Vitamin C: The known and the unknown and Goldilocks
Open accessAbstract
Vitamin C (Ascorbic Acid), the antiscorbutic vitamin, cannot be synthesized by humans and other primates, and has to be obtained from diet. Ascorbic acid is an electron donor and acts as a cofactor for fifteen mammalian enzymes. Two sodium-dependent transporters are specific for ascorbic acid, and its oxidation product dehydroascorbic acid is transported by glucose transporters. Ascorbic acid is differentially accumulated by most tissues and body fluids. Plasma and tissue vitamin C concentrations are dependent on amount consumed, bioavailability, renal excretion, and utilization. To be biologically meaningful or to be clinically relevant, in vitro and in vivo studies of vitamin C actions have to take into account physiologic concentrations of the vitamin. In this paper, we review vitamin C physiology; the many phenomena involving vitamin C where new knowledge has accrued or where understanding remains limited; raise questions about the vitamin that remain to be answered; and explore lines of investigations that are likely to be fruitful.
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Typical symptoms of scurvy include muscle weakness, swollen and bleeding gums, loss of teeth, petechial hemorrhaging, spontaneous ecchymoses, anemia, impaired wound healing, hyperkeratosis, weakness, myalgia, arthralgia, and weight loss.
“Typical symptoms of scurvy are muscle weakness, swollen and bleeding gums, loss of teeth, petechial hemorrhaging, spontaneous ecchymoses, anemia, impaired would healing, hyperkeratosis, weakness, myalgia, arthralgia, and weight loss”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
The Scurvy section (page unavailable) lists hyperkeratosis, swollen gingivae, anemia, petechial hemorrhage, purpura, arthralgia, wound breakdown, and bleeding into the skin. The oral-health and collagen-hydroxylation sections also describe bleeding gums, tooth loss, and poor wound healing. The copy does not identify muscle weakness, myalgia, or weight loss as typical symptoms, or explicitly describe ecchymoses as spontaneous. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRecommendations for vitamin C intake differ substantially from 40 to 120 mg/day in various countries.
“Recommendations differ substantially from 40 to 120 mg/day in various countries.”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
The Recommended Dietary Allowance for vitamin C section (page unavailable) gives US and Canadian recommendations of 75 mg/day for women and 90 mg/day for men and says many countries have increased theirs. It does not give a cross-country range of 40–120 mg/day; instead, it describes many countries’ current recommendations as similar to, or slightly higher than, those in the US and Canada. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe plasma levels of dehydroascorbic acid are very low in healthy humans, while ascorbyl radical is undetectable.
“The plasma levels of dehydro-ascorbic acid are very low in healthy humans, while that of an ascorbyl radical are undetectable [6,53,54,62,67].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
The ‘Ascorbic acid and dehydroascorbic acid transport’ section estimates that DHA in physiological plasma is less than 1–2% of ascorbate, supporting the first part of the claim. The ‘Chemistry and metabolism of vitamin C’ section does not say ascorbate radical is undetectable in healthy plasma; it says the radical can be measured in blood and extracellular fluid samples under some conditions. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDehydroascorbic acid has a half-life of about 6 minutes and is decomposed to 2,3-diketo-1-gulonic acid, losing vitamin C activity.
“It has a half-life of about 6 minutes. It is decomposed to 2,3-diketo-1-gulonic acid (Figure 4) and, in this way, it loses its activity of vitamin C [6,68,73].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
The Chemistry and metabolism of vitamin C section (page not provided) says dehydroascorbic acid has a half-life of only minutes and breaks down by hydrolytic ring rupture into 2,3-diketogulonic acid, which cannot reform vitamin C precursors. It does not give the claimed half-life of about 6 minutes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPhysiologically high vitamin C levels (2-10 mM) are found in neurons and endocrine cells, particularly the adrenal and pituitary gland, apparently related to the synthesis of hormones and neuro-mediators.
“Physiologically high levels (2–10 mM) are found in neurons and endocrine cells (particularly, the adrenal and pituitary gland), which is apparently related to the synthesis of hormones and neuro-mediators described below [4,6,8,72,73].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
The sections on adrenal secretion and enzymology report high vitamin C in the adrenal gland and its role in synthesizing norepinephrine and activating peptide hormones. But our copy does not establish a 2–10 mM range specifically for neurons, endocrine cells, or the pituitary gland; it gives approximately 12–15 mM for adrenal chromaffin granules. No page numbers were available in the indexed passages. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Biochemically, vitamin C plasma levels below 11 μM are considered to coincide with clinical symptoms of scurvy.
“Biochemically, vitamin C plasma levels below 11 µM are considered to coincide with clinical symptoms of scurvy.”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
The Scurvy section says concentrations below 11.4 µM indicate deficiency and that scurvy can occur at low concentrations. But it also says there is no definitive diagnostic concentration: healthy subjects reached 8 µM without developing scurvy, and physical signs may appear only at 3–5 µM. Thus, below 11 µM does not necessarily coincide with clinical symptoms. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe first symptoms of vitamin C deficiency such as lassitude and tiredness, occurring at plasma levels approximately below 20 μM, can be due to decreased synthesis of carnitine.
