Pharmaceutical Research

, Volume 24, Issue 3, pp 575–584

Transport of Nicotinate and Structurally Related Compounds by Human SMCT1 (SLC5A8) and Its Relevance to Drug Transport in the Mammalian Intestinal Tract

  • Elangovan Gopal
  • Seiji Miyauchi
  • Pamela M. Martin
  • Sudha Ananth
  • Penny Roon
  • Sylvia B. Smith
  • Vadivel Ganapathy
Research Paper



To examine the involvement of human SMCT1, a Na+-coupled transporter for short-chain fatty acids, in the transport of nicotinate/structural analogs and monocarboxylate drugs, and to analyze its expression in mouse intestinal tract.

Materials and Methods

We expressed human SMCT1 in X. laevis oocytes and monitored its function by [14C]nicotinate uptake and substrate-induced inward currents. SMCT1 expression in mouse intestinal tract was examined by immunofluorescence.


[14C]Nicotinate uptake was several-fold higher in SMCT1-expressing oocytes than in water-injected oocytes. The uptake was inhibited by short-chain/medium-chain fatty acids and various structural analogs of nicotinate. Exposure of SMCT1-expressing oocytes to nicotinate induced Na+-dependent inward currents. Measurements of nicotinate flux and associated charge transfer into oocytes suggest a Na+:nicotinate stoichiometry of 2:1. Monocarboxylate drugs benzoate, salicylate, and 5-aminosalicylate are also transported by human SMCT1. The transporter is expressed in the small intestine as well as colon, and the expression is restricted to the lumen-facing apical membrane of intestinal and colonic epithelial cells.


Human SMCT1 transports not only nicotinate and its structural analogs but also various monocarboxylate drugs. The transporter is expressed on the luminal membrane of the epithelial cells lining the intestinal tract. SMCT1 may participate in the intestinal absorption of monocarboxylate drugs.

