiratta, S., Hill, K. E., and Burk, R. F. (1998) Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. J. Biol. Chem. 273, 23039–23045
- 24May, J. M., Mendiratta, S., Hill, K. E., and Burk, R. F. (1997) Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. J. Biol. Chem. 272, 22607–22610
- 25Park, J. B., and Levine, M. (1996) Purification, cloning and expression of dehydroascorbic acid-reducing activity from human neutrophils: identification as glutaredoxin. Biochem. J. 315, 931–938
- 26Levine, M. (1986) New concepts in the biology and biochemistry of ascorbic acid. New Engl. J. Med. 314, 892–902
- 27Bendich, A., and Cohen, M. (1990) Ascorbic acid safety: analysis of factors affecting iron absorption. Toxicol. Lett. 51, 189–201
- 28Halliwell, B., and Gutteridge, J. M. C. (1986) Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts. Arch. Biochem. Biophys. 246, 501–514
- 29Halliwell, B., and Gutteridge, J. M. C. (1989) Free Radicals in Biology and Medicine. Clarendon Press, Oxford
- 30Woodall, A. A., and Ames, B. N. (1997) Diet and oxidative damage to DNA: the importance of ascorbate as an antioxidant. In Vitamin C in Health and Disease ( L. Packer, and J. Fuchs, eds) pp. 193–203, Marcel Dekker, Inc., New York
- 31Poulsen, H. E., Prieme, H., and Loft, S. (1998) Role of oxidative DNA damage in cancer initiation and promotion. Eur. J. Cancer Prev. 7, 9–16
- 32Enstrom, J. E. (1997) Vitamin C in prospective epidemiological studies. In Vitamin C in Health and Disease ( L. Packer, and J. Fuchs, eds) pp. 381–398, Marcel Dekker, Inc., New York
- 33Block, G. (1991) Vitamin C and cancer prevention: the epidemiologic evidence. Am. J. Clin. Nutr. 53, 270S–282S
- 34Jenner, A., England, T. G., Aruoma, O. I., and Halliwell, B. (1998) Measurement of oxidative DNA damage by gas chromatographymass spectrometry: ethanethiol prevents artifactual generation of oxidized DNA bases. Biochem. J. 331, 365–369
- 35Collins, A., Cadet, J., Epe, B., and Gedik, C. (1997) Problems in the measurement of 8-oxoguanine in human DNA. Carcinogenesis 18, 1833–1836
- 36Helbock, H. J., Beckman, K. B., Shigenaga, M. K., Walter, P. B., Woodall, A. A., Yeo, H. C., and Ames, B. N. (1998) DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine. Proc. Natl. Acad. Sci. U. S. A. 95, 288–293
- 37Pflaum, M., Will, O., and Epe, B. (1997) Determination of steady-state levels of oxidative DNA base modifications in mammalian cells by means of repair endonucleases. Carcinogenesis 18, 2225–2231
- 38Drouin, R., Rodriguez, H., Gao, S. W., Gebreyes, Z., O'Connor, T. R., Holmquist, G. P., and Akman, S. A. (1996) Cupric ion/ascorbate/hydrogen peroxide-induced DNA damage: DNA-bound copper ion primarily induces base modifications. Free Rad. Biol. Med. 21, 261–273
- 39Fischer-Nielsen, A., Poulsen, H. E., and Loft, S. (1992) 8-Hydroxydeoxyguanosine in vitro: effects of glutathione, ascorbate, and 5-aminosalicylic acid. Free Rad. Biol. Med. 13, 121–126
- 40Hu, M. L., and Shih, M. K. (1997) Ascorbic acid inhibits lipid peroxidation but enhances DNA damage in rat liver nuclei incubated with iron ions. Free Rad. Res. 26, 585–592
- 41Fiala, E. S., Sodum, R. S., Bhattacharya, M., and Li, H. (1996) (-)-Epigallocatechin gallate, a polyphenolic tea antioxidant, inhibits peroxynitrite-mediated formation of 8-oxodeoxyguanosine and 3-nitrotyrosine. Experientia 52, 922–926
