Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1979 Oct;76(10):5303–5307. doi: 10.1073/pnas.76.10.5303

Tetraethylthiuram disulfide (Antabuse) inhibits the human malaria parasite Plasmodium falciparum.

L W Scheibel, A Adler, W Trager
PMCID: PMC413130  PMID: 388434

Abstract

Plasmodium falciparum in culture grows optimally at 3% oxygen. Oxygen levels down to 0.5% still support growth, but anaerobic conditions do not. These findings, and the absence of the Krebs cycle in Plasmodium, suggested that in this organism oxygen may not function in electron transport but rather may act through metalloprotein oxygenases. Tetraethylthiuram disulfide (Antabuse, disulfiram) and its reduction product diethyldithiocarbamate inhibit many metalloprotein oxygenases and have a lipid/H2O partition coefficient and high binding constant for metal ions, favoring selective toxicity to the malaria parasite. These compounds exhibited active antimalarial effects in vitro in concentrations down to 0.1 microgram/ml, the lowest level tested. Tetraethylthiuram disulfide at a level as low as 1 microgram/ml inhibited parasite glycolysis with no effect on glycolysis of normal erythrocytes. Erythrocytes pretreated with this drug at 10 microgram/ml did not support growth of the parasite.

Full text

PDF
5303

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Cobby J., Mayersohn M., Selliah S. The rapid reduction of disulfiram in blood and plasma. J Pharmacol Exp Ther. 1977 Sep;202(3):724–731. [PubMed] [Google Scholar]
  2. DIVATIA K. J., HINE C. H., BURBRIDGE T. N. A simple method for the determination of tetraethylthiuramdisulfide (antabuse) and blood levels obtained experimentally in animals and clinically in man. J Lab Clin Med. 1952 Jun;39(6):974–982. [PubMed] [Google Scholar]
  3. Fairbairn D. Biochemical adaptation and loss of genetic capacity in helminth parasites. Biol Rev Camb Philos Soc. 1970 Feb;45(1):29–72. doi: 10.1111/j.1469-185x.1970.tb01075.x. [DOI] [PubMed] [Google Scholar]
  4. GOLDSTEIN M., ANAGNOSTE B., LAUBER E., MCKEREGHAM M. R. INHIBITION OF DOPAMINE-BETA-HYDROXYLASE BY DISULFIRAM. Life Sci. 1964 Jul;3:763–767. doi: 10.1016/0024-3205(64)90031-1. [DOI] [PubMed] [Google Scholar]
  5. GRAHAM W. D. In vitro inhibition of liver aldehyde dehydrogenase by tetraethylthiuram disulphide. J Pharm Pharmacol. 1951 Mar;3(3):160–168. doi: 10.1111/j.2042-7158.1951.tb13056.x. [DOI] [PubMed] [Google Scholar]
  6. Jensen J. B. Concentration from continuous culture of erythrocytes infected with trophozoites and schizonts of Plasmodium falciparum. Am J Trop Med Hyg. 1978 Nov;27(6):1274–1276. doi: 10.4269/ajtmh.1978.27.1274. [DOI] [PubMed] [Google Scholar]
  7. Jensen J. B., Trager W. Plasmodium falciparum in culture: establishment of additional strains. Am J Trop Med Hyg. 1978 Jul;27(4):743–746. doi: 10.4269/ajtmh.1978.27.743. [DOI] [PubMed] [Google Scholar]
  8. Jensen J. B., Trager W. Plasmodium falciparum in culture: use of outdated erthrocytes and description of the candle jar method. J Parasitol. 1977 Oct;63(5):883–886. [PubMed] [Google Scholar]
  9. KAARS SIJPESTEIJN A., JANSSEN M. J. On the mode of action of dialkyldithiocarbamates on moulds and bacteria. Antonie Van Leeuwenhoek. 1959;25:422–438. doi: 10.1007/BF02542865. [DOI] [PubMed] [Google Scholar]
