Energy dependence of chloroquine accumulation and chloroquine efflux in Plasmodium falciparum.
Chloroquine inhibits the growth of susceptible malaria parasites at low (nanomolar) concentrations because of an energy-requiring drug-concentrating mechanism in the parasite secondary lysosome (food vacuole) which is dependent on the acidification of that vesicle. Chloroquine resistance results from another energy-requiring process: efflux of chloroquine from the resistant parasite with a half-time of 2 min. Chloroquine efflux is inhibited reversibly by the removal of metabolizable substrate (glucose); it is also reduced by the ATPase inhibitor vanadate. These results suggest that chloroquine efflux is an energy-requiring process dependent on the generation and hydrolysis of ATP. Chloroquine efflux cannot be explained by differences in drug accumulation between chloroquine-susceptible and -resistant parasites because the 40-50-fold difference in initial efflux rates between -susceptible and -resistant parasites is unchanged when both parasites contain the same amount of chloroquine. Although chloroquine efflux is phenotypically similar to the efflux of anticancer drugs from multidrug-resistant (mdr) mammalian cells, it is not linked to either of the mdr-like genes of the parasite.
Krogstad
D J
DJ
Department of Medicine, Washington University School of Medicine, St Louis, MO 63110.
Gluzman
I Y
IY
Herwaldt
B L
BL
Schlesinger
P H
PH
Wellems
T E
TE
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000818:Animals; D001693:Biological Transport, Active; D002738:Chloroquine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D003470:Culture Media; D015195:Drug Design; D004351:Drug Resistance / Q000235:genetics; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014638:Vanadates / Q000494:pharmacology
D003470:Culture Media; D014638:Vanadates; D002738:Chloroquine; D000251:Adenosine Triphosphatases; D005947:Glucose