- 42Wei, H., Cai, Q., Tian, L., and Lebwohl, M. (1998) Tamoxifen reduces endogenous and UV light-induced oxidative damage to DNA, lipid, and protein in vitro and in vivo. Carcinogenesis 19, 1013–1018
- 43Noroozi, M., Angerson, W. J., and Lean, M. E. J. (1998) Effects of flavonoids and vitamin C on oxidative DNA damage to human lymphocytes. Am. J. Clin. Nutr. 67, 1210–1218
- 44Fischer-Nielsen, A., Loft, S., and Jensen, K. G. (1993) Effect of ascorbate and 5-aminosalicylic acid on light-induced 8-hydroxydeoxyguanosine formation in V79 Chinese hamster cells. Carcinogenesis 14, 2431–2433
- 45Pflaum, M., Kielbassa, C., Garmyn, M., and Epe, B. (1998) Oxidative DNA damage induced by visible light in mammalian cells: extent, inhibition by antioxidants and genotoxic effects. Mutat. Res. 408, 137–146
- 46Singh, N. P. (1997) Sodium ascorbate induces DNA single-strand breaks in human cells in vitro. Mutat. Res. 375, 195–203
- 47Anderson, D., Yu, T. W., Phillips, B. J., and Schmezer, P. (1994) The effect of various antioxidants and other modifying agents on oxygen-radical-generated DNA damage in human lymphocytes in the COMET assay. Mutat. Res. 307, 261–271
- 48Green, M. H. L., Lowe, J. E., Waugh, A. P. W., Aldridge, K. E., Cole, J., and Arlett, C. F. (1994) Effect of diet and vitamin C on DNA strand breakage in freshly-isolated human white blood cells. Mutat. Res. 316, 91–102
- 49Cadenas, S., Barja, G., Poulsen, H. E., and Loft, S. (1997) Oxidative DNA damage estimated by oxo8dG in the liver of guinea-pigs supplemented with graded dietary doses of ascorbic acid and α-tocopherol. Carcinogenesis 18, 2373–2377
- 50Reddy, V. N., Giblin, F. J., Lin, J. R., and Chakrapani, B. (1998) The effect of aqueous humor ascorbate on ultraviolet-B-induced DNA damage in lens epithelium. Invest. Opthalmol. Vis. Sci. 39, 344–350
- 51Podmore, I. D., Griffiths, H. R., Herbert, K. E., Mistry, N., Mistry, P., and Lunec, J. (1998) Vitamin C exhibits pro-oxidant properties. Nature (London) 392, 559
- 52Cooke, M. S., Evans, M. D., Podmore, I. D., Herbert, K. E., Mistry, N., Mistry, P., Hickenbotham, P. T., Hussieni, A., Griffiths, H. R., and Lunec, J. (1998) Novel repair action of vitamin C upon in vivo oxidative DNA damage. FEBS Lett. 363, 363–367
- 53Rehman, A., Collis, C. S., Yang, M., Kelly, M., Diplock, A. T., Halliwell, B., and Rice-Evans, C. (1998) The effects of iron and vitamin C co-supplementation on oxidative damage to DNA in healthy volunteers. Biochem. Biophys. Res. Commun. 246, 293–298
- 54Fraga, C. G., Motchnik, P. A., Shigenaga, M. K., Helbock, H. J., Jacob, R. A., and Ames, B. N. (1991) Ascorbic acid protects against endogenous oxidative DNA damage in human sperm. Proc. Natl. Acad Sci. U. S. A. 88, 11003–11006
- 55Lee, B. M., Lee, S. K., and Kim, H. S. (1998) Inhibition of oxidative DNA damage, 8-OHdG, and carbonyl contents in smokers treated with antioxidants (vitamin E, vitamin C, β-carotene and red ginseng). Cancer Lett. 132, 219–227
- 56Prieme, H., Loft, S., Nyyssonen, K., Salonen, J. T., and Poulsen, H. E. (1997) No effect of supplementation with vitamin E, ascorbic acid, or coenzyme Q10 on oxidative DNA damage estimated by 8-oxo-7,8-dihydro-2′-deoxyguanosine excretion in smokers. Am. J. Clin. Nutr. 65, 503–507
