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Review
. 2021 Feb 13;13(2):615.
doi: 10.3390/nu13020615.

Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination

Martin Doseděl  1 , Eduard Jirkovský  2 , Kateřina Macáková  3 , Lenka Kujovská Krčmová  4   5 , Lenka Javorská  5 , Jana Pourová  2 , Laura Mercolini  6 , Fernando Remião  7 , Lucie Nováková  4 , Přemysl Mladěnka  2 , On Behalf Of The Oemonom
Affiliations
Review

Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination

Martin Doseděl et al. Nutrients. .

Abstract

Vitamin C (L-ascorbic acid) has been known as an antioxidant for most people. However, its physiological role is much larger and encompasses very different processes ranging from facilitation of iron absorption through involvement in hormones and carnitine synthesis for important roles in epigenetic processes. Contrarily, high doses act as a pro-oxidant than an anti-oxidant. This may also be the reason why plasma levels are meticulously regulated on the level of absorption and excretion in the kidney. Interestingly, most cells contain vitamin C in millimolar concentrations, which is much higher than its plasma concentrations, and compared to other vitamins. The role of vitamin C is well demonstrated by miscellaneous symptoms of its absence-scurvy. The only clinically well-documented indication for vitamin C is scurvy. The effects of vitamin C administration on cancer, cardiovascular diseases, and infections are rather minor or even debatable in the general population. Vitamin C is relatively safe, but caution should be given to the administration of high doses, which can cause overt side effects in some susceptible patients (e.g., oxalate renal stones). Lastly, analytical methods for its determination with advantages and pitfalls are also discussed in this review.

