Primaquine-Induced Oxidative Stress in Isolated Hepatocytes as a Result of Reductive Activation

  • José M. Silva
  • Peter J. O’Brien
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 283)


Primaquine,6-methoxy-8-(4-amino-l-methylbutylamino)quinoline, is one of the most effective antimarial agents but because of its low therapeutic index its use is limited. Unlike the 4-aminoquinolines it is believed to act on the liver schizont stage and not the erythrocyte stage of the parasites life cycle. However the drug is reported to cause hemolytic anemia, especially in individuals whose erythrocytes are deficient in glucose-6-phosphate dehydrogenase (Beutler, 1969). In erythrocytes, primaquine or its liver metabolite 5-OH-primaquine is reported to cause intraerythrocytic superoxide and hydrogen peroxide formation, methemoglobinemia, the formation of Heinz bodies, and occasionally the induction of hemolysis (Cohen and Hochstein, 1964; Summerfield and Tudhope, 1978).


Redox Cycling Pulse Radiolysis Parasite Life Cycle Heinz Body Live Metabolite 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations used:


reduced glutathione


oxidised glutathione


4-(2- hydroxyethyl)-1-piperazine-ethane-sulphonic acid


high performance liquid chromatography


Diethylenetriamine penta-acetic acid


hydrogen peroxide.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Augusto, O., Weingrill, C. L., Schreier, S. and Amemiya,H. (1986). Hydroxyl radical formation as a result of the interaction between primaquine and reduced pyridine nucleotides. Arch. Biochem. Biophys. 244, 147–155.PubMedCrossRefGoogle Scholar
  2. Beutler, E. (1969). Drug-induced hemolytic anemia. Pharmacol. Rev. 21, 73–97.PubMedGoogle Scholar
  3. Bisby, R. H. (1988). One-electron reduction of the antimalarial drug primaquine, studied by pulse radiolysis. Free Rad. Res. Comms. 5, 117–124.CrossRefGoogle Scholar
  4. Cohen, G. and Hochstein, P. (1964). Glutathione peroxidase:The primary agent for the elimination of hydrogen peroxide in erythrovytes by hemolytic agents. Biochem. 3, 895–903.CrossRefGoogle Scholar
  5. Gutierrez, P. L. (1988). The influence of ascorbic acid on the free-radical metabolism of xenobiotics: The example ofdiaziquone. Drug Metab. Rev. 19, 319–343.Google Scholar
  6. Hopkins, J. and Tudhope, G. R. (1978). Studies with primaquine in vitro: superoxide radical formation and oxidation of haemoglobin. Br. J. Clin. Pharmacol. 6, 319–323.Google Scholar
  7. Moldeus, P., Hogberg, J. and Orrenius, S. (1978). Isolation and use of liver cells. Methods. Enzymol. 52, 60–71.PubMedCrossRefGoogle Scholar
  8. Reed, D. J., Babson, J. R., Beatty, P. W., Brodie, A. F.,Ellis, W. W. and Potter, D. W. (1980). High-performance liquid chromatogrophy analysis of nanomole levels of glutathione, glutathione disulfide, and related thiols and disulfides. Anal. Biochem. 106, 55–62.PubMedCrossRefGoogle Scholar
  9. Rossi, L., Silva, J. M., McGirr, L. and O’Brien, P. J.,(1988). Nitrofurantoin-mediated oxidative stress cytotoxicity in isolated hepatocytes. Biochem. Pharmacol. 37, 3109–3117.PubMedCrossRefGoogle Scholar
  10. Strother, A., Allahyari, R., Buchholz, J., Fraser, I.M. and Tilton, B. E. (1984). In vitro metabolism of the antimalarial agent primaquine by mouse liver enzymes and identification of a methemoglobin-forming metabolite. Drug Metab. Dispos. 12, 35–44.PubMedGoogle Scholar
  11. Summerfield, M. and Tudhope, G. R. (1978). Primaquine and oxidation of hemoglobin. Br. J. Pharmacol. 6, 319–323.Google Scholar
  12. Thornalley, P.J.,Stern, A. and Bannister, J. V. (1983). A mechanism for primaquine mediated oxidation of NADPH in red blood cells. Biochem. Pharmacol. 32, 3571–3575.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • José M. Silva
    • 1
  • Peter J. O’Brien
    • 1
  1. 1.Faculty of PharmacyUniversity of TorontoTorontoCanada

Personalised recommendations