Key words

SMCT1 intestinal tract monocarboxylate drugs aminosalicylates electrophysiology 


  1. 1.
    S. Miyauchi, E. Gopal, Y. J. Fei, and V. Ganapathy. Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na+-coupled transporter for short-chain fatty acids. J. Biol. Chem. 279:13293–13296 (2004).PubMedCrossRefGoogle Scholar
  2. 2.
    M. J. Coady, M. H. Chang, F. M. Charron, C. Plata, B. Wallendorff, J. F. Sah, S. D. Markowitz, M. F. Romero, and J. Y. Lapointe. The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter. J. Physiol. 557:719–731 (2004).PubMedCrossRefGoogle Scholar
  3. 3.
    E. Gopal, Y. J. Fei, M. Sugawara, S. Miyauchi, L. Zhuang, P. M. Martin, S. B. Smith, P. D. Prasad, and V. Ganapathy. Expression of slc5a8 in kidney and its role in Na+-coupled transport of lactate. J. Biol. Chem. 279:44522–44532 (2004).PubMedCrossRefGoogle Scholar
  4. 4.
    H. Li, L. Myeroff, D. Smiraglia, M. F. Romero, T. P. Pretlow, L. Kasturi, J. Lutterbaugh, R. M. Rerko, G. Casey, J. P. Issa, J. Willis, J. K. Willson, C. Plass, and S. D. Markowitz. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc. Natl. Acad. Sci. U. S. A. 100:8412–8417 (2003).PubMedCrossRefGoogle Scholar
  5. 5.
    V. Ganapathy, E. Gopal, S. Miyauchi, and P. D. Prasad. Biological functions of SLC5A8, a candidate tumour suppressor. Biochem. Soc. Trans. 33:237–240 (2005).PubMedCrossRefGoogle Scholar
  6. 6.
    N. Gupta, P. M. Martin, P. D. Prasad, and V. Ganapathy. SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sci. 78:2419–2425 (2006).PubMedCrossRefGoogle Scholar
  7. 7.
    M. Thangaraju, S. Ananth, P. M. Martin, P. Roon, S. B. Smith, E. Sterneck, P. D. Prasad, and V. Ganapathy. c/ebpd null mouse as a model for the double-knockout of slc5a8 and slc5a12 in kidney. J. Biol. Chem. 281:26769–26773 (2006).PubMedCrossRefGoogle Scholar
  8. 8.
    P. M. Martin, E. Gopal, S. Ananth, L. Zuang, S. Itagaki, B. M. Prasad, S. B. Smith, P. D. Prasad, and V. Ganapathy. Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of l-lactate and ketone bodies in the brain. J. Neurochem. 98:279–288 (2006).PubMedCrossRefGoogle Scholar
  9. 9.
    R. L. Veech, B. Chance, Y. Kashiwaya, H. A. Lardy, and G. F. Cahill, Jr. Ketone bodies, potential therapeutic uses. IUBMB Life 51:241–247 (2001).PubMedCrossRefGoogle Scholar
  10. 10.
    K. Casteels and C. Mathieu. Diabetic ketoacidosis. Rev. Endocr. Metab. Disord. 4:159–166 (2003).PubMedCrossRefGoogle Scholar
  11. 11.
    A. M. Rodriguez, B. Perron, L. Lacroix, B. Caillou, G. Leblanc, M. Schlumberger, J. M. Bidart, and T. Pourcher. Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes. J. Clin. Endocrinol. Metab. 87:3500–3503 (2002).PubMedCrossRefGoogle Scholar
  12. 12.
    V. Paroder, S. R. Spencer, M. Paroder, D. Arango, S. Schwartz, Jr., J. M. Mariadason, L. H. Augenlicht, S. Eskandari, and N. Carrasco. Na+/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: molecular characterization of SMCT. Proc. Natl. Acad. Sci. U. S. A. 103:7270–7275 (2006).PubMedCrossRefGoogle Scholar
  13. 13.
    E. Gopal, Y. J. Fei, S. Miyauchi, L. Zhuang, P. D. Prasad, and V. Ganapathy. Sodium-coupled and electrogenic transport of B-complex vitamin nicotinic acid by slc5a8, a member of the Na/glucose co-transporter gene family. Biochem. J. 388:309–316 (2005).PubMedCrossRefGoogle Scholar
  14. 14.
    S. Itagaki, E. Gopal, L. Zuang, Y. J. Fei, S. Miyauchi, P. D. Prasad, and V. Ganapathy. Interaction of ibuprofen and other structurally related NSAIDs with the sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8). Pharm. Res. 23:1209–1216 (2006).PubMedCrossRefGoogle Scholar
  15. 15.
    H. Wang, Y. J. Fei, R. Kekuda, T. L. Yang-Feng, L. D. Devoe, F. H. Leibach, P. D. Prasad, and V. Ganapathy. Structure, function, and genomic organization of human Na+-dependent high-affinity dicarboxylate transporter. Am. J. Physiol. 278:C1019–C1030 (2000).Google Scholar
  16. 16.
    K. Inoue, Y. J. Fei, L. Zhuang, E. Gopal, S. Miyauchi, and V. Ganapathy. Functional features and genomic organization of mouse NaCT, a sodium-coupled transporter for tricarboxylic acid cycle intermediates. Biochem. J. 378:949–957 (2004).PubMedCrossRefGoogle Scholar
  17. 17.
    S. Schuette and R. C. Rose. Renal transport and metabolism of nicotinic acid. Am. J. Physiol. 250:C694–C703 (1986).PubMedGoogle Scholar
  18. 18.
    K. Inoue, L. Zhuang, D. M. Maddox, S. B. Smith, and V. Ganapathy. Structure, function, and expression pattern of a novel sodium-coupled citrate transporter (NaCT) cloned from mammalian brain. J. Biol. Chem. 277:39469–39476 (2002).PubMedCrossRefGoogle Scholar
  19. 19.
    K. Inoue, L. Zhuang, and V. Ganapathy. Human Na+-coupled citrate transporter (NaCT): Primary structure, genomic organization, and transport function. Biochem. Biophys. Res. Commun. 299:465–471 (2002).PubMedCrossRefGoogle Scholar
  20. 20.
    K. Inoue, L. Zhuang, D. M. Maddox, S. B. Smith, and V. Ganapathy. Human NaCT, the ortholog of Drosophila Indy, as a novel target for lithium action. Biochem. J. 374:21–26 (2003).PubMedCrossRefGoogle Scholar
  21. 21.
    M. Panayatova-Heiermann, D. D. Loo, and E. M. Wright. Kinetics of steady-state currents and charge movements associated with the rat Na+/glucose cotransporter. J. Biol. Chem. 270:27099–27105 (1995).CrossRefGoogle Scholar
  22. 22.
    S. Eskandari, D. D. Loo, G. Dai, O. Levy, E. M. Wright, and N. Carrasco. Thyroid Na+/I symporter. Mechanism, stoichiometry, and specificity. J. Biol. Chem. 272:27230–27238 (1997).PubMedCrossRefGoogle Scholar
  23. 23.
    M. D. Regueiro. Diagnosis and treatment of ulcerative colitis. J. Clin. Gastroenterol. 38:733–740 (2004).PubMedCrossRefGoogle Scholar
  24. 24.
    C. T. Xu, S. Y. Meng, and B. R. Pan. Drug therapy for ulcerative colitis. World J. Gastroenterol. 10:2311–2317 (2004).PubMedGoogle Scholar
  25. 25.
    R. P. MacDermott. Progress in understanding the mechanisms of action of 5-aminosalicylic acid. Am.J. Gastroenterol. 95:3343–3345 (2000).PubMedCrossRefGoogle Scholar
  26. 26.
    J. P. Gisbert, F. Gomollon, J. Mate, and J. M. Pajares. Role of 5-aminosalicylic acid (5-ASA) in treatment of inflammatory bowel disease: a systematic review. Dig. Dis. Sci. 47:471–488 (2002).PubMedCrossRefGoogle Scholar
  27. 27.
    B. E. Enerson, and L. R. Drewes. Molecular features, regulation, and function of monocarboxylate transporters: Implications for drug delivery. J. Pharm. Sci. 92:1531–1544 (2003).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Elangovan Gopal
    • 1
  • Seiji Miyauchi
    • 1
  • Pamela M. Martin
    • 1
  • Sudha Ananth
    • 1
  • Penny Roon
    • 2
  • Sylvia B. Smith
    • 2
  • Vadivel Ganapathy
    • 1
  1. 1.Departments of Biochemistry and Molecular BiologyMedical College of GeorgiaAugustaUSA
  2. 2.Departments of Cellular Biology and AnatomyMedical College of GeorgiaAugustaUSA

Personalised recommendations