A family of mammalian Na+-dependent L-ascorbic acid transporters


Vitamin C (L-ascorbic acid) is essential for many enzymatic reactions, in which it serves to maintain prosthetic metal ions in their reduced forms (for example, Fe2+, Cu+)1,2, and for scavenging free radicals in order to protect tissues from oxidative damage3. The facilitative sugar transporters of the GLUT type can transport the oxidized form of the vitamin, dehydroascorbic acid4,5,6, but these transporters are unlikely to allow significant physiological amounts of vitamin C to be taken up in the presence of normal glucose concentrations, because the vitamin is present in plasma essentially only in its reduced form7. Here we describe the isolation of two L-ascorbic acid transporters, SVCT1 and SVCT2, from rat complementary DNA libraries, as the first step in investigating the importance of L-ascorbic acid transport in regulating the supply and metabolism of vitamin C. We find that SVCT1 and SVCT2 each mediate concentrative, high-affinity L-ascorbic acid transport that is stereospecific and is driven by the Na+ electrochemical gradient. Despite their close sequence homology and similar functions, the two isoforms of the transporter are discretely distributed: SVCT1 is mainly confined to epithelial systems (intestine, kidney, liver), whereas SVCT2 serves a host of metabolically active cells and specialized tissues in the brain, eye and other organs.

Figure 1: Sequence and putative membrane topology of SVCT1 and SVCT2.
Figure 2: Functional characterization of SVCT expressed in Xenopus oocytes.
Figure 3: Localization of SVCT1 and SVCT2 mRNA in rat tissues detected by insitu hybridization.
Figure 4: Localization of SVCT2 mRNA in the albino rabbit eye detected by in situ hybridization.


  1. 1

    Englard, S. & Seifter, S. The biochemical functions of ascorbic acid. Annu. Rev. Nutr. 6, 365–406 (1986).

    CAS  Article  Google Scholar 

  2. 2

    Padh, H. Vitamin C: newer insights into its biochemical functions. Nutr. Rev. 49, 65–70 (1991).

    CAS  Article  Google Scholar 

  3. 3

    Rose, R. C. & Bode, A. M. Biology of the free radical scavengers: an evaluation of ascorbate. FASEB J. 7, 1135–1142 (1993).

    Article  Google Scholar 

  4. 4

    Vera, J. C., Rivas, C. I. & Fischbarg, J. Mammalian facilitative hexose transporters mediate the transport of dehydroascorbic acid. Nature 364, 79–82 (1993).

    ADS  CAS  Article  Google Scholar 

  5. 5

    Rumsey, S. C. et al . Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid. J. Biol. Chem. 272, 18982–18989 (1997).

    Article  Google Scholar 

  6. 6

    Agus, D. B. et al . Vitamin C crosses the blood-brain barrier in the oxidized from through the glucose transporters. J. Clin. Invest. 100, 2842–2848 (1997).

    Article  Google Scholar 

  7. 7

    Dhariwal, K. R., Hartzell, W. O. & Levine, M. Ascorbic acid and dehydroascorbic acid measurements in human plasma and serum. Am. J. Clin. Nutr. 54, 712–716 (1991).

    CAS  Article  Google Scholar 

  8. 8

    Nagase, T. et al . Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201 -KIAA0280 ) deduced by analysis of cDNA clones from cell line KG-1 and brain. DNA Res. 3, 321–354 (1996).

    ADS  CAS  Article  Google Scholar 

  9. 9

    Guimaraes, M. J. et al . Anew approach to the study of haematopoietic development in the yolk sac and embryoid bodies. Development 121, 3335–3346 (1995).

    CAS  PubMed  Google Scholar 

  10. 10

    Diallinas, G., Gorfinkiel, L., Arst, H. N., Cecchetto, G. & Scazzocchio, C. Genetic and molecular characterization of a gene encoding a wide specificity purine permease of Aspergillus nidulans reveals a novel family of transporters conserved in prokaryotes and eukaryotes. J. Biol. Chem. 270, 8610–8622 (1995).

    CAS  Article  Google Scholar 

  11. 11

    Wright, E. M., Loo, D. D. F., Turk, E. & Hirayama, B. A. Sodium cotransporters. Curr. Opin. Cell Biol. 8, 468–473 (1996).

    Article  Google Scholar 

  12. 12

    Hazama, A., Loo, D. D. F. & Wright, E. M. Presteady-state currents of the rabbit Na+/glucose cotransporter (SGLT1). J. Membr. Biol. 155, 175–186 (1997).

