Role for the plasmodium falciparum digestive vacuole in chloroquine resistance.
We have developed a method for the isolation of pure and intact Plasmodium falciparum digestive vacuoles capable of ATP-dependent chloroquine (CQ) accumulation in vitro. The method is rapid and reliable, and it produces a high yield of vacuoles (20%). CQ accumulation in isolated vacuoles was found to be ATP-, Mg2+-, and temperature-dependent. We then investigated the CQ-accumulating capabilities of vacuoles isolated from CQ-resistant (CQR) and CQ-sensitive (CQS) parasites. At external CQ concentrations of 100 and 250 nM, vacuoles isolated from two CQS strains (D10 and RSA3) (Vm: 380-424 fmol/10(6) vacuoles/hr) accumulated significantly more CQ (approximately 3 times) than those isolated from three (FAC8, RSA11, and RSA15) of the four CQ-resistant strains of P. falciparum tested (Vmax: 127-156 fmol/10(6) vacuoles/hr) (P < or = 0.05). We propose that the low level of CQ accumulation observed in vacuoles isolated from most of the CQ-resistant parasites tested contributes to the decreased CQ accumulation seen in these strains and, hence, to CQ resistance. Although it is often suggested that the digestive vacuole of the P. falciparum parasite is involved in the mechanism of CQ resistance, to our knowledge this is the first direct confirmation.
Saliba
K J
KJ
Department of Pharmacology, University of Cape Town, Medical School, South Africa.
Folb
P I
PI
Smith
P J
PJ
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000648:ultrastructure; D014617:Vacuoles / Q000378:metabolism*
D000962:Antimalarials; D002738:Chloroquine; D000255:Adenosine Triphosphate