- 57Anderson, D., Phillips, B. J., Yu, T., Edwards, A. J., Ayesh, R., and Butterworth, K. R. (1997) The effects of vitamin C supplementation on biomarkers of oxygen radical generated damage in human volunteers with ‘low’ or ‘high’ cholesterol levels. Environ. Mol. Mutagen. 30, 161–174
- 58Panayiotidis, M., and Collins, A. R. (1997) Ex vivo assessment of lymphocyte antioxidant status using the comet assay. Free Rad. Res. 27, 533–537
- 59Poulsen, H. E., Weimann, A., Salonen, J. T., Nyyssonen, K., Loft, S., Cadet, J., Douki, T., and Ravanat, J. (1998) Does vitamin C have a pro-oxidant effect? Nature (London) 395, 231–232
- 60Levine, M. A., Daruwala, R. C., Park, J. B., Rumsey, S. C., and Wang, Y. (1998) Does vitamin C have a pro-oxidant effect? Nature (London) 395, 231
- 61Wood, M. L., Esteve, A., Morningstar, M. L., Kuziemko, G. M., and Essigmann, J. M. (1992) Genetic effects of oxidative DNA damage: comparative mutagenesis of 7,8-dihydro-8-oxoguanine and 7,8-dihydro-8-oxoadenine in Escherichia coli. Nucleic Acids Res. 20, 6023–6032
- 62Podmore, I. D., Griffiths, H. R., Herbert, K. E., Mistry, N., Mistry, P., and Lunec, J. (1998) Does vitamin C have a pro-oxidant effect? Nature (London) 395, 232
- 63Fraga, C. G., Motchnik, P. A., Wyrobek, A. J., Rempel, D. M., and Ames, B. N. (1996) Smoking and low antioxidant levels increase oxidative damage to sperm DNA. Mutat. Res. 351, 199–203
- 64Lindahl, T. (1993) Instability and decay of the primary structure of DNA. Nature (London) 362, 709–715
- 65Steinbrecher, U. P., Zhang, H., and Lougheed, M. (1990) Role of oxidatively modified LDL in atherosclerosis. Free Rad. Biol. Med. 9, 155–168
- 66Frei, B. (1997) Vitamin C as an antiatherogen: mechanisms of action. In Vitamin C in Health and Disease ( L. Packer, and J. Fuchs, eds) pp. 163–182, Marcel Dekker, Inc., New York
- 67de Zwart, L. L., Meerman, J. H. N., Commandeur, J. N. M., and Vermeulen, N. P. E. (1999) Biomarkers of free radical damage: applications in experimental animals and in humans. Free Rad. Biol. Med. 26, 202–226
- 68Gniwotta, C., Morrow, J. D., Roberts, L. J., and Kuhn, H. (1997) Prostaglandin F2-like compounds, F2-isoprostanes, are present in increased amounts in human atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 17, 3236–3241
- 69Pratico, D., Luliano, L., Mauriello, A., Spagnoli, L., Lawson, J. A., Maclouf, J., Violi, F., and Fitzgerald, G. A. (1997) Localization of distinct F2-isoprostanes in human atherosclerotic lesions. J. Clin. Invest. 100, 2028–2034
- 70Suarna, C., Dean, R. T., Southwell-Keeley, P. T., Moore, D. E., and Stocker, R. (1997) Separation and characterization of cholesterol oxo- and hydroxy-linoleate isolated from human atherosclerotic plaque. Free Rad. Res. 27, 397–408
10.3109/10715769709065779 Google Scholar
- 71Lynch, S. M., Gaziano, J. M., and Frei, B. (1996) Ascorbic acid and atherosclerotic cardiovascular disease. In Ascorbic Acid: Biochemistry and Biomedical Cell Biology ( J.R. Harris, ed) pp. 331–367, Plenum Press, New York
- 72Jha, P., Flather, M., Lonn, E., Farkouh, M., and Yusuf, S. (1995) The antioxidant vitamins and cardiovascular disease: a critical review of epidemiologic and clinical trial data. Ann. Int. Med. 123, 860–872
