{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T19:28:12Z","timestamp":1793734092448,"version":"4.6.1"},"reference-count":139,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2013,12,16]],"date-time":"2013-12-16T00:00:00Z","timestamp":1387152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Research progress to understand the role of vitamin C (ascorbic acid) in human health has been slow in coming. This is predominantly the result of several flawed approaches to study design, often lacking a full appreciation of the redox chemistry and biology of ascorbic acid. In this review, we summarize our knowledge surrounding the limitations of common approaches used in vitamin C research. In human cell culture, the primary issues are the high oxygen environment, presence of redox-active transition metal ions in culture media, and the use of immortalized cell lines grown in the absence of supplemental ascorbic acid. Studies in animal models are also limited due to the presence of endogenous ascorbic acid synthesis. Despite the use of genetically altered rodent strains lacking synthesis capacity, there are additional concerns that these models do not adequately recapitulate the effects of vitamin C deprivation and supplementation observed in humans. Lastly, several flaws in study design endemic to randomized controlled trials and other human studies greatly limit their conclusions and impact. There also is anecdotal evidence of positive and negative health effects of vitamin C that are widely accepted but have not been substantiated. Only with careful attention to study design and experimental detail can we further our understanding of the possible roles of vitamin C in promoting human health and preventing or treating disease.<\/jats:p>","DOI":"10.3390\/nu5125161","type":"journal-article","created":{"date-parts":[[2013,12,16]],"date-time":"2013-12-16T15:23:30Z","timestamp":1387207410000},"page":"5161-5192","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["Myths, Artifacts, and Fatal Flaws: Identifying Limitations and Opportunities in Vitamin C Research"],"prefix":"10.3390","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4528-7976","authenticated-orcid":false,"given":"Alexander","family":"Michels","sequence":"first","affiliation":[{"name":"Linus Pauling Institute, 307 Linus Pauling Science Center, Oregon State University, Corvallis,  OR 97331, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balz","family":"Frei","sequence":"additional","affiliation":[{"name":"Linus Pauling Institute, 307 Linus Pauling Science Center, Oregon State University, Corvallis,  OR 97331, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2013,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1080\/10408398.2011.649149","article-title":"Authors\u2019 perspective: What is the optimum intake of vitamin C in humans?","volume":"52","author":"Frei","year":"2012","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1017\/S0007114509993229","article-title":"Is vitamin C supplementation beneficial? Lessons learned from randomised controlled trials","volume":"103","author":"Lykkesfeldt","year":"2010","journal-title":"Br. J. Nutr."},{"key":"ref_3","unstructured":"Stipanuk, M.H., and Caudill, M.A. (2012). Biochemical, Physiological, and Molecular Aspects of Human Nutrition, Elsevier\/Saunders. [3rd ed.]."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1093\/ajcn\/69.6.1086","article-title":"Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans","volume":"69","author":"Carr","year":"1999","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.3945\/ajcn.111.027995","article-title":"Effects of vitamin C supplementation on blood pressure: A meta-analysis of randomized controlled trials","volume":"95","author":"Juraschek","year":"2012","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0014-5793(03)00235-7","article-title":"Oxidative stress in cell culture: An under-appreciated problem?","volume":"540","author":"Halliwell","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1006\/abbi.1993.1074","article-title":"The pecking order of free radicals and antioxidants: Lipid peroxidation, \u03b1-tocopherol, and ascorbate","volume":"300","author":"Buettner","year":"1993","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"532","DOI":"10.2307\/3579271","article-title":"Catalytic metals, ascorbate and free radicals: Combinations to avoid","volume":"145","author":"Buettner","year":"1996","journal-title":"Radiat. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ab.2009.09.040","article-title":"Keeping the intracellular vitamin C at a physiologically relevant level in endothelial cell culture","volume":"397","author":"Lykkesfeldt","year":"2010","journal-title":"Anal. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1290\/1071-2690(2001)037<0026:MOAAAC>2.0.CO;2","article-title":"Monitoring of ascorbate at a constant rate in cell culture: Effect on cell growth","volume":"37","author":"Chepda","year":"2001","journal-title":"In Vitro Cell. Dev. Biol. Anim."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1080\/10715760310001607041","article-title":"Factors affecting the ascorbate- and phenolic-dependent generation of hydrogen peroxide in Dulbecco\u2019s Modified Eagles Medium","volume":"37","author":"Wee","year":"2003","journal-title":"Free Radic. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1089\/152308601750100687","article-title":"The in vitro cytotoxicity of ascorbate depends on the culture medium used to perform the assay and involves hydrogen peroxide","volume":"3","author":"Clement","year":"2001","journal-title":"Antioxid. Redox Signal."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1182\/blood.V75.10.1903.1903","article-title":"Manipulations of cellular iron metabolism for modulating normal and malignant cell proliferation: Achievements and prospects","volume":"75","author":"Cazzola","year":"1990","journal-title":"Blood"},{"key":"ref_14","unstructured":"Halliwell, B., and Gutteridge, J.M.C. (2007). Free Radicals in Biology and Medicine, Oxford University Press. [4th ed.]."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0165-022X(88)90100-5","article-title":"In the absence of catalytic metals ascorbate does not autoxidize at pH 7: Ascorbate as a test for catalytic metals","volume":"16","author":"Buettner","year":"1988","journal-title":"J. Biochem. Biophys. Methods"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1042\/bj2820459","article-title":"Iron-induced ascorbate oxidation in plasma as monitored by ascorbate free radical formation. No spin-trapping evidence for the hydroxyl radical in iron-overloaded plasma","volume":"282","author":"Minetti","year":"1992","journal-title":"Biochem. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1096\/fasebj.13.9.1007","article-title":"Does vitamin C act as a pro-oxidant under physiological conditions?","volume":"13","author":"Carr","year":"1999","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"E1406","DOI":"10.1152\/ajpendo.2000.279.6.E1406","article-title":"Vitamin C suppresses oxidative lipid damage in vivo, even in the presence of iron overload","volume":"279","author":"Chen","year":"2000","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15656","DOI":"10.1074\/jbc.272.25.15656","article-title":"Antioxidant activity of vitamin C in iron-overloaded human plasma","volume":"272","author":"Berger","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"439","DOI":"10.3109\/10715769609149066","article-title":"Vitamin C: Antioxidant or pro-oxidant in vivo?","volume":"25","author":"Halliwell","year":"1996","journal-title":"Free Radic. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.bbrc.2009.08.069","article-title":"Artefacts in cell culture: Pyruvate as a scavenger of hydrogen peroxide generated by ascorbate or epigallocatechin gallate in cell culture media","volume":"388","author":"Long","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.bbrc.2011.01.091","article-title":"Artefacts in cell culture: \u03b1-Ketoglutarate can scavenge hydrogen peroxide generated by ascorbate and epigallocatechin gallate in cell culture media","volume":"406","author":"Long","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/0891-5849(93)90508-R","article-title":"Ascorbate free radical as a marker of oxidative stress: An EPR study","volume":"14","author":"Buettner","year":"1993","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13604","DOI":"10.1073\/pnas.0506390102","article-title":"Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues","volume":"102","author":"Chen","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1093\/clinchem\/36.10.1807","article-title":"Spontaneous decay of oxidized ascorbic acid (dehydro-l-ascorbic acid) evaluated by high-pressure liquid chromatography","volume":"36","author":"Bode","year":"1990","journal-title":"Clin. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1742-4658.2006.05607.x","article-title":"Vitamin C. Biosynthesis, recycling and degradation in mammals","volume":"274","author":"Linster","year":"2007","journal-title":"FEBS J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"15531","DOI":"10.1016\/S0021-9258(18)82289-X","article-title":"Ascorbic acid recycling in human neutrophils","volume":"268","author":"Washko","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"18982","DOI":"10.1074\/jbc.272.30.18982","article-title":"Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid","volume":"272","author":"Rumsey","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/364079a0","article-title":"Mammalian facilitative hexose transporters mediate the transport of dehydroascorbic acid","volume":"364","author":"Vera","year":"1993","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S0014-5793(02)03167-8","article-title":"The physiological role of dehydroascorbic acid","volume":"527","author":"Wilson","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1002\/jcb.21515","article-title":"Calcium oxalate crystals in fetal bovine serum: Implications for cell culture, phagocytosis and biomineralization studies in vitro","volume":"103","author":"Pedraza","year":"2008","journal-title":"J. Cell. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"688","DOI":"10.5483\/BMBRep.2010.43.10.688","article-title":"Preventable effect of l-threonate, an ascorbate metabolite, on androgen-driven balding via repression of dihydrotestosterone-induced dickkopf-1 expression in human hair dermal papilla cells","volume":"43","author":"Kwack","year":"2010","journal-title":"BMB Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1096\/fj.01-0825fje","article-title":"Vitamin C matters: Increased oxidative stress in cultured human aortic endothelial cells without supplemental ascorbic acid","volume":"16","author":"Smith","year":"2002","journal-title":"FASEB J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"17399","DOI":"10.1074\/jbc.M002248200","article-title":"Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin","volume":"275","author":"Huang","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.1016\/S0021-9258(19)39841-2","article-title":"Millimolar concentrations of ascorbic acid in purified human mononuclear leukocytes. Depletion and reaccumulation","volume":"265","author":"Bergsten","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1161\/01.ATV.17.8.1583","article-title":"Both intracellular and extracellular vitamin C inhibit atherogenic modification of LDL by human vascular endothelial cells","volume":"17","author":"Martin","year":"1997","journal-title":"Arterioscler. Thromb. Vas. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.bbrc.2012.08.054","article-title":"Mechanisms of ascorbic acid stimulation of norepinephrine synthesis in neuronal cells","volume":"426","author":"May","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1179\/135100002125000604","article-title":"Lipoic acid and vitamin C potentiate nitric oxide synthesis in human aortic endothelial cells independently of cellular glutathione status","volume":"7","author":"Visioli","year":"2002","journal-title":"Redox Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1146\/annurev.nu.06.070186.002053","article-title":"The biochemical functions of ascorbic acid","volume":"6","author":"Englard","year":"1986","journal-title":"Annu. Rev. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1126\/science.1066373","article-title":"A conserved family of prolyl-4-hydroxylases that modify HIF","volume":"294","author":"Bruick","year":"2001","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1042\/BJ20091609","article-title":"Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents","volume":"427","author":"Flashman","year":"2010","journal-title":"Biochem. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0945-053X(03)00006-4","article-title":"Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis","volume":"22","author":"Myllyharju","year":"2003","journal-title":"Matrix Biol."},{"key":"ref_43","first-page":"1764","article-title":"Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells","volume":"63","author":"Knowles","year":"2003","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2879","DOI":"10.1073\/pnas.78.5.2879","article-title":"Regulation of collagen synthesis by ascorbic acid","volume":"78","author":"Murad","year":"1981","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1163S","DOI":"10.1093\/ajcn\/54.6.1163s","article-title":"Multicompartmental secretion of ascorbate and its dual role in dopamine \u03b2-hydroxylation","volume":"54","author":"Diliberto","year":"1991","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/embor.2013.29","article-title":"Breathing-in epigenetic change with vitamin C","volume":"14","author":"Monfort","year":"2013","journal-title":"EMBO Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1016\/j.freeradbiomed.2012.03.022","article-title":"Ascorbate stimulates endothelial nitric oxide synthase