Protection and Recycling of α-Tocopherol in Human Erythrocytes by Intracellular Ascorbic Acid
Abstract
Ascorbic acid can recycle alpha-tocopherol from the tocopheroxyl free radical in lipid bilayers and in micelles, but such recycling has not been demonstrated to occur across cell membranes. In this work the ability of intracellular ascorbate to protect and to recycle alpha-tocopherol in intact human erythrocytes and erythrocyte ghosts was investigated. In erythrocytes that were 80% depleted of intracellular ascorbate by treatment with the nitroxide Tempol, both 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) and ferricyanide oxidized alpha-tocopherol to a greater extent than in cells not depleted of ascorbate. In contrast, in erythrocytes in which the intracellular ascorbate concentration had been increased by loading with dehydroascorbate, loss of alpha-tocopherol was less with both oxidants than in control cells. Protection against AAPH-induced oxidation of alpha-tocopherol was not prevented by extracellular ascorbate oxidase, indicating that the protection was due to intracellular and not to extracellular ascorbate. Incubation of erythrocytes with lecithin liposomes also generated an oxidant stress, which caused lipid peroxidation in the liposomes and depleted erythrocyte alpha-tocopherol, leading to hemolysis. Ascorbate loading of the erythrocytes delayed liposome oxidation and decreased loss of alpha-tocopherol from both cells and from alpha-tocopherol-loaded liposomes. When erythrocyte ghosts were resealed to contain ascorbate and challenged with free radicals generated by AAPH outside the ghosts, intravesicular ascorbate was totally depleted over 1 h of incubation, whereas alpha-tocopherol decreased only after ascorbate was substantially oxidized. These results suggest that ascorbate within the erythrocyte protects alpha-tocopherol in the cell membrane by a direct recycling mechanism.
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Recycling of α-tocopherol radicals occurs by the oxidation of ascorbate.
“It was demonstrated that recycling of α-tocopherol radicals, next to diffusion of new molecules out of plasma, occurs by the oxidation of ascorbate (24, 121).”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [121]
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May, J. M., Qu, Z., & Cobb, C. E. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312548200 · Cited by 92 · see citing works
Self-citation(2002) · PubMed · Cited by 92 · see citing works
Munné‐Bosch, S., & Alegre, L. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03041-7 · Cited by 91 · see citing works
Approaches for Reactive Oxygen Species and Oxidative Stress Quantification in Epilepsy
Taiwo, R. O., Sandouka, S., Saadi, A., & Shekh‐Ahmad, T. (2020) · Antioxidants · doi:10.3390/antiox9100990 · Cited by 91 · see citing works
Zhang, L., Liu, F., Sun, X., Wei, G., Tian, Y., Liu, Z., Huang, R. T., Yu, Y., & Peng, H. (2017) · Analytical Chemistry · doi:10.1021/acs.analchem.6b04168 · Cited by 87 · see citing works
Protection by Vitamin C of Loss of Vitamin E in Cultured Rat Hepatocytes
Halpner, A. D., Handelman, G. J., Harris, J. M., Belmont, C. A., & Blumberg, J. B. (1998) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1998.0914 · Cited by 86 · see citing works
Ascorbic acid efficiently enhances neuronal synthesis of norepinephrine from dopamine
May, J. M., Qu, Z., Nazarewicz, R. R., & Dikalov, S. (2012) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2012.09.009 · Cited by 85 · see citing works
Self-citationYuan, X., Wang, J., Yao, H., & Chen, F. (2004) · LWT · doi:10.1016/j.lwt.2004.09.012 · Cited by 83 · see citing works
Mechanisms of ascorbic acid recycling in human erythrocytes
May, J. M., Qu, Z.-C., & Morrow, J. D. (2001) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/s0304-4165(01)00188-x · Cited by 81 · see citing works
Self-citationNitrite uptake and metabolism and oxidant stress in human erythrocytes
May, J. M., Qu, Z., Li, X., & Cobb, C. E. (2000) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.2000.279.6.c1946 · Cited by 82 · see citing works
Self-citationMay, J. M., Qu, Z., & Li, X. (2001) · Biochemical Pharmacology · doi:10.1016/s0006-2952(01)00736-5 · Cited by 81 · see citing works
Self-citationSchröder, H., Navarro, E., Mora, J., Galiano, D., & Tramullas, A. (2001) · European Journal of Nutrition · doi:10.1007/s003940170006 · Cited by 80 · see citing works
