Efflux of Chloroquine from Plasmodium falciparum: Mechanism of Chloroquine Resistance
Abstract
Chloroquine-resistant Plasmodium falciparum accumulate significantly less chloroquine than susceptible parasites, and this is thought to be the basis of their resistance. However, the reason for the lower accumulation of chloroquine was unknown. The resistant parasite has now been found to release chloroquine 40 to 50 times more rapidly than the susceptible parasite, although their initial rates of chloroquine accumulation are the same. Verapamil and two other calcium channel blockers, as well as vinblastine and daunomycin, each slowed the release and increased the accumulation of chloroquine by resistant (but not susceptible) Plasmodium falciparum. These results suggest that a higher rate of chloroquine release explains the lower chloroquine accumulation, and thus the resistance observed in resistant Plasmodium falciparum.
References
MORBIDITY AND MORTALITY WEEKLY REPORT 34: 185 (1985).
MORBIDITY AND MORTALITY WEEKLY REPORT 36: 13 (1987).
WHO WKLY EPIDEMIOL R 59: 221 (1984).
AKIYAMA, S, CIRCUMVENTION OF MULTIPLE-DRUG RESISTANCE IN HUMAN CANCER-CELLS BY THIORIDAZINE, TRIFLUOPERAZINE, AND CHLORPROMAZINE, JOURNAL OF THE NATIONAL CANCER INSTITUTE 76: 839 (1986).
CORNWELL, M.M., CERTAIN CALCIUM-CHANNEL BLOCKERS BIND SPECIFICALLY TO MULTIDRUG-RESISTANT HUMAN-KB CARCINOMA MEMBRANE-VESICLES AND INHIBIT DRUG-BINDING TO P-GLYCOPROTEIN, JOURNAL OF BIOLOGICAL CHEMISTRY 262: 2166 (1987).
CORNWELL, M.M., MEMBRANE-VESICLES FROM MULTIDRUG-RESISTANT HUMAN CANCER-CELLS CONTAIN A SPECIFIC 150-KDA TO 170-KDA PROTEIN DETECTED BY PHOTOAFFINITY-LABELING, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 83: 3847 (1986).
FITCH, C.D., CHLOROQUINE-RESISTANT PLASMODIUM-FALCIPARUM - DIFFERENCE IN HANDLING OF AMODIAQUIN-C-14 AND CHLOROQUINE-C-14, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 3: 545 (1973).
FITCH, C.D., PLASMODIUM FALCIPARUM IN OWL MONKEYS - DRUG RESISTANCE AND CHLOROQUINE BINDING CAPACITY, SCIENCE 169: 289 (1970).
FOJO, A, CANCER RES 34: 3002 (1985).
GIBBS, C.L., CARDIOVASC PHARM 7: 556 (1986).
GLUZMAN, I.Y., ANTIMICROB AGENTS CH 31: 21 (1987).
KROGSTAD, D.J., THE BASIS OF ANTIMALARIAL ACTION - NON-WEAK BASE EFFECTS OF CHLOROQUINE ON ACID VESICLE PH, AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE 36: 213 (1987).
KROGSTAD, D.J., A PERSPECTIVE ON ANTIMALARIAL ACTION - EFFECTS OF WEAK BASES ON PLASMODIUM-FALCIPARUM, BIOCHEMICAL PHARMACOLOGY 35: 547 (1986).
KROGSTAD, D.J., ANTIMALARIALS INCREASE VESICLE PH IN PLASMODIUM-FALCIPARUM, JOURNAL OF CELL BIOLOGY 101: 2302 (1985).
KROGSTAD, D.J., unpublished data.
MARTIN, S.K., REVERSAL OF CHLOROQUINE RESISTANCE IN PLASMODIUM-FALCIPARUM BY VERAPAMIL, SCIENCE 235: 899 (1987).
MILLER, L.H., RESEARCH TOWARD MALARIA VACCINES, SCIENCE 234: 1349 (1986).
ODUOLA, AMJ, unpublished data.
PFALLER, M.A., OXYGEN ENHANCES THE ANTI-MALARIAL ACTIVITY OF THE IMIDAZOLES, AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE 32: 660 (1983).
PFALLER, M.A., IMIDAZOLE AND POLYENE ACTIVITY AGAINST CHLOROQUINE-RESISTANT PLASMODIUM-FALCIPARUM, JOURNAL OF INFECTIOUS DISEASES 144: 372 (1981).
ROOS, A, INTRACELLULAR PH, PHYSIOLOGICAL REVIEWS 61: 296 (1981).
SCHEIBEL, L.W., PLASMODIUM-FALCIPARUM - MICROAEROPHILIC REQUIREMENTS IN HUMAN RED BLOOD-CELLS, EXPERIMENTAL PARASITOLOGY 47: 410 (1979).
STAHL, P, RECEPTOR-MEDIATED PINOCYTOSIS OF MANNOSE GLYCOCONJUGATES BY MACROPHAGES - CHARACTERIZATION AND EVIDENCE FOR RECEPTOR RECYCLING, CELL 19: 207 (1980).
TEKLEHAIMANOT, A, EVALUATION OF SPORONTOCIDAL COMPOUNDS USING PLASMODIUM-FALCIPARUM GAMETOCYTES PRODUCED INVITRO, AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE 34: 429 (1985).
TRAGER, W, HUMAN MALARIA PARASITES IN CONTINUOUS CULTURE, SCIENCE 193: 673 (1976).
VONFIGURA, K, STUDIES ON SECRETION AND ENDOCYTOSIS OF MACROMOLECULES BY CULTIVATED SKIN FIBROBLASTS - EFFECTS OF ANTI-MICROTUBULAR AGENTS ON SECRETION AND ENDOCYTOSIS OF LYSOSOMAL HYDROLASES AND OF SULFATED GLYCOSAMINOGLYCANS, BIOCHEMICAL JOURNAL 170: 313 (1978).
WILLINGHAM, M.C., SINGLE CELL ANALYSIS OF DAUNOMYCIN UPTAKE AND EFFLUX IN MULTIDRUG-RESISTANT AND MULTIDRUG-SENSITIVE KB CELLS - EFFECTS OF VERAPAMIL AND OTHER DRUGS, CANCER RESEARCH 46: 5941 (1986).
WYLER, D.J., MALARIA - RESURGENCE, RESISTANCE, AND RESEARCH .1., NEW ENGLAND JOURNAL OF MEDICINE 308: 875 (1983).
YAYON, A, IDENTIFICATION OF THE ACIDIC COMPARTMENT OF PLASMODIUM-FALCIPARUM-INFECTED HUMAN-ERYTHROCYTES AS THE TARGET OF THE ANTIMALARIAL DRUG CHLOROQUINE, EMBO JOURNAL 3: 2695 (1984).
YAYON, A, SUSCEPTIBILITY OF HUMAN MALARIA PARASITES TO CHLOROQUINE IS PH DEPENDENT, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 82: 2784 (1985).
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Science
Volume 238 | Issue 4831
27 November 1987
27 November 1987
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© 1987.
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Published in print: 27 November 1987
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