- 73Frei, B., Yamamoto, Y., Niclas, D., and Ames, B. N. (1988) Evaluation of an isoluminol chemiluminescence assay for the detection of hydroperoxides in human blood plasma. Anal. Biochem. 175, 120–130
- 74Frei, B., and Gaziano, J. M. (1993) Content of antioxidants, preformed lipid hydroperoxides, and cholesterol as predictors of the susceptibility of human LDL to metal ion-dependent and -independent oxidation. J. Lipid Res. 34, 2135–2145
- 75Frei, B., Stocker, R., and Ames, B. N. (1988) Antioxidant defenses and lipid peroxidation in human blood plasma. Proc. Natl. Acad. Sci. U. S. A. 85, 9748–9752
- 76Lynch, S. M., Morrow, J. D., Roberts, L. J., and Frei, B. (1994) Formation of non-cyclooxygenase-derived prostanoids (F2-isoprostanes) in plasma and low density lipoprotein exposed to oxidative stress in vitro. J. Clin. Invest. 93, 998–1004
- 77Thomas, S. R., Davies, M. J., and Stocker, R. (1998) Oxidation and antioxidation of human low-density lipoprotein and plasma exposed to 3-morpholinosydnonimine and reagent peroxynitrite. Chem. Res. Toxicol. 11, 484–494
- 78Cross, C. E., O'Neill, C. A., Reznick, A. Z., Hu, M. L., Marcocci, L., Packer, L., and Frei, B. (1993) Cigarette smoke oxidation of human plasma constituents. Ann. NY Acad. Sci. 686, 72–89
- 79Frei, B., Forte, T. M., Ames, B. N., and Cross, C. E. (1991) Gas phase oxidants of cigarette smoke induce lipid peroxidation and changes in lipoprotein properties in human blood plasma: protective effects of ascorbic acid. Biochem. J. 277, 133–138
- 80Berger, T. M., Polidori, M. C., Dabbagh, A., Evans, P. J., Halliwell, B., Morrow, J. D., Roberts, L. J., and Frei, B. (1997) Antioxidant activity of vitamin C in iron-overloaded human plasma. J. Biol. Chem. 272, 15656–15660
- 81Dasgupta, A., and Zdunek, T. (1992) In vitro lipid peroxidation of human serum catalyzed by cupric ion: antioxidant rather than prooxidant role of ascorbate. Life Sci. 50, 875–882
- 82Kunert, K. J., and Tappel, A. L. (1983) The effect of vitamin C on in vivo lipid peroxidation in guinea pigs as measured by pentane and ethane production. Lipids 18, 271–274
- 83Dillard, C. J., Kunert, K. J., and Tappel, A. L. (1982) Effects of vitamin E, ascorbic acid and mannitol on alloxan-induced lipid peroxidation in rats. Arch. Biochem. Biophys. 216, 204–212
- 84Kang, S. A., Jang, Y. J., and Park, H. (1998) In vivo dual effect of vitamin C on paraquat-induced lung damage: dependence on released metals from the damaged tissue. Free Rad. Res. 28, 93–107
- 85Barja, G., Lopez-Torres, M., Perez-Campo, R., Rojas, C., Cadenas, S., Prat, J., and Pamplona, R. (1994) Dietary vitamin C decreases endogenous protein oxidative damage, malondialdehyde, and lipid peroxidation and maintains fatty acid unsaturation in the guinea pig liver. Free Rad. Biol. Med. 17, 105–115
- 86Cadenas, S., Rojas, C., and Barja, G. (1998) Endotoxin increases oxidative injury to proteins in guinea pig liver: protection by dietary vitamin C. Pharmacol. Toxicol. 82, 11–18
- 87Cadenas, S., Lertsiri, S., Otsuka, M., Barga, G., and Miyazawa, T. (1996) Phospholipid hydroperoxides and lipid peroxidation in liver and plasma of ODS rats supplemented with a-tocopherol and ascorbic acid. Free Rad. Res. 24, 485–493
