Recycling of Vitamin C by a Bystander Effect
Open accessAbstract
Human cells transport dehydroascorbic acid through facilitative glucose transporters, in apparent contradiction with evidence indicating that vitamin C is present in human blood only as ascorbic acid. On the other hand, activated host defense cells undergoing the oxidative burst show increased vitamin C accumulation. We analyzed the role of the oxidative burst and the glucose transporters on vitamin C recycling in an in vitro system consisting of activated host-defense cells co-cultured with human cell lines and primary cells. We asked whether human cells can acquire vitamin C by a "bystander effect" by taking up dehydroascorbic acid generated from extracellular ascorbic acid by neighboring cells undergoing the oxidative burst. As activated cells, we used HL-60 neutrophils and normal human neutrophils activated with phorbol 12 myristate 13-acetate. As bystander cells, we used immortalized cell lines and primary cultures of human epithelial and endothelial cells. Activated cells produced superoxide anions that oxidized extracellular ascorbic acid to dehydroascorbic acid. At the same time, there was a marked increase in vitamin C uptake by the bystander cells that was blocked by superoxide dismutase but not by catalase and was inhibited by the glucose transporter inhibitor cytochalasin B. Only ascorbic acid was accumulated intracellularly by the bystander cells. Glucose partially blocked vitamin C uptake by the bystander cells, although it increased superoxide production by the activated cells. We conclude that the local production of superoxide anions by activated cells causes the oxidation of extracellular ascorbic acid to dehydroascorbic acid, which is then transported by neighboring cells through the glucose transporters and immediately reduced to ascorbic acid intracellularly. In addition to causing increased intracellular concentrations of ascorbic acid with likely associated enhanced antioxidant defense mechanisms, the bystander effect may allow the recycling of vitamin C in vivo, which may contribute to the low daily requirements of the vitamin in humans.
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Administered ascorbate becomes DHA, which resembles glucose and is efficiently imported through GLUT1 in KRAS or BRAF mutant cells.
“When ascorbate is administered, it is oxidized to DHA. Owing to its structural similarity to glucose, DHA is efficiently taken up via GLUT1 in KRAS or BRAF mutant cells47,48”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [48]
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- Authors
- Nualart, F. J., Rivas, C. I., Montecinos, V. P., Godoy, A. S., Guaiquil, V. H., Golde, D. W., & Vera, J. C.
- Affiliations
- University of Concepción (CL)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Vera, Juan Carlos
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-03
- Volume
- 278
- Issue
- 12
- Pages
- 10128-10133
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2074869909
- Cited by
- 170
- References
- 52
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 7 · 2022: 5 · 2021: 10 · 2020: 13 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 4 · 2015: 6 · 2014: 8 · 2013: 9 · 2012: 11
- FWCI
- 8.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- Americanae (AECID Library) (submittedVersion, other-oa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Greater South Information System
- Funders
- National Cancer Institute (CA30388)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- dehydroascorbic acid, bystander effect, glucose transporters, respiratory burst, superoxide, neutrophil activation, ascorbic acid uptake, superoxide dismutase, cytochalasin B, antioxidant defense, vitamin C requirement
- MeSH terms
- Ascorbic Acid, Cytochalasin B, Dehydroascorbic Acid, Glucose, Humans, Neutrophils, Superoxides, Tetradecanoylphorbol Acetate, Tumor Cells, Cultured, Respiratory Burst
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