PMID- 2669763
OWN - NLM
STAT- MEDLINE
DCOM- 19890911
LR  - 20190623
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 38
IP  - 16
DP  - 1989 Aug 15
TI  - Alkalinization of the food vacuole of malaria parasites by quinoline drugs and 
      alkylamines is not correlated with their antimalarial activity.
PG  - 2645-54
AB  - Quinoline-containing antimalarial drugs accumulate inside the acid food vacuole 
      of the parasite where they inhibit the digestion of ingested host cell cytosol, 
      and consequently, parasite growth. In order to verify whether this inhibition is 
      caused by drug-induced alkalinization of the food vacuole, we investigated the 
      accumulation of acridine orange (AO) as a vacuolar pH probe in intact Plasmodium 
      falciparum-infected human erythrocytes as affected by the drugs chloroquine (CQ), 
      7H-quinoleine (7HQ), quinine (Q) and mefloquine (MQ). It was established by 
      various criteria that AO accumulates primarily in the acid compartment(s) of the 
      parasite as a function of the pH difference between it and the extracellular 
      medium. This pH gradient was dissipated by the drugs in the rank order MQ greater 
      than CQ greater than Q greater than 7HQ. The kinetics of vacuolar alkalinization 
      and the concentration ranges at which it was observed imply that the monoprotic 
      drugs MQ and Q exerted their effect mostly by translocating protons across the 
      vacuolar membrane, i.e. they could cross the membrane as a protonated species, 
      while the diprotic drugs CQ and 7HQ raised the vacuolar pH mostly by proton 
      trapping. Similarly, hydrophobic alkylamines raised the vacuolar pH by proton 
      translocation, while their relatively more polar congeners and ammonia did so by 
      proton titration. However, the alkalinizing effect of each drug was observed at a 
      concentration which was 1-2 orders of magnitude larger than the IC50 of its 
      antimalarial effect. These results mean that vacuolar alkalinization is not the 
      primary effect of antiparasitic action of quinoline antimalarials.
FAU - Ginsburg, H
AU  - Ginsburg H
AD  - Department of Biological Chemistry, Hebrew University of Jerusalem, Israel.
FAU - Nissani, E
AU  - Nissani E
FAU - Krugliak, M
AU  - Krugliak M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Amines)
RN  - 0 (Antimalarials)
RN  - 0 (Quinolines)
RN  - 555-60-2 (Carbonyl Cyanide m-Chlorophenyl Hydrazone)
RN  - F30N4O6XVV (Acridine Orange)
RN  - O3C74ACM9V (Ethylmaleimide)
SB  - IM
MH  - Acridine Orange/pharmacology
MH  - Amines/*pharmacology
MH  - Animals
MH  - Antimalarials/*pharmacology
MH  - Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology
MH  - Erythrocytes/*drug effects/parasitology
MH  - Ethylmaleimide/pharmacology
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - In Vitro Techniques
MH  - Plasmodium falciparum/*drug effects
MH  - Quinolines/*pharmacology
MH  - Vacuoles/drug effects
EDAT- 1989/08/15 00:00
MHDA- 1989/08/15 00:01
CRDT- 1989/08/15 00:00
PHST- 1989/08/15 00:00 [pubmed]
PHST- 1989/08/15 00:01 [medline]
PHST- 1989/08/15 00:00 [entrez]
AID - 0006-2952(89)90550-9 [pii]
AID - 10.1016/0006-2952(89)90550-9 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 1989 Aug 15;38(16):2645-54. doi: 10.1016/0006-2952(89)90550-9.