- 88Kimura, H., Yamada, Y., Morita, Y., Ikeda, H., and Matsuo, T. (1992) Dietary ascorbic acid depresses plasma and low density lipoprotein lipid peroxidation in genetically scorbutic rats. J. Nutr. 122, 1904–1909
- 89Tanaka, K., Hashimoto, T., Tokumaru, S., Iguchi, H., and Kojo, S. (1997) Interactions between vitamin C and vitamin E are observed in tissues of inherently scorbutic rats. J. Nutr. 127, 2060–2064
- 90Helen, A., and Vijayammal, P. L. (1997) Vitamin C supplementation on hepatic oxidative stress induced by cigarette smoke. J. Appl. Toxicol. 17, 289–295
10.1002/(SICI)1099-1263(199709)17:5<289::AID-JAT448>3.0.CO;2-9 CASPubMedWeb of Science®Google Scholar
- 91Collis, C. S., Yang, M., Diplock, A. T., Hallinan, T., and Rice-Evans, C. A. (1997) Effects of co-supplementation of iron with ascorbic acid on antioxidant-pro-oxidant balance in the guinea pig. Free Rad. Res. 27, 113–121
- 92Reilly, M., Delanty, N., Lawson, J. A., and Fitzgerald, G. A. (1996) Modulation of oxidant stress in vivo in chronic cigarette smokers. Circulation 94, 19–25
- 93Gokce, N., Frei, B., Holbrook, M., Olesiak, M., and Vita, J. A. (1998) Chronic ascorbic acid treatment improves endothelial function in patients with coronary artery disease. Circulation 98, I–175 (abstr.)
- 94Samman, S., Brown, A. J., Beltran, C., and Singh, S. (1997) The effect of ascorbic acid on plasma lipids and oxidisability of LDL in male smokers. Eur. J. Clin. Nutr. 51, 472–477
- 95Nyyssonen, K., Poulsen, H. E., Hayn, M., Agerbo, P., Porkkala-Sarataho, E., Kaikkonen, J., Salonen, R., and Salonen, J. T. (1997) Effect of supplementation of smoking men with plain or slow-release ascorbic acid on lipoprotein oxidation. Eur. J. Clin. Nutr. 51, 154–163
- 96Fuller, C. J., Grundy, S. M., Norkus, E. P., and Jialal, I. (1996) Effect of ascorbate supplementation on low density lipoprotein oxidation in smokers. Atherosclerosis 119, 139–150
- 97Mulholland, C. W., Strain, J. J., and Trinick, T. R. (1996) Serum antioxidant potential, and lipoprotein oxidation in female smokers following vitamin C supplementation. Int. J. Food Sci. Nutr. 47, 227–231
10.3109/09637489609012585 Google Scholar
- 98Harats, D., Ben-Naim, M., Dabach, Y., Hollander, G., Havivi, E., Stein, O., and Stein, Y. (1990) Effect of vitamin C and E supplementation on susceptibility of plasma lipoproteins to peroxidation induced by acute smoking. Atherosclerosis 85, 47–54
- 99Naidoo, D., and Lux, O. (1998) The effect of vitamin C and E supplementation on lipid and urate oxidation products in plasma. Nutr. Res. 18, 953–961
- 100Cadenas, S., Rojas, C., Mendez, J., Herrero, A., and Barja, G. (1996) Vitamin E decreases urine lipid peroxidation products in young healthy human volunteers under normal conditions. Pharmacol. Toxicol. 79, 247–253
- 101Wen, Y., Cooke, T., and Feely, J. (1997) The effect of pharmacological supplementation with vitamin C on low-density lipoprotein oxidation. Br. J. Clin. Pharmacol. 44, 94–97
- 102Harats, D., Chevion, S., Nahir, M., Norman, Y., Sagee, O., and Berry, E. M. (1998) Citrus fruit supplementation reduces lipoprotein oxidation in young men ingesting a diet high in saturated fat: presumptive evidence for an interaction between vitamins C and E in vivo. Am. J. Clin. Nutr. 67, 240–245