Keywords: antioxidant; ascorbic acid; epigenetic; oxalate; prooxidant; scurvy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Optical isomers of vitamin C. (A) L-ascorbic acid, (B) erythorbic acid, and (C) D-ascorbic acid. Differences are shown in red and blue.
Figure 2
Figure 2
Vitamin C kinetics in the human body. (A): Absorption in the gastrointestinal tract. In the distal ileum, the absorption of ascorbate is mediated via SVCT1, while in the upper parts of the GIT, where pH is lower, the passive diffusion of non-ionized ascorbic acid is also possible. Absorption of dehydroascorbic acid does not seem to contribute significantly and is not shown. (B): reabsorption of vitamin C through the proximal tubules to the blood. Passive diffusion is also possible in acidic urine, likely in other parts of the urinary tract, but it does not seem to contribute significantly to vitamin C reabsorption and is, hence, not shown. (C): Distribution of vitamin C to most cells. (D): Distribution of vitamin C to the neurons. There are no specific transporters for ascorbate in the blood-brain barrier. Hence, the only possible way is the uptake and release of vitamin C in the form of dehydroascorbic acid via glucose transporters (GLUT). This transport is likely not the major contributor of vitamin C distribution to the brain (see corresponding part of the article). Contrarily, in the choroid plexus, the SVCT2 is expressed and this seems to be the major pathway for vitamin C kinetics to the brain. Neurons are also expressing SVCT2.
Figure 3
Figure 3
Relationship between a dose of vitamin C and bioavailability in humans. The data are from three studies—1 Graumlich et al. 1997 [57], 2 Levine et al., 1996 [55], and 3 Hornig et al., 1980 [56].
Figure 4
Figure 4
Dehydroascorbic acid and its decomposition. Dehydroascorbic acid (A) forms reversibly a hemiketal (B, a spatial structure shown in brackets). The structure is not stable and it is irreversibly transformed in 2,3-diketo-1-gulonic acid (C). This compound can be decarboxylated into L-xylonic acid (D) or L-lyxonic acid (E) or in L-erythrulose (F) and oxalate (G). 1: the reaction can be both spontaneous or mediated by an enzyme. 2: No enzyme mediating this reaction was reported. The reaction is likely spontaneous.
Figure 5
Figure 5
The summary of physiological functions of vitamin C.
Figure 6
Figure 6
The reaction catalyzed by human 4-hydroxyphenylpyruvate dioxygenase. 4-hydroxyphenylpyruvate is oxidized by molecular oxygen by the enzyme in the presence of ascorbate. The products of this reaction are homogentisate (2,5-dihydroxyphenylacetate) and carbon dioxide. The origin of oxygen is highlighted in a blue and red color.
Figure 7
Figure 7
Amidation catalysed by peptidyl-glycine α-amidating monooxygenase (PAM) -the likely mechanism. 1: Ascorbic acid reduces cupric ions in the active site of the peptidyl-glycine α-hydroxylating monooxygenase domain (shown in light blue). 2: two molecules of ascorbic acid are oxidized to ascorbyl radical (2a) and the active enzyme with reduced cuprous ions in the active site is formed (2b). 3: This active site binds the substrate and needs oxygen for the reaction as well. 4: One oxygen is incorporated in the water while the second is incorporated in the substrate. 5: The reaction continues, with the binding of the hydroxylated site to the active center with a zinc atom of the α-hydroxyglycine α-amidating lyase domain of the enzyme (shown in dark blue). 6: This results in the production of the α-amidated enzyme and the release of glyoxylate.
Figure 8
Figure 8
Interconnection between antioxidant effects of vitamin C and E. (A): Unsaturated fatty acid within the LDL (low-density lipoproteins) particle is oxidized (e.g., by other ROS, 1). (B): The lipid peroxy radical formed is neutralized by vitamin E (α-tocopherol, 2). (C): The reaction results in a lipid hydroperoxide (3) and the formation of the α-tocopheryl radical, which immediately reacts with vitamin C (ascorbate, 4). (D): This leads to the recovery of α-tocopherol (5) and the formation of an ascorbate free radical. Ascorbate can be recovered either via dehydroascorbic acid (6) or directly (7). The are several ways how these reactions can be accomplished either non-enzymatically or enzymatically.
Figure 9
Figure 9
Vitamin C, tetrahydrobiopterin, and endothelial NO-synthase (eNOS). (A): normal conditions, (B): lack of vitamin C and oxidative stress, (C): physiological levels of vitamin C and oxidative stress in the vascular system, (D): i.v. administration of high vitamin C doses. Under normal conditions, tetrahydrobiopterin (BH4) is used by the eNOS for the synthesis of NO (1). Trihydrobiopterin radical (BH3.) can be generated by eNOS. It can be recovered to BH4 by both eNOS itself or ascorbate (2). Ascorbate is recovered from the ascorbyl radical (3) by several pathways discussed in this article. Under the lack of vitamin C and under oxidative stress, BH4 is oxidized by reactive oxygen species (ROS). This decreases the availability of this cofactor and may lead to the formation of dihydrobiopterin (BH2, 4). BH2 can be reduced back to BH4 by dihydrofolate reductase (5). Similarly, if BH3. cannot be recovered to BH4, it can be oxidized to dihydrobiopterin (BH2, 6). BH2 binds to eNOS, but causes uncoupling. Such an enzyme can no longer produce NO, but produces superoxide instead (7). Oxidative stress is demonstrated since elevated levels of superoxide in circulation cannot be normalized by physiological concentrations of vitamin C, which has a lower affinity to superoxide (8) than superoxide has to NO. As a result, the protective NO is reacting with superoxide into highly reactive peroxynitrite (9). Peroxynitrite can also oxidize BH4 (10) and cause eNOS uncoupling, as was shown in part B (No. 4). However, when vitamin C is given in high doses intravenously, it reaches mM levels and is considered to compete with NO for the superoxide (11). The superoxide is neutralized by such a high concentration of vitamin C and NO can exert its endothelial protective function.
Figure 9
Figure 9
Vitamin C, tetrahydrobiopterin, and endothelial NO-synthase (eNOS). (A): normal conditions, (B): lack of vitamin C and oxidative stress, (C): physiological levels of vitamin C and oxidative stress in the vascular system, (D): i.v. administration of high vitamin C doses. Under normal conditions, tetrahydrobiopterin (BH4) is used by the eNOS for the synthesis of NO (1). Trihydrobiopterin radical (BH3.) can be generated by eNOS. It can be recovered to BH4 by both eNOS itself or ascorbate (2). Ascorbate is recovered from the ascorbyl radical (3) by several pathways discussed in this article. Under the lack of vitamin C and under oxidative stress, BH4 is oxidized by reactive oxygen species (ROS). This decreases the availability of this cofactor and may lead to the formation of dihydrobiopterin (BH2, 4). BH2 can be reduced back to BH4 by dihydrofolate reductase (5). Similarly, if BH3. cannot be recovered to BH4, it can be oxidized to dihydrobiopterin (BH2, 6). BH2 binds to eNOS, but causes uncoupling. Such an enzyme can no longer produce NO, but produces superoxide instead (7). Oxidative stress is demonstrated since elevated levels of superoxide in circulation cannot be normalized by physiological concentrations of vitamin C, which has a lower affinity to superoxide (8) than superoxide has to NO. As a result, the protective NO is reacting with superoxide into highly reactive peroxynitrite (9). Peroxynitrite can also oxidize BH4 (10) and cause eNOS uncoupling, as was shown in part B (No. 4). However, when vitamin C is given in high doses intravenously, it reaches mM levels and is considered to compete with NO for the superoxide (11). The superoxide is neutralized by such a high concentration of vitamin C and NO can exert its endothelial protective function.
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References

    1. Linster C.L., Van Schaftingen E. Vitamin C. Biosynthesis, recycling and degradation in mammals. FEBS J. 2007;274:1–22. doi: 10.1111/j.1742-4658.2006.05607.x. - DOI - PubMed
    1. Granger M., Eck P. Dietary vitamin C in human health. Adv. Food Nutr. Res. 2018;83:281–310. doi: 10.1016/bs.afnr.2017.11.006. - DOI - PubMed
    1. World Health Organization . Scurvy and its Prevention and Control in Major Emergencies/Prepared by Zita Weise Prinzo. World Health Organization; Geneva, Switzerland: 1999.
    1. Englard S., Seifter S. The biochemical functions of ascorbic acid. Annu. Rev. Nutr. 1986;6:365–406. doi: 10.1146/annurev.nu.06.070186.002053. - DOI - PubMed
    1. Levine M., Rumsey S., Daruwala R., Park J., Wang Y. Criteria and recommendations for vitamin C intake. JAMA. 1999;281:1415–1423. doi: 10.1001/jama.281.15.1415. - DOI - PubMed

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