“The first mentioned symptoms of vitamin C deficiency such as lassitude and tiredness, occurring at plasma levels approximately below 20 µM, can be due to decreased synthesis of carnitine since a deficiency in carnitine leads to decreased oxidation of fatty acids in muscles and other tissues.”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
The Recommended Dietary Allowance section reports fatigue at plasma vitamin C concentrations below about 20 µM, and the Scurvy section reports lassitude during depletion. The Enzymology and vitamin C section describes an in-vitro role for ascorbate in carnitine synthesis but says its role in vivo is difficult to characterize; it does not link reduced carnitine synthesis to the reported symptoms. The Enzymology in vivo and in situ section instead suggests impaired norepinephrine biosynthesis as a possible explanation for lassitude. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSymptoms of scurvy are not seen unless the total vitamin C content in the body falls below 300-400 mg.
“Similarly, symptoms are not seen unless the total vitamin C content in the body falls below 300–400 mg [2,3,6,157,170].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
The Scurvy section (page not provided) says scurvy is thought to occur when body stores fall below 300 mg. It does not give a 300–400 mg threshold, and it cautions that there is no definitive concentration at which scurvy develops. The claim presents an approximate, uncertain threshold as a firm rule for symptoms. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNotwithstanding that the effect is absent in the general population, vitamin C can be effective under specific conditions, such as low levels of vitamin C, e.g., in people under physical stress.
“Notwithstanding that the effect is absent in the general population, vitamin C can be effective under specific conditions, such as low levels of vitamin C, e.g., in people under physical stress [6,191,195,198].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
In “Some common questions about vitamin C” (page unavailable), the paper reports that prophylactic vitamin C did not reduce common-cold incidence in the general population but halved the risk among people undergoing severe exercise. It does not say that the exercisers had low vitamin C levels or that low levels explain that benefit. It also reports modest reductions in cold duration and severity in the general population, so the absence of an effect applies only to incidence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredVitamin C absorption is relatively slow, as maximal plasma levels are reached after 2-4 h.
“In general, vitamin C absorption is relatively slow, as maximal plasma levels are reached after 2–4 h [6,8,40,58].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
Erythrocytes are very active in mediating the reduction of dehydroascorbic acid.
“Erythrocytes are very active in mediating this reduction [6,52].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
The influence of genetic variations on vitamin C pharmacokinetics is based on single nucleotide polymorphisms (SNPs) found in SLC23A1 and SLC23A2 genes with a possible association to human diseases.
“The influence of genetic variations on vitamin C pharmacokinetics is based on single nucleotide polymorphisms (SNPs) found in SLC23A1 and SLC23A2 genes with a possible association to human diseases (reviewed in References [2,6]).”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
Vitamin C function appears to be linked dominantly with its electron-donating property.
“Its function appears to be linked dominantly with its electron-donating property [6].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
The involvement of vitamin C as an endogenous antioxidant (e.g., scavenger of ROS) is still a matter of debate.
“The involvement of vitamin C as an endogenous antioxidant, e.g., scavenger of ROS, is still a matter of debate.”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
The role of vitamin C as an antioxidant has been clearly and repeatedly demonstrated in vitro, but in vivo the situation is less clear.
“Its role has been clearly and repeatedly demonstrated in vitro, but in vivo, the situation is less clear [5,6,154,155,156].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
In pregnant women, an additional 5-10 mg of vitamin C is recommended, and 25 mg in lactating mothers.
“In pregnant women, an additional 5–10 mg is recommended (25 mg in lactating mothers) [3,4,5,6].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [6]
The Recommended Dietary Allowance for vitamin C section gives a general RDA of 75 mg for women but does not specify an increase for pregnancy or lactation. Searches for pregnancy, lactation, and the additional 5–10 mg and 25 mg amounts found no passage stating those recommendations; the pregnancy passages instead discuss intervention trials. Page numbers were not available in our copy. (LLM, conf=0.74)
Experimental — accuracy not yet measuredAt millimolar plasma concentrations achievable by intravenous administration, vitamin C can act as a pro-oxidant.
“it can also function as a pro-oxidant at millimolar plasma concentrations, which can be achieved by intravenous administration of pharmacological ascorbate4”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [4]
Vitamin C is a critical cofactor for numerous enzymes, including copper-containing monooxygenases and Fe2+- and αKG-dependent dioxygenases.
“vitamin C also functions as a critical cofactor for numerous enzymes by readily donating its electrons to prosthetic metal ions to achieve full enzymatic activity4”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [4]
Ascorbate levels in phagocytes and lymphocytes are 10-100 times higher than in plasma.
“Although not much is known about how ascorbate is utilized by the various cells that make up the tumour microenvironment, studies have shown that phagocytes and lymphocytes have ascorbate concentrations 10–100 times greater than plasma4.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [4]
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- Authors
- Padayatty, S., & Levine, M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Padayatty, SJ
- ORCID
- Levine, M
- Venue
- Oral Diseases
- Publisher
- Wiley
- Published
- 2016-04-14
- Volume
- 22
- Issue
- 6
- Pages
- 463-493
- ISSN
- 1354-523X (ISSN-L)
- 1601-0825
- PMC
- PMC4959991
- OpenAlex
- W2290836807
- Cited by
- 753
- References
- 336
- Citations by year
- 2026: 62 · 2025: 92 · 2024: 107 · 2023: 113 · 2022: 125 · 2021: 98 · 2020: 82 · 2019: 39 · 2018: 25 · 2017: 9 · 2016: 1
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Oral Diseases (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institutes of Health (1ZIADK053211‐08)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- vitamin C, dehydroascorbic acid, glucose transporters, plasma vitamin C concentration, vitamin C bioavailability, renal excretion, electron donors, scurvy
- MeSH terms
- Ascorbic Acid, Humans, Oral Health, Recommended Dietary Allowances, In Vitro Techniques
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