May, J. M., & Qu, Z.-C. (2005) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2004.10.023 · Cited by 79 · see citing works
Self-citationLipid peroxidation associated with anemia in rats experimentally infected with Trypanosoma evansi
Wolkmer, P., Silva, A. S. D., Traesel, C. K., Paim, F. C., Cargnelutti, J. F., Pagnoncelli, M., Emanuelli, M. P., Monteiro, S. G., & Lopes, S. T. D. A. (2009) · Veterinary Parasitology · doi:10.1016/j.vetpar.2009.06.032 · Cited by 77 · see citing works
Omodeo‐Salè, F., Motti, A., Dondorp, A. M., White, N. J., & Taramelli, D. (2005) · European Journal Of Haematology · doi:10.1111/j.1600-0609.2004.00352.x · Cited by 76 · see citing works
Perera, J., Tan, J. H., Jeevathayaparan, S., Chakravarthi, S., & Haleagrahara, N. (2011) · Cell & Bioscience · doi:10.1186/2045-3701-1-12 · Cited by 76 · see citing works
Erythrocytic oxidative damage in crossbred cattle naturally infected with Babesia bigemina
Saleh, M. A. (2008) · Research in Veterinary Science · doi:10.1016/j.rvsc.2008.05.005 · Cited by 75 · see citing works
Kumar, D., Schatz, F., Moore, R. M., Mercer, B. M., Rangaswamy, N., Mansour, J. M., Lockwood, C. J., & Moore, J. J. (2011) · Placenta · doi:10.1016/j.placenta.2011.01.006 · Cited by 75 · see citing works
Key Roles of Vitamins A, C, and E in Aflatoxin B1-Induced Oxidative Stress
Alpsoy, L., & YALVAÇ, M. E. (2011) · Vitamins and hormones · doi:10.1016/b978-0-12-386960-9.00012-5 · Cited by 73 · see citing works
Time-Resolved Resonance Raman Spectroscopy: Exploring Reactive Intermediates
Sahoo, S. K., Umapathy, S., & Parker, A. W. (2011) · Applied Spectroscopy · doi:10.1366/11-06406 · Cited by 73 · see citing works
Pallotta, V., Gevi, F., D’Alessandro, A., & Zolla, L. (2014) · PubMed Central · doi:10.2450/2014.0266-13 · Cited by 73 · see citing works
Jiang, Y., Wong, J. H., Fu, M., Ng, T. B., Liu, Z. K., Wang, C. R., Li, N., Qiao, W., Wen, T., & Liu, F. (2010) · Phytomedicine · doi:10.1016/j.phymed.2010.04.010 · Cited by 74 · see citing works
Ascorbate and plasma membrane electron transport—Enzymes vs efflux
Lane, D. J. R., & Lawen, A. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.06.003 · Cited by 71 · see citing works
Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice
Harrison, F. E., Allard, J., Bixler, R., Usoh, C., Li, L., May, J. M., & McDonald, M. P. (2009) · Nutritional Neuroscience · doi:10.1179/147683009x423364 · Cited by 70 · see citing works
Self-citationSerum Antioxidants Are Associated with Serum Reproductive Hormones and Ovulation among Healthy Women
Mumford, S. L., Browne, R. W., Schliep, K. C., Schmelzer, J., Plowden, T. C., Michels, K. A., Sjaarda, L. A., Zarek, S. M., Perkins, N. J., Messer, L. C., et al. (2015) · Journal of Nutrition · doi:10.3945/jn.115.217620 · Cited by 70 · see citing works
VanDuijn, M. M., Tijssen, K., VanSteveninck, J., den Broek, P. J. A. V., & Jolanda Van der, Z. E. E. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m910281199 · Cited by 70 · see citing works
Ullegaddi, R., Powers, H. J., & Gariballa, S. (2005) · European Journal of Clinical Nutrition · doi:10.1038/sj.ejcn.1602248 · Cited by 69 · see citing works
Rana, T., Bera, A. K., Das, S., Bhattacharya, D., Bandyopadhyay, S., Pan, D., & Das, S. K. (2010) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2010.06.002 · Cited by 68 · see citing works
Molecular Basis of Cardioprotective Effect of Antioxidant Vitamins in Myocardial Infarction
Rodrigo, R., Libuy, M., Feliú, F., & Hasson, D. (2013) · BioMed Research International · doi:10.1155/2013/437613 · Cited by 68 · see citing works
Reduction and uptake of methylene blue by human erythrocytes
May, J. M., Qu, Z., & Cobb, C. E. (2004) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00512.2003 · Cited by 68 · see citing works
Self-citationAscorbic acid attenuates endothelial permeability triggered by cell-free hemoglobin
Kuck, J. L., Bastarache, J. A., Shaver, C. M., Fessel, J. P., Dikalov, S., May, J. M., & Ware, L. B. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.11.058 · Cited by 67 · see citing works
Self-citationAscorbic acid protects SH-SY5Y neuroblastoma cells from apoptosis and death induced by β-amyloid
Huang, J., & May, J. M. (2006) · Brain Research · doi:10.1016/j.brainres.2006.04.047 · Cited by 66 · see citing works