enzyme activity by rapid modulation of its phosphorylation status","volume":"52","author":"Ladurner","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"C169","DOI":"10.1152\/ajpcell.00674.2008","article-title":"Transfer of ascorbic acid across the vascular endothelium: Mechanism and self-regulation","volume":"297","author":"May","year":"2009","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.freeradbiomed.2006.10.033","article-title":"Ascorbate inhibits NADPH oxidase subunit p47phox expression in microvascular endothelial cells","volume":"42","author":"Wu","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3945\/jn.112.168690","article-title":"Recent applications of engineered animal antioxidant deficiency models in human nutrition and chronic disease","volume":"143","author":"Yu","year":"2013","journal-title":"J. Nutr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3507","DOI":"10.1073\/pnas.1222878110","article-title":"Genomic responses in mouse models poorly mimic human inflammatory diseases","volume":"110","author":"Seok","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0014-5793(96)00548-0","article-title":"Glutathione depletion induces glycogenolysis dependent ascorbate synthesis in isolated murine hepatocytes","volume":"388","author":"Braun","year":"1996","journal-title":"FEBS Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.bbrc.2004.03.022","article-title":"Glycogenolysis is directed towards ascorbate synthesis by glutathione conjugation","volume":"317","author":"Chan","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/S0891-5849(97)00062-2","article-title":"Ascorbate metabolism and its regulation in animals","volume":"23","author":"Banhegyi","year":"1997","journal-title":"Free Radic. Biol. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s10528-013-9574-0","article-title":"Conserved or lost: Molecular evolution of the key gene GULO in vertebrate vitamin C biosynthesis","volume":"51","author":"Yang","year":"2013","journal-title":"Biochem. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1016\/S0016-5085(63)80086-4","article-title":"Studies on intestinal absorption of l-ascorbic acid-1-C-14","volume":"44","author":"Spencer","year":"1963","journal-title":"Gastroenterology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/0006-291X(73)90969-8","article-title":"Site of intestinal absorption of ascorbic acid in guinea pigs and rats","volume":"52","author":"Hornig","year":"1973","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1749-6632.1975.tb29271.x","article-title":"Distribution of ascorbic acid, metabolites and analogues in man and animals","volume":"258","author":"Hornig","year":"1975","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1093\/ajcn\/22.3.318","article-title":"Existence and characteristics of Na positive-dependent active transport of ascorbic acid in guinea pig","volume":"22","author":"Stevenson","year":"1969","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_60","first-page":"G461","article-title":"Dehydroascorbic acid and ascorbic acid transport systems in the guinea pig ileum","volume":"250","author":"Bianchi","year":"1986","journal-title":"Am. J. Physiol."},{"key":"ref_61","first-page":"E374","article-title":"Ascorbic acid flux across mucosal border of guinea pig and human ileum","volume":"233","author":"Mellors","year":"1977","journal-title":"Am. J. Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/S0016-5085(19)32749-0","article-title":"Active transport of l-ascorbic acid in the human ileum","volume":"67","author":"Stevenson","year":"1974","journal-title":"Gastroenterology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"9092","DOI":"10.1074\/jbc.M112.436790","article-title":"Intestinal dehydroascorbic acid (DHA) transport mediated by the facilitative sugar transporters, GLUT2 and GLUT8","volume":"288","author":"Corpe","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1093\/jn\/117.2.291","article-title":"Effect of dietary ascorbic acid intake on tissue vitamin C in mice","volume":"117","author":"Tsao","year":"1987","journal-title":"J. Nutr."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1111\/j.1439-0396.2007.00681.x","article-title":"Allometric scaling, metabolic body size and interspecies comparisons of basal nutritional requirements","volume":"91","author":"Rucker","year":"2007","journal-title":"J. Anim. Physiol. Anim. Nutr."},{"key":"ref_66","first-page":"137","article-title":"An acute study on the relative gastro-intestinal absorption of a novel form of calcium ascorbate","volume":"57","author":"Bush","year":"1987","journal-title":"Res. Commun. Chem. Pathol. