EXPRESSION OF THE PLASMODIAL PFMDR1 GENE IN MAMMALIAN-CELLS IS ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO CHLOROQUINE
- Author(s)
- VANES, HHG; KARCZ, S; CHU, F; Cowman, AF; VIDAL, S; Gros, P; Schurr, E;
- Details
- Publication Year 1994-04,Volume 14,Issue #4,Page 2419-2428
- Journal Title
- MOLECULAR AND CELLULAR BIOLOGY
- Publication Type
- Journal Article
- Abstract
- Chloroquine (CQ)-resistant (CQR) Plasmodium falciparum malaria parasites show a strong decrease in CQ accumulation in comparison with chloroquine-sensitive parasites. Controversy exists over the role of the plasmodial pfmdr1 gene in the CQR phenotype. pfmdr1 is a member of the superfamily of ATP-binding cassette transporters. Other members of this family are the mammalian multidrug resistance genes and the CFTR gene. We have expressed the pfmdr1-encoded protein, Pgh1, in CHO cells and Xenopus oocytes. CHO cells expressing the Pgh1 protein demonstrated an increased, verapamil-insensitive susceptibility to CQ. Conversely, no increase in drug susceptibility to primaquine, quinine, adriamycin, or colchicine was observed in Pgh1-expressing cells. CQ uptake experiments revealed an increased, ATP-dependent accumulation of CQ in Pgh1-expressing cells over the level in nonexpressing control cells. The increased CQ accumulation in Pgh1-expressing cells coincided with an enhanced in vivo inhibition of lysosomal alpha-galactosidase by CQ. CHO cells expressing Pgh1 carrying two of the CQR-associated Pgh1 amino acid changes (S1034C and N1042D) did not display an increased CQ sensitivity. Immunofluorescence experiments revealed an intracellular localization of both mutant and wild-type forms of Pgh1. We conclude from our results that wild-type Pgh1 protein can mediate an increased intracellular accumulation of CQ and that this function is impaired in CQR-associated mutant forms of the protein. We speculate that the Pgh1 protein plays an important role in CQ import in CQ-sensitive malaria parasites.
- Publisher
- AMER SOC MICROBIOLOGY
- Keywords
- MULTIDRUG-RESISTANCE GENE; P-GLYCOPROTEIN; MALARIA PARASITES; FALCIPARUM; EFFLUX; ERYTHROCYTES; ACCUMULATION; FIBROBLASTS; INHIBITION; VERAPAMIL
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Creation Date: 1994-04-01 12:00:00