Advertisement

Cell Biology and Toxicology

, Volume 22, Issue 3, pp 183–187 | Cite as

The antitrypanosomal drug melarsoprol competitively inhibits thiamin uptake in mouse neuroblastoma cells

  • P. Szyniarowski
  • L. Bettendorff
  • M. E. Schweingruber
Article

Abstract

Melarsoprol is the main drug used for the treatment of late-stage sleeping sickness, although it causes severe side-effects such as encephalopathy and polyneuropathy leading to death in some patients. Recent data suggest that melarsoprol and its active metabolite melarsenoxide interfere with thiamin transport and metabolism in E. coli and yeast, but there are no data concerning their possible effects on thiamin metabolism in mammalian cells. We tested both drugs on thiamin transport in cultured mouse neuroblastoma cells using 14C-labeled thiamin. Melarsoprol, competitively inhibits high-affinity thiamin transport in mouse neuroblastoma cells with a Ki of 44 μmol/L. However, the active compound melarsenoxide has no inhibitory effect. This suggests that the side effects of melarsoprol treatment are unlikely to be due to inhibition of thiamin transport by melarsenoxide, its main metabolite in the brain.

Keywords

encephalopathies melarsoprol melarsenoxide sleeping sickness thiamin transport trypanosomiasis 

Abbreviations

Mel B

melarsoprol

Mel Ox

melarsenoxide

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bettendorff L, Wins P. Mechanism of thiamin transport in neuroblastoma cells: Inhibition of a high affinity carrier by sodium channel activators and dependence of thiamine uptake on membrane potential and intracellular ATP. J Biol Chem. 1994;269:14379–85.PubMedGoogle Scholar
  2. Blum J, Nkunku S, Burri C. Clinical description of encephalopathic syndromes and risk factors for their occurrence and outcome during melarsoprol treatment of human African trypanosomiasis. Trop Med Int Health. 2001;6:390–400.CrossRefPubMedGoogle Scholar
  3. Carter NS, Fairlamb AH. Arsenical-resistant trypanosomes lack an unusual adenosine transporter. Nature 1993;361:173–6.CrossRefPubMedGoogle Scholar
  4. Diaz GA, Banikazemi M, Oishi K, Desnick RJ, Gelb BD. Mutations in a new gene encoding a thiamine transporter cause thiamin-responsive megaloblastic anaemia syndrome. Nat Genet. 1999;22:309–12.CrossRefPubMedGoogle Scholar
  5. Docampo R, Moreno SNJ. Current chemotherapy of human African trypanosomiasis. Parasitol Res. 2003;90:S10–3.PubMedGoogle Scholar
  6. Dutta B, Huang W, Molero M, et al. Cloning of the human thiamin transporter, a member of the folate transporter family. J Biol Chem. 1999;45:31925–9.CrossRefGoogle Scholar
  7. Eudy JD, Spiegelstein O, Barber RC, Wlodarczyk BJ, Talbot J, Finnell RH. Identification and characterization of the human and mouse SLC19A3 gene: a novel member of the reduced folate family of micronutrient transporter genes. Mol Gen Metab. 2000;71:581–90.CrossRefGoogle Scholar
  8. Friedheim, EAH. Mel B in the treatment of human trypanosomiasis. Am J Trop Med. 1949;29:173–80.Google Scholar
  9. Hubert D, Barrett MP. Uptake and mode of action of drugs used against sleeping sickness. Biochem Parasitol. 2000;61:1–5.Google Scholar
  10. Keiser J, Ericsson O, Burri C. Investigations of the metabolites of the trypanocidal drug melarsoprol. Clin Pharmacol Ther. 2000;67:478–88.CrossRefPubMedGoogle Scholar
  11. Klebe RJ Ruddle FH. Neuroblastoma: cell culture analysis of a differentiating stem cell system. J Cell Biol. 1969;43:69a.Google Scholar
  12. Mäser P, Sütterlin C, Kralli A, Kaminsky RA. A nucleoside transporter from Trypanosoma brucei involved in drug resistance. Science. 1999;285:242–44.CrossRefPubMedGoogle Scholar
  13. Mäser P, Lüscher A, Kaminsky RA. Drug transport and drug resistance in African trypanosomes. Drug Resist Update. 2003;6:281–90.CrossRefGoogle Scholar
  14. Nok AJ. Arsenicals (melarsoprol), pentamidine and suramin in the treatment of human African trypanosomiasis. Parasitol Res. 2003;90:71–9.CrossRefPubMedGoogle Scholar
  15. Peterson GL. A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem. 1977;83:346–56.CrossRefPubMedGoogle Scholar
  16. Rajgopal A, Edmondson A, Goldman D, Zhao R. SLC19A3 encodes a second thiamin transporter ThTr2. Biochim Biophys Acta. 2001;1537:175–8.PubMedGoogle Scholar
  17. Said HM, Balamurugan K, Subramanian VS, Marchant JS. Expression and functional contribution of hTHTR-2 in thiamine absorption in human intestine. Am J Physiol Gastrointest Liver Physiol. 2004;286:G491–8.CrossRefPubMedGoogle Scholar
  18. Schweingruber ME. The melaminophenyl arsenicals melarsoprol and melarsenoxide interfere with thiamin metabolism in the fission yeast Schizosaccharomyces pombe. Antimicrob Agents Chemother. 2004;48:3268–71.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • P. Szyniarowski
    • 1
    • 2
  • L. Bettendorff
    • 1
    • 4
  • M. E. Schweingruber
    • 3
  1. 1.Center for Cellular and Molecular NeurobiologyUniversity of LiègeLiègeBelgium
  2. 2.Department of Analytical Biochemistry, Faculty of BiotechnologyJagiellonian UniversityCracowPoland
  3. 3.Institute of Cell BiologyUniversity of BernBernSwitzerland
  4. 4.Center for Cellular and Molecular NeurobiologyUniversity of LiègeLiège 1 (Sart-Tilman)Belgium

Personalised recommendations