PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
 
J Clin Invest. 1997 December 1; 100(11): 2842–2848.
PMCID: PMC508490

Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters.

Abstract

Vitamin C concentrations in the brain exceed those in blood by 10-fold. In both tissues, the vitamin is present primarily in the reduced form, ascorbic acid. We identified the chemical form of vitamin C that readily crosses the blood-brain barrier, and the mechanism of this process. Ascorbic acid was not able to cross the blood-brain barrier in our studies. In contrast, the oxidized form of vitamin C, dehydroascorbic acid (oxidized ascorbic acid), readily entered the brain and was retained in the brain tissue in the form of ascorbic acid. Transport of dehydroascorbic acid into the brain was inhibited by d-glucose, but not by l-glucose. The facilitative glucose transporter, GLUT1, is expressed on endothelial cells at the blood-brain barrier, and is responsible for glucose entry into the brain. This study provides evidence showing that GLUT1 also transports dehydroascorbic acid into the brain. The findings define the transport of dehydroascorbic acid by GLUT1 as a mechanism by which the brain acquires vitamin C, and point to the oxidation of ascorbic acid as a potentially important regulatory step in accumulation of the vitamin by the brain. These results have implications for increasing antioxidant potential in the central nervous system.

Full Text

The Full Text of this article is available as a PDF (359K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Chatterjee IB, Majumder AK, Nandi BK, Subramanian N. Synthesis and some major functions of vitamin C in animals. Ann N Y Acad Sci. 1975 Sep 30;258:24–47. [PubMed]
  • Rose RC, Choi JL, Koch MJ. Intestinal transport and metabolism of oxidized ascorbic acid (dehydroascorbic acid). Am J Physiol. 1988 Jun;254(6 Pt 1):G824–G828. [PubMed]
  • Spector R, Lorenzo AV. Ascorbic acid homeostasis in the central nervous system. Am J Physiol. 1973 Oct;225(4):757–763. [PubMed]
  • Spector R. Vitamin homeostasis in the central nervous system. N Engl J Med. 1977 Jun 16;296(24):1393–1398. [PubMed]
  • Hodges RE, Hood J, Canham JE, Sauberlich HE, Baker EM. Clinical manifestations of ascorbic acid deficiency in man. Am J Clin Nutr. 1971 Apr;24(4):432–443. [PubMed]
  • Englard S, Seifter S. The biochemical functions of ascorbic acid. Annu Rev Nutr. 1986;6:365–406. [PubMed]
  • Padh H. Cellular functions of ascorbic acid. Biochem Cell Biol. 1990 Oct;68(10):1166–1173. [PubMed]
  • Kaufman S. Coenzymes and hydroxylases: ascorbate and dopamine-beta-hydroxylase; tetrahydropteridines and phenylalanine and tyrosine hydroxylases. Pharmacol Rev. 1966 Mar;18(1):61–69. [PubMed]
  • Schreiber M, Trojan S. Ascorbic acid in the brain. Physiol Res. 1991;40(4):413–418. [PubMed]
  • Reese TS, Karnovsky MJ. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol. 1967 Jul;34(1):207–217. [PMC free article] [PubMed]
  • Brightman MW. Morphology of blood-brain interfaces. Exp Eye Res. 1977;25 (Suppl):1–25. [PubMed]
  • Pardridge WM. Brain metabolism: a perspective from the blood-brain barrier. Physiol Rev. 1983 Oct;63(4):1481–1535. [PubMed]
  • Vera JC, Rivas CI, Fischbarg J, Golde DW. Mammalian facilitative hexose transporters mediate the transport of dehydroascorbic acid. Nature. 1993 Jul 1;364(6432):79–82. [PubMed]
  • Vera JC, Rivas CI, Zhang RH, Farber CM, Golde DW. Human HL-60 myeloid leukemia cells transport dehydroascorbic acid via the glucose transporters and accumulate reduced ascorbic acid. Blood. 1994 Sep 1;84(5):1628–1634. [PubMed]
  • Vera JC, Rivas CI, Velásquez FV, Zhang RH, Concha II, Golde DW. Resolution of the facilitated transport of dehydroascorbic acid from its intracellular accumulation as ascorbic acid. J Biol Chem. 1995 Oct 6;270(40):23706–23712. [PubMed]
  • Siliprandi L, Vanni P, Kessler M, Semenza G. Na+-dependent, electroneutral L-ascorbate transport across brush border membrane vesicles from guinea pig small intestine. Biochim Biophys Acta. 1979 Mar 23;552(1):129–142. [PubMed]
  • Patterson LT, Nahrwold DL, Rose RC. Ascorbic acid uptake in guinea pig intestinal mucosa. Life Sci. 1982 Dec 13;31(24):2783–2791. [PubMed]