  10. KAARS SIJPESTEIJN A., VAN DER KERK G. J. Investigations on organic fungicides. X. Pyruvic acid accumulation and its relation to the phenomenon of inversion growth as effected by sodium dimethyldithiocarbamate. Biochim Biophys Acta. 1956 Feb;19(2):280–288. doi: 10.1016/0006-3002(56)90429-2. [DOI] [PubMed] [Google Scholar]
  11. KADOTA I., MIDORIKAWA O. Diabetogenic action of organic reagents: destructive lesions of islets of Langerhans caused by sodium diethyldithiocarbamate and potassium ethylxanthate. J Lab Clin Med. 1951 Nov;38(5):671–688. [PubMed] [Google Scholar]
  12. LINDERHOLM H., BERG K. A method for the determination of tetraethylthiuram disulphide (Antabus, Abstinyl) and diethyldithiocarbamate in blood and urine; some studies on the metabolism of tetraethylthiuram disulphide. Scand J Clin Lab Invest. 1951;3(2):96–102. doi: 10.3109/00365515109060580. [DOI] [PubMed] [Google Scholar]
  13. LOWRY O. H., PASSONNEAU J. V., HASSELBERGER F. X., SCHULZ D. W. EFFECT OF ISCHEMIA ON KNOWN SUBSTRATES AND COFACTORS OF THE GLYCOLYTIC PATHWAY IN BRAIN. J Biol Chem. 1964 Jan;239:18–30. [PubMed] [Google Scholar]
  14. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  15. MANTEN A., KLOPPING H. L., van der KERK G. J. M. Investigations on organic fungicides. I. The antimicrobial spectrum of the antifungal substance tetramethyl-thiuram disulphide. Antonie Van Leeuwenhoek. 1950;16(1):45–55. doi: 10.1007/BF02274400. [DOI] [PubMed] [Google Scholar]
  16. PERMAN E. S. Studies on the antabuse--alcohol reaction in rabbits. Acta Physiol Scand Suppl. 1962;55(190):1–46. [PubMed] [Google Scholar]
  17. SIJPESTEIJN A. K., JANSSEN M. J., VAN DER KERK G. J. Investigations on organic fungicides. XI. The role of metals and chelating agents in the fungitoxic action of sodium dimethyldithiocarbamate. Biochim Biophys Acta. 1957 Mar;23(3):550–557. doi: 10.1016/0006-3002(57)90376-1. [DOI] [PubMed] [Google Scholar]
  18. STROEMME J. H. METHAEMOGLOBIN FORMATION INDUCED BY THIOLS. Biochem Pharmacol. 1963 Sep;12:937–948. doi: 10.1016/0006-2952(63)90016-9. [DOI] [PubMed] [Google Scholar]
  19. STROMME J. H. Effects of diethyldithiocarbamate and disulfiram on glucose metabolism and glutathione content of human erythrocytes. Biochem Pharmacol. 1963 Jul;12:705–715. doi: 10.1016/0006-2952(63)90046-7. [DOI] [PubMed] [Google Scholar]
  20. Scheibel L. W., Ashton S. H., Trager W. Plasmodium falciparum: microaerophilic requirements in human red blood cells. Exp Parasitol. 1979 Jun;47(3):410–418. doi: 10.1016/0014-4894(79)90094-8. [DOI] [PubMed] [Google Scholar]
  21. Scheibel L. W., Miller J. Cytochrome oxidase activity in platelet-free preparations of Plasmodium knowlesi. J Parasitol. 1969 Aug;55(4):825–829. [PubMed] [Google Scholar]
  22. Scheibel L. W., Miller J. Glycolytic and cytochrome oxidase activity in Plasmodia. Mil Med. 1969 Sep;134(10):1074–1080. [PubMed] [Google Scholar]
  23. Scheibel L. W., Pflaum W. K. Cytochrome oxidase activity in platelet-free preparations of Plasmodium falciparum. J Parasitol. 1970 Dec;56(6):1054–1054. [PubMed] [Google Scholar]
  24. Trager W., Jensen J. B. Human malaria parasites in continuous culture. Science. 1976 Aug 20;193(4254):673–675. doi: 10.1126/science.781840. [DOI] [PubMed] [Google Scholar]
  25. WESTERFELD W. W. Effect of metal-binding agents on metalloproteins. Fed Proc. 1961 Sep;20(3):158–176. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES