title: Potentiation of the antimalarial action of chloroquine in rodent malaria by drugs known to reduce cellular glutathione levels.
abstract: Ferriprotoporphyrin IX (FP) is released inside the food vacuole of the malaria parasite during the digestion of host cell hemoglobin. FP is detoxified by its biomineralization to hemozoin. This process is effectively inhibited by 4-aminoquinolines. As a result FP accumulates in the membrane fraction and associates with enzymes of infected cells in parallel with parasite killing. Free FP is degraded by reduced glutathione (GSH). This degradation is inhibited by chloroquine (CQ) and amodiaquine (AQ) but not by quinine (Q) or mefloquine (MQ). Increased GSH levels in Plasmodium falciparum-infected cells confer resistance to CQ and vice versa, and sensitize CQ-resistant Plasmodium berghei by inhibiting the synthesis of glutathione. Some drugs are known to reduce GSH in body tissues when used in excess, either due to their pro-oxidant activity or their ability to form conjugates with GSH. We show that acetaminophen, indomethacin and disulfiram were able to potentiate the antimalarial action of sub-curative doses of CQ and AQ in P. berghei- or Plasmodium vinckei petteri-infected mice, but not that of Q and MQ. In contrast, N-acetyl-cysteine which is expected to increase the cellular levels of GSH, antagonized the action of CQ. Although these results imply that alteration in GSH are involved, measurement of total glutathione either in uninfected or P. berghei-infected mice, treated with these drugs did not reveal major changes. In conclusion, experimental evidences provided in this study suggest that some off the counter drugs can be used in combination with some antimalarials to which the parasite has become resistant.
authors.affiliation: Centre IRD, BP 165, Cayenne, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Deharo
authors.forename: Daniel
authors.initials: D
authors.lastname: Barkan
authors.forename: Miriam
authors.initials: M
authors.lastname: Krugliak
authors.forename: Jacob
authors.initials: J
authors.lastname: Golenser
authors.forename: Hagai
authors.initials: H
authors.lastname: Ginsburg
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000111:Acetylcysteine / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002738:Chloroquine / Q000627:therapeutic use*; D004221:Disulfiram / Q000494:pharmacology; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism*; D007213:Indomethacin / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D010962:Plasmodium berghei; D010963:Plasmodium falciparum
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D000082:Acetaminophen; D002738:Chloroquine; D005978:Glutathione; C001920:4-aminoquinoline; D004221:Disulfiram; D000111:Acetylcysteine; D007213:Indomethacin