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/0002-8223(94)91950-X","article-title":"Comparison of the absorption and excretion of three commercially available sources of vitamin C","volume":"94","author":"Johnston","year":"1994","journal-title":"J. Am. Diet. Assoc."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"292","DOI":"10.3945\/ajcn.110.004853","article-title":"Dietary ascorbate intake affects steady state tissue concentrations in vitamin C-deficient mice: Tissue deficiency after suboptimal intake and superior bioavailability from a food source (kiwifruit)","volume":"93","author":"Vissers","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.3390\/nu5093684","article-title":"A randomized steady-state bioavailability study of synthetic versus natural (Kiwifruit-Derived) vitamin C","volume":"5","author":"Carr","year":"2013","journal-title":"Nutrients"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.nut.2010.04.010","article-title":"Time course of vitamin C distribution and absorption after oral administration in SMP30\/GNL knockout mice","volume":"27","author":"Iwama","year":"2011","journal-title":"Nutrition"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1359\/JBMR.050406","article-title":"Spontaneous fractures in the mouse mutant sfx are caused by deletion of the gulonolactone oxidase gene, causing vitamin C deficiency","volume":"20","author":"Mohan","year":"2005","journal-title":"J. Bone Miner. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.bbrc.2011.09.146","article-title":"Differential regulation of the ascorbic acid transporter SVCT2 during development and in response to ascorbic acid depletion","volume":"414","author":"Meredith","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.bbrc.2005.06.069","article-title":"Polarized localization of vitamin C transporters, SVCT1 and SVCT2, in epithelial cells","volume":"334","author":"Boyer","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"9035","DOI":"10.1074\/jbc.M205119200","article-title":"Up-regulation and polarized expression of the sodium-ascorbic acid transporter SVCT1 in post-confluent differentiated CaCo-2 cells","volume":"278","author":"Maulen","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1079\/BJN2001492","article-title":"Decreased expression of the vitamin C transporter SVCT1 by ascorbic acid in a human intestinal epithelial cell line","volume":"87","author":"MacDonald","year":"2002","journal-title":"Br. J. Nutr."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1172\/JCI39191","article-title":"Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice","volume":"120","author":"Corpe","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s00726-007-0555-7","article-title":"SVCT1 and SVCT2: Key proteins for vitamin C uptake","volume":"34","author":"Savini","year":"2008","journal-title":"Amino Acids"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/j.cell.2008.01.042","article-title":"Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C","volume":"132","author":"Kinet","year":"2008","journal-title":"Cell"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/S8756-3282(00)00369-0","article-title":"Spontaneous fracture (sfx): A mouse genetic model of defective peripubertal bone formation","volume":"27","author":"Beamer","year":"2000","journal-title":"Bone"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1073\/pnas.97.2.841","article-title":"Aortic wall damage in mice unable to synthesize ascorbic acid","volume":"97","author":"Maeda","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1111\/jnc.12069","article-title":"Behavioral and monoamine changes following severe vitamin C deficiency","volume":"124","author":"Ward","year":"2013","journal-title":"J. Neurochem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5723","DOI":"10.1073\/pnas.0511225103","article-title":"Senescence marker protein 30 functions as gluconolactonase in l-ascorbic acid biosynthesis, and its knockout mice are prone to scurvy","volume":"103","author":"Kondo","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1093\/jn\/115.12.1630","article-title":"Requirement for ascorbic acid in a rat mutant unable to synthesize ascorbic acid","volume":"115","author":"Horio","year":"1985","journal-title":"J. Nutr."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1016\/S0024-3205(01)01261-9","article-title":"A newly established strain of spontaneously hypertensive rat with a defect of ascorbic acid biosynthesis","volume":"69","author":"Horio","year":"2001","journal-title":"Life Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0008-6363(01)00247-4","article-title":"Postischemic myocardial recovery and oxidative stress status of vitamin C deficient rat hearts","volume":"51","author":"Vergely","year":"2001","journal-title":"Cardiovasc. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1007\/BF01954844","article-title":"Expression of the mutant gene for l-gulono-gamma-lactone oxidase in scurvy-prone rats","volume":"45","author":"Nishikimi","year":"1989","journal-title":"Experientia"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1016\/0026-0495(89)90046-2","article-title":"Dietary fat-mediated changes in hepatic apoprotein B\/E receptor in the guinea pig: Effect of polyunsaturated, monounsaturated, and saturated fat","volume":"38","author":"Fernandez","year":"1989","journal-title":"Metabolism"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"H1704","DOI":"10.1152\/ajpheart.2001.281.4.H1704","article-title":"Vitamin C and quinapril abrogate LVH and endothelial dysfunction in aortic-banded guinea pigs","volume":"281","author":"Bell","year":"2001","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1093\/cvr\/cvn107","article-title":"Vascular tolerance to nitroglycerin in ascorbate deficiency","volume":"79","author":"Wolkart","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1080\/09687680110033774","article-title":"Vitamin C transport systems of mammalian cells","volume":"18","author":"Liang","year":"2001","journal-title":"Mol. Membr. Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"C1696","DOI":"10.1152\/ajpcell.00461.2001","article-title":"Regulation of the human vitamin C transporters expressed in COS-1 cells by protein kinase C [corrected]","volume":"283","author":"Liang","year":"2002","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"27719","DOI":"10.1074\/jbc.M400876200","article-title":"A C-terminal region dictates the apical plasma membrane targeting of the human sodium-dependent vitamin C transporter-1 in polarized epithelia","volume":"279","author":"Subramanian","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1016\/j.freeradbiomed.2012.02.017","article-title":"Essential role of intracellular glutathione in controlling ascorbic acid transporter expression and function in rat hepatocytes and hepatoma cells","volume":"52","author":"Mardones","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"10128","DOI":"10.1074\/jbc.M210686200","article-title":"Recycling of vitamin C by a bystander effect","volume":"278","author":"Nualart","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.bbrc.2007.06.072","article-title":"Maturational loss of the vitamin C transporter in erythrocytes","volume":"360","author":"May","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"4729","DOI":"10.1182\/blood-2008-05-159269","article-title":"The Glut1 and Glut4 glucose transporters are differentially expressed during perinatal and postnatal erythropoiesis","volume":"112","author":"Blanc","year":"2008","journal-title":"Blood"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"28246","DOI":"10.1074\/jbc.M000988200","article-title":"Dehydroascorbic acid transport by GLUT4 in Xenopus oocytes and isolated rat adipocytes","volume":"275","author":"Rumsey","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"11105","DOI":"10.1073\/pnas.0804226105","article-title":"Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice","volume":"105","author":"Chen","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/j.freeradbiomed.2009.03.002","article-title":"Vitamins E and C in the prevention of cardiovascular disease and cancer in men","volume":"46","author":"Roberts","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1475-2891-6-41","article-title":"Is plasma vitamin C an appropriate biomarker of vitamin C intake? A systematic review and meta-analysis","volume":"6","author":"Dehghan","year":"2007","journal-title":"Nutr. J."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1024\/0300-9831.70.5.226","article-title":"Vitamin C concentrations in plasma as a function of intake: A meta-analysis","volume":"70","author":"Brubacher","year":"2000","journal-title":"Int. J. Vitam. Nutr. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.3945\/ajcn.2008.27016","article-title":"Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003\u20132004 National Health and Nutrition Examination Survey (NHANES)","volume":"90","author":"Schleicher","year":"2009","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1146\/annurev-nutr-071812-161246","article-title":"Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function","volume":"33","author":"Michels","year":"2013","journal-title":"Annu. Rev. Nutr."