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Antimicrobial Agents and Chemotherapy, July 2006, p. 2415-2419, Vol. 50, No. 7
0066-4804/06/$08.00+0     doi:10.1128/AAC.01652-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Accelerated Denaturation of Hemoglobin and the Antimalarial Action of Chloroquine

Coy D. Fitch* and Natrice V. Russell

Department of Internal Medicine, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St. Louis, Missouri 63104

Received 30 December 2005/ Returned for modification 30 January 2006/ Accepted 20 April 2006

To study the antimalarial action of chloroquine, normal mouse erythrocytes were used as surrogates for erythrocytoid bodies. These bodies form in the endosomes of intraerythrocytic malaria parasites as they feed on their host and consist of erythrocyte cytoplasm enclosed in a vestige of the erythrocyte membrane. In suspensions of normal erythrocytes or lysates (equivalent to 5 µl of erythrocytes per ml in each case), hemoglobin underwent denaturation when it was incubated at 38°C in 150 mM sodium acetate (pH 5). It is reasonable to assume that the same phenomenon occurs in acidic endosomes. Addition of 100 µM chloroquine to the incubation mixture caused the rate of hemoglobin denaturation to double to 40 nanomoles per hour per ml of packed erythrocytes. This effect required the presence of erythrocyte stroma and was inhibited by reducing the temperature to 24°C or increasing the pH to 6. We propose that the primary antimalarial action of chloroquine is to bind to ferriprotoporphyrin IX (FP) and remove it from oxidized hemoglobin, thus producing toxic FP-chloroquine complexes and an excess of denatured globin. Furthermore, we suggest that these substances inhibit endosomal maturation and thereby cause hemoglobin accumulation in immature endosomes and masking of the lipids needed for FP dimerization. The term "masking" is used to signify that unsaturated lipids are present in parasitized erythrocytes but are specifically unavailable to promote FP dimerization.

* Corresponding author. Present address: Medical Service 111JC, VA Medical Center, 915 N. Grand Blvd., St. Louis, MO 63106. Phone: (314) 289-7030. Fax: (314) 289-6389. E-mail: coy.fitch{at}va.gov.

Antimicrobial Agents and Chemotherapy, July 2006, p. 2415-2419, Vol. 50, No. 7
0066-4804/06/$08.00+0     doi:10.1128/AAC.01652-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Omodeo-Sale, F., Cortelezzi, L., Basilico, N., Casagrande, M., Sparatore, A., Taramelli, D. (2009). Novel Antimalarial Aminoquinolines: Heme Binding and Effects on Normal or Plasmodium falciparum-Parasitized Human Erythrocytes. Antimicrob. Agents Chemother. 53: 4339-4344 [Abstract] [Full Text]  


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