- 103Rifici, V. A., and Khachadurian, A. K. (1993) Dietary supplementation with vitamins C and E inhibits in vitro oxidation of lipoproteins. J. Am. Coll. Nutr. 12, 631–637
- 104Alessio, H. M., Goldfarb, A.H., and Cao, G. (1997) Exercise-induced oxidative stress before and after vitamin C supplementation. Int. J. Sport Nutr. 7, 1–9
- 105Sanchez-Quesada, J. L., Jorba, O., Payes, A., Otal, C., Serra-Grima, R., Gonzalez-Sastre, F., and Ordonez-Llanos, J. (1998) Ascorbic acid inhibits the increase in low-density lipoprotein (LDL) susceptibility to oxidation and the proportion of electronegantive LDL induced by intense aerobic exercise. Coronary Artery Dis. 9, 249–255
- 106Morrow, J. D., Frei, B., Longmire, A. W., Gaziano, J. M., Lynch, S. M., Shyr, Y., Strauss, W. E., Oates, J. A., and Roberts, L. J. (1995) Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. New Engl. J. Med. 332, 1198–1203
- 107Stocker, R., Bowry, V. W., and Frei, B. (1991) Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does α-tocopherol. Proc. Natl. Acad. Sci. U. S. A. 88, 1646–1650
- 108Wayner, D. D., Burton, G. W., and Ingold, K. U. (1986) The antioxidant efficiency of vitamin C is concentration-dependent. Biochim. Biophys. Acta 884, 119–123
- 109Dean, R. T., Fu, S., Stocker, R., and Davies, M. J. (1997) Biochemistry and pathology of radical-mediated protein oxidation. Biochem. J. 324, 1–18
- 110Taylor, A., Dorey, C. K., and Nowell, T. (1997) Oxidative stress and ascorbate in relation to risk for cataract and age-related maculopathy. In Vitamin C in Health and Disease ( L. Packer, and J. Fuchs, eds) pp. 231–264, Marcel Dekker, Inc., New York
- 111Berlett, B. S., and Stadtman, E. R. (1997) Protein oxidation in aging, disease, and oxidative stress. J. Biol. Chem. 272, 20313–20316
- 112Ortwerth, B. J., and Monnier, V. M. (1997) Protein glycation by the oxidation products of ascorbic acid. In Vitamin C in Health and Disease ( L. Packer, and J. Fuchs, eds) pp. 123–142, Marcel Dekker, Inc., New York
- 113Leeuwenburgh, C., Hardy, M. M., Hazen, S. L., Wagner, P., Oh-ishi, S., Steinbrecher, U. P., and Heinecke, J. W. (1997) Reactive nitrogen intermediates promote low density lipoprotein oxidation in human atherosclerotic intima. J. Biol. Chem. 272, 1433–1436
- 114Hazen, S. L., and Heinecke, J. W. (1997) 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima. J. Clin. Invest. 99, 2075–2081
- 115Fu, S., Davies, M. J., Stocker, R., and Dean, R. T. (1998) Evidence for roles of radicals in protein oxidation in advanced human atherosclerotic plaque. Biochem. J. 333, 519–525
- 116Smith, M. A., Richey Harris, P. L., Sayer, L. M., Beckman, J. S., and Perry, G. (1997) Widespread peroxynitrite-mediated damage in Alzheimer's disease. J. Neurosci. 17, 2653–2657
- 117Lee, K. W., Mossine, V., and Ortwerth, B. J. (1998) The relative ability of glucose and ascorbate to glycate and crosslink lens proteins in vitro. Exp. Eye Res. 67, 95–104
- 118Atalay, A., Ogus, A., Bateman, O., and Slingsby, C. (1998) Vitamin C induced oxidation of eye lens gamma crystallins. Biochimie (Paris) 80, 283–288
10.1016/S0300-9084(98)80068-0 Google Scholar