Self-citationProtective Effects of Antioxidants in Huntington’s Disease: an Extensive Review
Essa, M. M., Moghadas, M., Ba-Omar, T., Qoronfleh, M. W., Guillemin, G. J., Manivasagam, T., Justin‐Thenmozhi, A., Ray, B., Bhat, A., Chidambaram, S. B., et al. (2019) · Neurotoxicity Research · doi:10.1007/s12640-018-9989-9 · Cited by 68 · see citing works
Jiang, Y., Xiao, X., Li, C., Luo, Y., Chen, S., Shi, G., Han, K., & Gu, H. C. (2020) · Analytical Chemistry · doi:10.1021/acs.analchem.9b05484 · Cited by 65 · see citing works
Ascorbic acid recycling in human erythrocytes is induced by smoking in vivo
Lykkesfeldt, J., Viscovich, M., & Poulsen, H. E. (2003) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2003.08.006 · Cited by 65 · see citing works
Vitamin C distribution and retention in the mouse brain
Harrison, F. E., Green, R. J., Dawes, S. M., & May, J. M. (2010) · Brain Research · doi:10.1016/j.brainres.2010.05.090 · Cited by 63 · see citing works
Self-citationTheoretical insight into the antioxidant properties of melatonin and derivatives
Johns, J. R., & Platts, J. A. (2014) · Organic & Biomolecular Chemistry · doi:10.1039/c4ob01396d · Cited by 63 · see citing works
Alpha-lipoic acid improves acute deltamethrin-induced toxicity in rats
Abdou, R., & Abdel‐Daim, M. M. (2014) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2014-0280 · Cited by 63 · see citing works
Qiao, H., Bell, J., Juliao, S. F., Li, L., & May, J. M. (2008) · Journal of Vascular Research · doi:10.1159/000135661 · Cited by 61 · see citing works
Self-citationAntioxidant defence during cardiopulmonary bypass surgery
Luyten, C., van Overveld, F. J., DEBACKER, L., SADOWSKA, A., Rodrigus, I. E. R., Hert, S. G. D., & DeBacker, W. (2005) · European Journal of Cardio-Thoracic Surgery · doi:10.1016/j.ejcts.2004.12.013 · Cited by 61 · see citing works
Combined Selenium and Vitamin E Deficiency Causes Fatal Myopathy in Guinea Pigs
Hill, K. E., Motley, A. K., Li, X., May, J. M., & Burk, R. F. (2001) · Journal of Nutrition · doi:10.1093/jn/131.6.1798 · Cited by 60 · see citing works
Self-citationSelf-Assembly and Antioxidant Properties of Octanoyl-6-O-ascorbic Acid
Nostro, P. L., Capuzzi, G., Romani, A., & Mulinacci, N. (1999) · Langmuir · doi:10.1021/la990796j · Cited by 59 · see citing works
Trans-Plasma Membrane Electron Transport in Mammals: Functional Significance in Health and Disease
Principe, D. D., Avigliano, L., Savini, I., & Catani, M. V. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3247 · Cited by 58 · see citing works
Ascorbate Transport and Recycling by SH-SY5Y Neuroblastoma Cells: Response to Glutamate Toxicity
May, J. M., Li, L., Hayslett, K., & Qu, Z. (2006) · Neurochemical Research · doi:10.1007/s11064-006-9077-z · Cited by 58 · see citing works
Self-citationEl‐Deeb, W., & Younis, E. (2009) · Veterinary Parasitology · doi:10.1016/j.vetpar.2009.06.002 · Cited by 57 · see citing works
Recycling of vitamin C from its oxidized forms by human endothelial cells
May, J. M., Qu, Z., Neel, D. R., & Li, X. (2003) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(03)00043-0 · Cited by 56 · see citing works
Self-citation
- Authors
- May, J. M., Qu, Z.-C., & Mendiratta, S.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- May, James M.
- ORCID
- May, James M.
- Venue
- Archives of Biochemistry and Biophysics
- Publisher
- Elsevier BV
- Published
- 1998-01
- Volume
- 349
- Issue
- 2
- Pages
- 281-289
- ISSN
- 0003-9861 (ISSN-L)
- OpenAlex
- W1999371223
- Cited by
- 316
- References
- 49
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 8 · 2021: 3 · 2020: 9 · 2019: 3 · 2018: 6 · 2017: 6 · 2016: 6 · 2015: 12 · 2014: 12 · 2013: 13 · 2012: 14
- FWCI
- 11.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Biochemistry and Biophysics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK050435, DK-50435)
- Topics
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- alpha-tocopherol, vitamin C, tocopheroxyl radical, human erythrocytes, erythrocyte ghosts, lipid peroxidation, ascorbate depletion, dehydroascorbic acid, ferricyanide, lecithin liposomes, hemolysis, plasma membrane
- MeSH terms
- Amidines, Antioxidants, Ascorbic Acid, Cyclic N-Oxides, Dehydroascorbic Acid, Erythrocyte Membrane, Erythrocytes, Ferricyanides, Glutathione, Humans, Kinetics, Liposomes, Oxidation-Reduction, Phosphatidylcholines, Spin Labels, Vitamin E, Oxidants
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