    Article  Google Scholar 

  13. 13

    Mackenzie, B., Loo, D. D. F., Panayotova-Heiermann, M. & Wright, E. M. Biophysical characteristics of the pig kidney Na+/glucose cotransporter SGLT2 reveal a common mechanism for SGLT1 and SGLT2. J. Biol. Chem. 271, 32678–32683 (1996).

    CAS  Article  Google Scholar 

  14. 14

    Mackenzie, B., Loo, D. D. F. & Wright, E. M. Relationships between Na+/glucose cotransporter currents and fluxes. J. Membr. Biol. 162, 101–106 (1998).

    Article  Google Scholar 

  15. 15

    Gunshin, H. et al . Cloning and characterization of a proton-coupled mammalian metal-ion transporter. Nature 388, 482–488 (1997).

    Article  Google Scholar 

  16. 16

    Eskandari, S. et al . Thyroid Na+/I symporter: mechanism, stoichiometry, and specificity. J. Biol. Chem. 272, 27230–27238 (1997).

    Article  Google Scholar 

  17. 17

    Segel, I. H. Biochemical Calculations2nd edn(Wiley, New York, (1976).

    Google Scholar 

  18. 18

    Bowers-Komro, D. M. & McCormick, D. B. Characterization of ascorbic acid uptake by isolated rat kidney cells. J. Nutr. 121, 57–64 (1991).

    Article  Google Scholar 

  19. 19

    Toggenburger, G. et al . Na+-dependent, potential-sensitive L-ascorbate transport across brush border membrane vesicles from kidney cortex. Biochim. Biophys. Acta 646, 433–443 (1981).

    Google Scholar 

  20. 20

    Helbig, H. et al . Electrogenic Na+-ascorbate cotransport in cultured bovine pigmented ciliary epithelial cells. Am. J. Physiol. 256, C44–C49 (1989).

    CAS  Article  Google Scholar 

  21. 21

    Rose, R. C. & Wilson, J. X. in Vitamin C in Health and Disease(eds Packer, L. & Fuchs, J.) 143–161 (Dekker, New York, (1997).

    Google Scholar 

  22. 22

    Franceschi, R. T., Wilson, J. X. & Dixon, S. J. Requirement for Na+-dependent ascorbic acid transport in osteoblast function. Am. J. Physiol. 268, C1430–C1439 (1995).

    CAS  Article  Google Scholar 

  23. 23

    Hammarström, L. Autoradiographic studies on the distribution of C14-labelled ascorbic acid and dehydroascorbic acid. Acta Physiol. Scand. 70 (suppl.)289, 1–75 (1966).

    Article  Google Scholar 

  24. 24

    Rose, R. C. & Bode, A. M. Ocular ascorbate transport and metabolism. Comp. Biochem. Physiol. 100, 273–285 (1991).

    Article  Google Scholar 

  25. 25

    Reiss, G. R., Werness, P. G., Zollman, P. E. & Brubaker, R. F. Ascorbic acid levels in the aqueous humor of nocturnal and diurnal mammals. Arch. Ophthalmol. 104, 753–755 (1986).

    CAS  Article  Google Scholar 

  26. 26

    Kodama, T., Kabasawa, I., Tamura, O. & Reddy, V. N. Dynamics of ascorbate in the aqueous humor and tissues surrounding ocular chambers. Ophthalmic Res. 17, 331–337 (1985).

    CAS  Article  Google Scholar 

  27. 27

    Romero, M. F., Kanai, Y., Gunshin, H. & Hediger, M. A. Expression cloning using Xenopus laevis oocytes. Methods Enzymol. 296, 17–52 (1998).

    Google Scholar 

  28. 28

    Mackenzie, B. in Biomembrane Transport(ed. Van Winkle, L. J.) 327–342 (Academic, San Diego, (1999).

    Google Scholar 

  29. 29

    Schaeren-Wiemers, N. & Gerfin-Moser, A. Asingle protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: in situ hybridization using digoxigenin-labelled cRNA probes. Histochemistry 100, 431–440 (1993).

    Article  Google Scholar 

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We thank E. Brown for providing MC3T3-E1 cells and P. Fong for providing the pTLN2 vector. This research was supported by the NIH, the National Kidney Foundation, the American Heart Association Massachusetts Affiliate, Cooley's Anemia Foundation, and the International Human Frontier Science Program.

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Correspondence to Matthias A. Hediger.

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Tsukaguchi, H., Tokui, T., Mackenzie, B. et al. A family of mammalian Na+-dependent L-ascorbic acid transporters. Nature 399, 70–75 (1999). https://doi.org/10.1038/19986

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