- 119Miyata, T., Inagi, R., Asahi, K., Yamada, Y., Horie, K., Sakai, H., Uchida, K., and Kurokawa, K. (1998) Generation of protein carbonyls by glycoxidation and lipoxidation reactions with autoxidation products of ascorbic acid and polyunsaturated fatty acids. FEBS Lett. 437, 24–28
- 120Linetsky, M., Ranson, N., and Ortwerth, B. J. (1998) The aggregation in human lens proteins blocks the scavenging of UVA-generated singlet oxygen by ascorbic acid and glutathione. Arch. Biochem. Biophys. 351, 180–188
- 121Varma, S. D., Ali, A. H., Devamanoharan, P. S., and Morris, S. M. (1997) Nitrite-induced photo-oxidation of thiol and its implications in smog toxicity to the eye: prevention by ascorbate. J. Ocular Pharmacol. Ther. 13, 179–187
- 122Reznick, A. Z., Cross, C. E., Hu, M. L., Suzuki, Y. J., Khwaja, S., Safadi, A., Motchnik, P. A., Packer, L., and Halliwell, B. (1992) Modification of plasma proteins by cigarette smoke as measured by protein carbonyl formation. Biochem. J. 286, 607–611
- 123Hu, M., Louie, S., Cross, C. E., Motchnik, P., and Halliwell, B. (1993) Antioxidant protection against hypochlorous acid in human plasma. J. Lab. Clin. Med. 121, 257–262
- 124Yamaguchi, T., Hishizume, T., Tanaka, M., Nakayama, M., Sugimoto, A., Ikeda, S., Nakajimi, H., and Horio, F. (1997) Bilirubin oxidation provoked by endotoxin treatment is suppressed by feeding ascorbic acid in a rat mutant unable to synthesize ascorbic acid. Eur. J. Biochem. 245, 233–240
- 125Blondin, J., Baraji, V., Schwartz, E., Sadowski, J. A., and Taylor, A. (1986) Delay of UV-induced eye lens protein damage in guinea pigs by dietary ascorbate. J. Free Rad. Biol. Med. 2, 275–281
- 126Tsao, C. S., Xu, L., and Young, M. (1990) Effect of dietary ascorbic acid on heat-induced eye lens protein damage in guinea pigs. Ophthalmic Res. 22, 106–110
- 127Mannick, E. E., Bravo, L. E., Zarama, G., Realpe, J. L., Zhang, X. J., Ruiz, B., Fontham, E. T., Mera, R., Miller, M. J., and Correa, P. (1996) Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. Cancer Res. 56, 3238–3243
- 128Yan, L., Traber, M. G., Kobuchi, H., Matsugo, S., Tritschler, H. J., and Packer, L. (1996) Efficacy of hypochlorous acid scavengers in the prevention of protein carbonyl formation. Arch. Biochem. Biophys. 327, 330–334
- 129Hazell, L. J., and Stocker, R. (1993) Oxidation of low-density lipoprotein with hypochlorite causes transformation of the lipoprotein into a high-uptake form for macrophages. Biochem. J. 290, 165–172
- 130Young, I. S., Trouton, T. G., Torney, J. J., McMaster, D., Callender, M. E., and Trimble, E. R. (1994) Antioxidant status and lipid peroxidation in hereditary haemochromatosis. Free Rad. Biol. Med. 16, 393–397
- 131Livrea, M. A., Tesoriere, L., Pintaudi, A. M., Calabrese, A., Maggio, A., Freisleben, H. J., D'Arpa, D., D'Anna, R., and Bongiorno, A. (1996) Oxidative stress and antioxidant status in β-thalassemia major: iron overload and depletion of lipidsoluble antioxidants. Blood 88, 3608–3614
- 132Herbert, V. (1994) The antioxidant supplement myth. Am. J. Clin. Nutr. 60, 157–158
- 133Kiechl, S., Willeit, J., Egger, G., Poewe, W., and Oberhollenzer, F. (1997) Body iron stores and the risk of carotid atherosclerosis: prospective results from the Bruneck study. Circulation 96, 3300–3307