  • Diliberto EJ, Jr, Heckman GD, Daniels AJ. Characterization of ascorbic acid transport by adrenomedullary chromaffin cells. Evidence for Na+-dependent co-transport. J Biol Chem. 1983 Nov 10;258(21):12886–12894. [PubMed]
  • Padh H, Aleo JJ. Characterization of the ascorbic acid transport by 3T6 fibroblasts. Biochim Biophys Acta. 1987 Jul 23;901(2):283–290. [PubMed]
  • DiMattio J. Active transport of ascorbic acid into lens epithelium of the rat. Exp Eye Res. 1989 Nov;49(5):873–885. [PubMed]
  • Helbig H, Korbmacher C, Wohlfarth J, Berweck S, Kühner D, Wiederholt M. Electrogenic Na+-ascorbate cotransport in cultured bovine pigmented ciliary epithelial cells. Am J Physiol. 1989 Jan;256(1 Pt 1):C44–C49. [PubMed]
  • Wilson JX, Dixon SJ. High-affinity sodium-dependent uptake of ascorbic acid by rat osteoblasts. J Membr Biol. 1989 Oct;111(1):83–91. [PubMed]
  • Dyer DL, Kanai Y, Hediger MA, Rubin SA, Said HM. Expression of a rabbit renal ascorbic acid transporter in Xenopus laevis oocytes. Am J Physiol. 1994 Jul;267(1 Pt 1):C301–C306. [PubMed]
  • Dhariwal KR, Hartzell WO, Levine M. Ascorbic acid and dehydroascorbic acid measurements in human plasma and serum. Am J Clin Nutr. 1991 Oct;54(4):712–716. [PubMed]
  • Abdel el Motal SM, Sharp GW. Inhibition of glucose-induced insulin release by xylazine. Endocrinology. 1985 Jun;116(6):2337–2340. [PubMed]
  • Hsu WH, Hummel SK. Xylazine-induced hyperglycemia in cattle: a possible involvement of alpha 2-adrenergic receptors regulating insulin release. Endocrinology. 1981 Sep;109(3):825–829. [PubMed]
  • Kawamoto T, Shimizu M. A method for preparing whole-body sections suitable for autoradiographic, histological and histochemical studies. Stain Technol. 1986 May;61(3):169–183. [PubMed]
  • Triguero D, Buciak J, Pardridge WM. Capillary depletion method for quantification of blood-brain barrier transport of circulating peptides and plasma proteins. J Neurochem. 1990 Jun;54(6):1882–1888. [PubMed]
  • Crone C. Facilitated transfer of glucose from blood into brain tissue. J Physiol. 1965 Nov;181(1):103–113. [PubMed]
  • Pardridge WM, Boado RJ, Farrell CR. Brain-type glucose transporter (GLUT-1) is selectively localized to the blood-brain barrier. Studies with quantitative western blotting and in situ hybridization. J Biol Chem. 1990 Oct 15;265(29):18035–18040. [PubMed]
  • Cangiano C, Cardelli-Cangiano P, James JH, Rossi-Fanelli F, Patrizi MA, Brackett KA, Strom R, Fischer JE. Brain microvessels take up large neutral amino acids in exchange for glutamine. Cooperative role of Na+-dependent and Na+-independent systems. J Biol Chem. 1983 Jul 25;258(14):8949–8954. [PubMed]
  • van Uitert RL, Sage JI, Levy DE, Duffy TE. Comparison of radio-labeled butanol and iodoantipyrine as cerebral blood flow markers. Brain Res. 1981 Oct 19;222(2):365–372. [PubMed]
  • Rose RC. Cerebral metabolism of oxidized ascorbate. Brain Res. 1993 Nov 19;628(1-2):49–55. [PubMed]
  • Hornig D. Distribution of ascorbic acid, metabolites and analogues in man and animals. Ann N Y Acad Sci. 1975 Sep 30;258:103–118. [PubMed]
  • Pardridge WM, Oldendorf WH. Kinetics of blood-brain transport of hexoses. Biochim Biophys Acta. 1975 Mar 25;382(3):377–392. [PubMed]
  • Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, Park JB, Lazarev A, Graumlich JF, King J, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3704–3709. [PubMed]
  • Wells WW, Xu DP, Yang YF, Rocque PA. Mammalian thioltransferase (glutaredoxin) and protein disulfide isomerase have dehydroascorbate reductase activity. J Biol Chem. 1990 Sep 15;265(26):15361–15364. [PubMed]
  • Winkler BS. Unequivocal evidence in support of the nonenzymatic redox coupling between glutathione/glutathione disulfide and ascorbic acid/dehydroascorbic acid. Biochim Biophys Acta. 1992 Oct 27;1117(3):287–290. [PubMed]
  • Bode AM, Green E, Yavarow CR, Wheeldon SL, Bolken S, Gomez Y, Rose RC. Ascorbic acid regeneration by bovine iris-ciliary body. Curr Eye Res. 1993 Jul;12(7):593–601. [PubMed]
  • Guaiquil VH, Farber CM, Golde DW, Vera JC. Efficient transport and accumulation of vitamin C in HL-60 cells depleted of glutathione. J Biol Chem. 1997 Apr 11;272(15):9915–9921. [PubMed]
  • May JM, Mendiratta S, Hill KE, Burk RF. Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. J Biol Chem. 1997 Sep 5;272(36):22607–22610. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation