Glutathione is involved in the antimalarial action of chloroquine and its modulation affects drug sensitivity of human and murine species of Plasmodium

被引:46
作者
Ginsburg, H [1 ]
Golenser, J
机构
[1] Hebrew Univ Jerusalem, Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel
[2] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Parasitol, IL-91904 Jerusalem, Israel
关键词
D O I
10.1179/135100003225002907
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 chloroquine (CQ) and amodiaquine (AQ). Undegraded FP accumulates in the membrane fraction and inhibits enzymes of infected cells in parallel with parasite killing. FP is demonstrably degraded by reduced glutathione (GSH) in a radical-mediated mechanism. This degradation is inhibited by CQ and AQ in a competitive manner, thus explaining the ability of increased GSH levels in Plasmodium falciparum-infected cells to increase resistance to CQ and vice versa, and to render Plasmodium berghei that were selected for CQ resistance in vivo sensitive to the CQ when glutathione synthesis is inhibited. Some over-the-counter drugs that are known to reduce GSH in body tissues when used in excess were found to enhance the antimalarial action of CQ and AQ in mice infected either with P. berghei or Plasmodium vinckei. In contrast, N-acetyl-cysteine which is expected to increase the cellular levels of GSH, antagonized the action of CQ. These results suggest that some over-the-counter drugs can be used in combination with some antimalarials to which the parasite has become resistant.
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页码:276 / 279
页数:4
相关论文
共 23 条
  • [1] The malaria parasite supplies glutathione to its host cell -: Investigation of glutathione transport and metabolism in human erythrocytes infected with Plasmodium falciparum
    Atamna, H
    Ginsburg, H
    [J]. EUROPEAN JOURNAL OF BIOCHEMISTRY, 1997, 250 (03): : 670 - 679
  • [2] PlasmoDB:: the Plasmodium genome resource.: An integrated database providing tools for accessing, analyzing and mapping expression and sequence data (both finished and unfinished)
    Bahl, A
    Brunk, B
    Coppel, RL
    Crabtree, J
    Diskin, SJ
    Fraunholz, MJ
    Grant, GR
    Gupta, D
    Huestis, RL
    Kissinger, JC
    Labo, P
    Li, L
    McWeeney, SK
    Milgram, AJ
    Roos, DS
    Schug, J
    Stoeckert Jr, CJ
    [J]. NUCLEIC ACIDS RESEARCH, 2002, 30 (01) : 87 - 90
  • [3] A family of drug transporters: The multidrug resistance-associated proteins
    Borst, P
    Evers, R
    Kool, M
    Wijnholds, J
    [J]. JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2000, 92 (16): : 1295 - 1302
  • [4] Metabolic indicators of oxidative stress correlate with haemichrome attachment to membrane, band 3 aggregation and erythrophagocytosis in β-thalassaemia intermedia
    Cappellini, MD
    Tavazzi, D
    Duca, L
    Graziadei, G
    Mannu, F
    Turrini, F
    Arese, P
    Fiorelli, G
    [J]. BRITISH JOURNAL OF HAEMATOLOGY, 1999, 104 (03) : 504 - 512
  • [5] A prodrug form of a Plasmodium falciparum glutathione reductase inhibitor conjugated with a 4-anilinoquinoline
    Davioud-Charvet, E
    Delarue, S
    Biot, C
    Schwöbel, B
    Boehme, CC
    Müssigbrodt, A
    Maes, L
    Sergheraert, C
    Grellier, P
    Schirmer, RH
    Becker, K
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (24) : 4268 - 4276
  • [6] Potentiation of the antimalarial action of chloroquine in rodent malaria by drugs known to reduce cellular glutathione levels
    Deharo, E
    Barkan, D
    Krugliak, M
    Golenser, J
    Ginsburg, H
    [J]. BIOCHEMICAL PHARMACOLOGY, 2003, 66 (05) : 809 - 817
  • [7] PLASMODIUM-BERGHEI - IMPLICATION OF INTRACELLULAR GLUTATHIONE AND ITS RELATED ENZYME IN CHLOROQUINE RESISTANCE IN-VIVO
    DUBOIS, VL
    PLATEL, DFN
    PAULY, G
    TRIBOULEYDURET, J
    [J]. EXPERIMENTAL PARASITOLOGY, 1995, 81 (01) : 117 - 124
  • [8] Egan Timothy J., 2001, Mini-Reviews in Medicinal Chemistry, V1, P113, DOI 10.2174/1389557013407188
  • [9] The treatment of Plasmodium falciparum-infected erythrocytes with chloroquine leads to accumulation of ferriprotoporphyrin IX bound to particular parasite proteins and to the inhibition of the parasite's 6-phosphogluconate dehydrogenase
    Famin, O
    Ginsburg, H
    [J]. PARASITE, 2003, 10 (01) : 39 - 50
  • [10] Kinetics of inhibition of glutathione-mediated degradation of ferriprotoporphyrin IX by antimalarial drugs
    Famin, O
    Krugliak, M
    Ginsburg, H
    [J]. BIOCHEMICAL PHARMACOLOGY, 1999, 58 (01) : 59 - 68