Journal article
Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo
Proceedings of the National Academy of Sciences - PNAS, Vol.104(21), pp.8749-8754
05/22/2007
DOI: 10.1073/pnas.0702854104
PMCID: PMC1885574
PMID: 17502596
Abstract
Ascorbate (ascorbic acid, vitamin C), in pharmacologic concentrations easily achieved in humans by i.v. administration, selectively kills some cancer cells but not normal cells. We proposed that pharmacologic ascorbate is a prodrug for preferential steady-state formation of ascorbate radical (Asc
•−
) and H
2
O
2
in the extracellular space compared with blood. Here we test this hypothesis
in vivo
. Rats were administered parenteral (i.v. or i.p.) or oral ascorbate in typical human pharmacologic doses (≈0.25–0.5 mg per gram of body weight). After i.v. injection, ascorbate baseline concentrations of 50–100 μM in blood and extracellular fluid increased to peaks of >8 mM. After i.p. injection, peaks approached 3 mM in both fluids. By gavage, the same doses produced ascorbate concentrations of <150 μM in both fluids. In blood, Asc
•−
concentrations measured by EPR were undetectable with oral administration and always <50 nM with parenteral administration, even when corresponding ascorbate concentrations were >8 mM. After parenteral dosing, Asc
•−
concentrations in extracellular fluid were 4- to 12-fold higher than those in blood, were as high as 250 nM, and were a function of ascorbate concentrations. By using the synthesized probe peroxyxanthone, H
2
O
2
in extracellular fluid was detected only after parenteral administration of ascorbate and when Asc
•−
concentrations in extracellular fluid exceeded 100 nM. The data show that pharmacologic ascorbate is a prodrug for preferential steady-state formation of Asc
•−
and H
2
O
2
in the extracellular space but not blood. These data provide a foundation for pursuing pharmacologic ascorbate as a prooxidant therapeutic agent in cancer and infections.
Details
- Title: Subtitle
- Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo
- Creators
- Qi Chen - Molecular and Clinical Nutrition Section andMichael Graham Espey - Radiation Biology Branch and theAndrew Y Sun - Molecular and Clinical Nutrition Section andJe-Hyuk Lee - Molecular and Clinical Nutrition Section andMurali C Krishna - Radiation Biology Branch and theEmily Shacter - Laboratory of Biochemistry, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892; andPeter L Choyke - Molecular Imaging Program, National Cancer Institute, Bethesda, MD 20892Chaya Pooput - Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892Kenneth L Kirk - Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892Garry R Buettner - Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IA 52242Mark Levine - Molecular and Clinical Nutrition Section and
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.104(21), pp.8749-8754
- DOI
- 10.1073/pnas.0702854104
- PMID
- 17502596
- PMCID
- PMC1885574
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 05/22/2007
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984046903602771
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