10.1046/j.1365-2362.1998.00370.x Google Scholar
- 134Franco, R. F., Zago, M. A., Trip, M. D., Cate, H., van den Ende, A., Prins, M. H., Kastelein, J. J., and Reitsma, P. H. (1998) Prevalence of hereditary haemochromatosis in premature atherosclerotic vascular disease. Br. J. Haematol. 102, 1172–1175
- 135Winterbourn, C. C. (1981) Hydroxyl radical production in body fluids: roles of metal ions, ascorbate and superoxide. Biochem. J. 198, 125–131
- 136Minetti, M., Forte, T., Soriani, M., Quarisima, V., Menditto, A., and Ferrari, M. (1992) Iron-induced ascorbate oxidation in plasma as monitored by ascorbate free radical formation: no spin-trapping evidence for the hydroxyl radical in iron-overload plasma. Biochem. J. 282, 459–465
- 137Collis, C. S., Yang, M., Peach, S. J., Diplock, A. T., and Rice-Evans, C. (1996) The effects of ascorbic acid and iron co-supplementation on the proliferation of 3T3 fibroblasts. Free Rad. Res. 25, 87–93
- 138Dabbagh, A. J., and Frei, B. (1995) Human suction blister interstitial fluid prevents metal ion-dependent oxidation of low density lipoprotein by macrophages and in cell-free systems. J. Clin. Invest. 96, 1958–1966
- 139Retsky, K. L., and Frei, B. (1995) Vitamin C prevents metal ion-dependent initiation and propagation of lipid peroxidation in human low-density lipoprotein. Biochim. Biophys. Acta 1257, 279–287
- 140Otero, P., Viana, M., Herrera, E., and Bonet, B. (1997) Antioxidant and prooxidant effects of ascorbic acid, dehydroascorbic acid and flavonoids on LDL submitted to different degrees of oxidation. Free Rad. Res. 27, 619–626
- 141Retsky, K. L., Chen, K., Zeind, J., and Frei, B. (1999) Inhibition of copper-induced LDL oxidation by vitamin C is associated with decreased copper-binding to LDL and 2-oxo-histidine formation. Free Rad. Biol. Med. 26, 90–98
- 142Tsao, C. S., Leung, P. Y., and Young, M. (1987) Effect of dietary ascorbic acid intake on tissue vitamin C in mice. J. Nutr. 117, 291–297
- 143Levine, M., Conry-Cantilena, C., Wang, Y., Welch, R. W., Washko, P. W., Dhariwal, K. R., Park, J. B., Lazarev, A., Graumlich, J. F., King, J., and Cantilena, L. R. (1996) Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc. Natl. Acad. Sci. U. S. A. 93, 3704–3709
- 144Lovstad, R. A. (1987) Copper catalyzed oxidation of ascorbate (vitamin C): inhibitory effect of catalase, superoxide dismutase, serum proteins (ceruloplasmin, albumin, apotransferrin) and amino acids. Int. J. Biochem. 19, 309–313
- 145Eiserich, J. P., Hristova, M., Cross, C. E., Jones, A. D., Freeman, B. A., Halliwell, B., and van der Vliet, A. (1998) Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature (London) 391, 393–397
- 146Cadet, J., Douki, T., and Ravanat, J. L. (1997) Artifacts associated with the measurement of oxidized DNA bases. Environ. Health Perspect. 105, 1034–1039
- 147Tsao, C. S. (1997) An overview of ascorbic acid chemistry and biochemistry. In Vitamin C in Health and Disease ( L. Packer, and J. Fuchs, eds) pp. 25–58, Marcel Dekker, Inc., New York
- 148Thomas, S. R., Neuzil, J., Mohr, D., and Stocker, R. (1995) Coantioxidants make a-tocopherol an efficient antioxidant for low density lipoprotein. Am. J. Clin. Nutr. 62, 1357S–1364S