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1001\/archinte.168.14.1493","article-title":"Plasma vitamin C level, fruit and vegetable consumption, and the risk of new-onset type 2 diabetes mellitus: The European prospective investigation of cancer\u2014Norfolk prospective study","volume":"168","author":"Harding","year":"2008","journal-title":"Arch. Intern. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"3704","DOI":"10.1073\/pnas.93.8.3704","article-title":"Vitamin C pharmacokinetics in healthy volunteers: Evidence for a recommended dietary allowance","volume":"93","author":"Levine","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"9842","DOI":"10.1073\/pnas.171318198","article-title":"A new recommended dietary allowance of vitamin C for healthy young women","volume":"98","author":"Levine","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"18","DOI":"10.4110\/in.2012.12.1.18","article-title":"The analysis of vitamin C concentration in organs of gulo\u2212\/\u2212 mice upon vitamin C withdrawal","volume":"12","author":"Kim","year":"2012","journal-title":"Immune Netw."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"800","DOI":"10.3945\/ajcn.112.053207","article-title":"Human skeletal muscle ascorbate is highly responsive to changes in vitamin C intake and plasma concentrations","volume":"97","author":"Carr","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1076\/ceyr.16.9.857.5039","article-title":"Vitamin C in human and guinea pig aqueous, lens and plasma in relation to intake","volume":"16","author":"Taylor","year":"1997","journal-title":"Curr. Eye Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1207\/S15327914NC4502_06","article-title":"Vitamin C supplementation decreases oxidative stress biomarker f2-isoprostanes in plasma of nonsmokers exposed to environmental tobacco smoke","volume":"45","author":"Dietrich","year":"2003","journal-title":"Nutr. Cancer"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.freeradbiomed.2008.09.030","article-title":"Vitamin C treatment reduces elevated C-reactive protein","volume":"46","author":"Block","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/0003-2697(90)90037-A","article-title":"Determination of dehydroascorbic acid using high-performance liquid chromatography with coulometric electrochemical detection","volume":"189","author":"Dhariwal","year":"1990","journal-title":"Anal. Biochem."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1006\/abio.2000.4592","article-title":"Determination of ascorbic acid and dehydroascorbic acid in biological samples by high-performance liquid chromatography using subtraction methods: Reliable reduction with tris[2-carboxyethyl]phosphine hydrochloride","volume":"282","author":"Lykkesfeldt","year":"2000","journal-title":"Anal. Biochem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.nutres.2011.11.005","article-title":"Ascorbate and dehydroascorbic acid as biomarkers of oxidative stress: Validity of clinical data depends on vacutainer system used","volume":"32","author":"Lykkesfeldt","year":"2012","journal-title":"Nutr. Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1038\/sj.ejcn.1602655","article-title":"Stability of whole blood and plasma ascorbic acid","volume":"61","author":"Karlsen","year":"2007","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/S0009-9120(01)00270-3","article-title":"Plasma ascorbic acid: Measurement, stability and clinical utility revisited","volume":"34","author":"Chung","year":"2001","journal-title":"Clin. Biochem."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Tveden-Nyborg, P., and Lykkesfeldt, J. (2013). Does Vitamin C deficiency increase lifestyle-associated vascular disease progression? Evidence based on experimental and clinical studies. Antioxid. Redox Signal.","DOI":"10.1089\/ars.2013.5382"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/ajcn\/73.1.93","article-title":"Effect of ascorbic acid intake on nonheme-iron absorption from a complete diet","volume":"73","author":"Cook","year":"2001","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1097\/01.ASN.0000146012.44570.20","article-title":"Dietary factors and the risk of incident kidney stones in men: New insights after 14 years of follow-up","volume":"15","author":"Taylor","year":"2004","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1001\/jamainternmed.2013.2296","article-title":"Ascorbic acid supplements and kidney stone incidence among men: A prospective study","volume":"173","author":"Thomas","year":"2013","journal-title":"JAMA Intern. Med."