Expression of the plasmodial pfmdr1 gene in XXXX cells is associated with increased susceptibility to @entity503 .

@entity1 @entity632 @entity5174 @entity1238 @entity535 @entity1855 @entity73246 @entity12433 @entity4807 @entity3964 @entity311 @entity503 @entity20049 @entity3812 @entity855
@entity503 (CQ)-resistant (CQR) @entity3964 @entity311 parasites show a strong decrease in CQ accumulation in comparison with @entity503 -sensitive parasites. Controversy exists over the role of the plasmodial pfmdr1 gene in the CQR phenotype. pfmdr1 is a member of the superfamily of @entity855 -binding cassette transporters. Other members of this family are the @entity1 multidrug resistance genes and the @entity5174 gene. We have expressed the pfmdr1-encoded protein, Pgh1, in CHO cells and @entity1238 oocytes. CHO cells expressing the Pgh1 protein demonstrated an increased, @entity1855 -insensitive susceptibility to CQ. Conversely, no increase in drug susceptibility to @entity12433 , @entity4807 , @entity632 , or @entity3812 was observed in Pgh1-expressing cells. CQ uptake experiments revealed an increased, @entity855 -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 @entity535 changes ( @entity73246 and @entity20049 ) 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 @entity311 parasites.
