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Title: Biochemical mechanisms of chloroquine uptake and resistance in malaria
Author: Diribe, C. O.
ISNI:       0000 0001 3425 2335
Awarding Body: London School of Hygiene & Tropical Medicine
Current Institution: London School of Hygiene and Tropical Medicine (University of London)
Date of Award: 1981
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Mechanisms of (14C) chloroquine accumulation and chloroquine resistance were studied in Plasmodium berghei (NK 65 and RC) in mouse erythrocytes in vitro. The quantity of chloroquine taken up by erythrocytes infected with the chloroquine resistant RC strain was similar to that found for the sensitive NK 65 strain when percentage of erythrocytes parasitised was taken into account. Chloroquine accumulation could be separated into saturable specific (high affinity), and an unsaturable non specific (low affinity) components. A specific receptor for chloroquine with a dissociation constant of 4.0 X 10-9 to 1.0 X 10-8 mol/l was found to be associated with uptake into erythrocytes infected with both NK 65 and RC, but was absent in uninfected erythrocytes or reticulocytes. This receptor was 6 times more abundant in erythrocytes infected with NK 65 strain than in those infected with RC - where non-specific uptake accounted for up to 80% of the total chloroquine accumulation. It was tentatively concluded that non-specific uptake was mainly related to chloroquine binding by erythrocyte macromolecules; whilst specific uptake was related to receptors associated with the parasite itself. Chloroquine uptake by NK 65 parasitised erythrocytes was highly dependent on glucose availability, which was not the case in uninfected erythrocytes. In parasitised erythrocytes, it seemed probable that only the specific component of uptake was dependent on D - glucose. The ionophores Monensin and Nigericin inhibited chloroquine uptake non-competitively in high sodium and potassium buffer5 respectively. This inhibition of uptake was achieved without significant changes in glycolytic rate. Partial alleviation by ouabain of the inhibitory effect of Monensin but not of Nigericin, suggested that the internal proton concentration of the erythrocyte compartment was involved in drug uptake. Valinomycin had much less effect indicating that membrane potential was a less important factor. Mean internal pH values of NK 65 and RC infected erythrocytes were found to be about 0.2 units lower than uninfected erythrocytes and 0.55 units lower than the plasma. It was concluded that chloroquine accumulation by P. berghei infected erythrocytes was dependent on several factors, but the basis of chloroquine resistance in RC strain was mainly a deficiency of specific receptor sites.
Supervisor: Warhurst, D. C. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Biochemistry