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1681\/ASN.2009030276","article-title":"DASH-style diet associates with reduced risk for kidney stones","volume":"20","author":"Taylor","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1093\/ndt\/gfq412","article-title":"Vitamin C supplementation in kidney failure: Effect on uraemic symptoms","volume":"26","author":"Singer","year":"2011","journal-title":"Nephrol. Dial. Transpl."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1093\/ajcn\/81.4.736","article-title":"Vitamins E and C are safe across a broad range of intakes","volume":"81","author":"Hathcock","year":"2005","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1136\/bmj.306.6881.841","article-title":"Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency","volume":"306","author":"Rees","year":"1993","journal-title":"BMJ"},{"key":"ref_125","first-page":"CD000980","article-title":"Vitamin C for preventing and treating the common cold","volume":"1","author":"Hemila","year":"2013","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"e168","DOI":"10.1371\/journal.pmed.0020168","article-title":"Vitamin C for preventing and treating the common cold","volume":"2","author":"Douglas","year":"2005","journal-title":"PLoS Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/sj.ejcn.1602261","article-title":"Effect of vitamin C on common cold: Randomized controlled trial","volume":"60","author":"Sasazuki","year":"2006","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"4284","DOI":"10.3390\/nu5114284","article-title":"Synthetic or food-derived vitamin C\u2014Are they equally bioavailable?","volume":"5","author":"Carr","year":"2013","journal-title":"Nutrients"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"533","DOI":"10.7326\/0003-4819-140-7-200404060-00010","article-title":"Vitamin C pharmacokinetics: Implications for oral and intravenous use","volume":"140","author":"Padayatty","year":"2004","journal-title":"Ann. Intern. Med."},{"key":"ref_130","first-page":"109","article-title":"Preventive action of vitamin C on nitrosamine formation","volume":"30","author":"Tannenbaum","year":"1989","journal-title":"Int. J. Vitam. Nutr. Res. Suppl."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1016\/j.phytochem.2009.09.028","article-title":"Covalent interaction of ascorbic acid with natural products","volume":"70","author":"Kesinger","year":"2009","journal-title":"Phytochemistry"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1021\/tx900042u","article-title":"Ascorbic acid promotes detoxification and elimination of 4-hydroxy-2(E)-nonenal in human monocytic THP-1 cells","volume":"22","author":"Miranda","year":"2009","journal-title":"Chem. Res. Toxicol."},{"key":"ref_133","first-page":"443","article-title":"Ascorbic acid: Chemistry, biology and the treatment of cancer","volume":"1826","author":"Du","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"6377","DOI":"10.1073\/pnas.86.16.6377","article-title":"Ascorbate is an outstanding antioxidant in human blood plasma","volume":"86","author":"Frei","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"10396","DOI":"10.1021\/ja4028346","article-title":"Ascorbic acid enhances Tet-mediated 5-methylcytosine oxidation and promotes DNA demethylation in mammals","volume":"135","author":"Yin","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1002\/stem.493","article-title":"Vitamin C promotes widespread yet specific DNA demethylation of the epigenome in human embryonic stem cells","volume":"28","author":"Chung","year":"2010","journal-title":"Stem Cells"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"3833","DOI":"10.1074\/jbc.M111.316018","article-title":"Vitamin C deficiency activates the purine nucleotide cycle in zebrafish","volume":"287","author":"Kirkwood","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"e29794","DOI":"10.1371\/journal.pone.0029794","article-title":"Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer","volume":"7","author":"Monti","year":"2012","journal-title":"PLoS One"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1007\/s00280-013-2070-8","article-title":"Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): Results from a phase I clinical trial","volume":"71","author":"Welsh","year":"2013","journal-title":"Cancer Chemother. Pharmacol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/5\/12\/5161\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:51:24Z","timestamp":1760219484000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/5\/12\/5161"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,12,16]]},"references-count":139,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2013,12]]}},"alternative-id":["nu5125161"],"URL":"https:\/\/doi.org\/10.3390\/nu5125161","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,12,16]]}}}