Expression of the plasmodial pfmdr1 gene in mammalian cells is associated with increased susceptibility to chloroquine.

Es, Helmuth H. G. van; Karcz, Steven R.; Chu, Fan; Cowman, Alan F.; Vidal, Silvia M.; Gros, Philippe; Schurr, Erwin

doi:10.1128/mcb.14.4.2419

Cited by 78 publications

(41 citation statements)

References 39 publications

(66 reference statements)

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“…Moreover, we have observed that Pgh-1 expression in CHO cells causes increased accumulation and susceptibility to CQ (26). In these cells, Pgh-1 was associated with the lysosomal compartment where we speculated it may act directly or indirectly as a CQ transporter/concentrator (26). This conclusion is supported by the observed loss of pftndrl amplification in selection for high-level CQ resistance in vitro (27).…”

supporting

confidence: 75%

“…The possible role of Pgh-1 as a drug transporter in P. falciparum is supported by the observed (i) structural homology between Pgh-1 and mammalian P-gps (17,19), (ii) pleiotropy of the two resistance phenomena, (iii) subcellular localization of Pgh-1 to the membrane of the food vacuole (24), (iv)pfindrl amplification and Pgh-1 expression in P. falciparum isolates resistant to HA and MFQ (7)(8)(9), and (v) Pgh-1 amino acid sequence polymorphisms (Kl allele, N86Y, near TM1; 7G8 allele, S1034/N1042 -> C1034/D1042 in TM11) associated with resistance in certain field isolates (25). Moreover, we have observed that Pgh-1 expression in CHO cells causes increased accumulation and susceptibility to CQ (26). In these cells, Pgh-1 was associated with the lysosomal compartment where we speculated it may act directly or indirectly as a CQ transporter/concentrator (26).…”

mentioning

confidence: 82%

“…Sci. USA 93 (1996) Mutant variants of pftndrl bearing a single Ser -> Cys substitution at position 1034 (S1034C, clone M1034), a single Asn -> Asp substitution at position 1042 (N1042D, clone M1042), or both mutations (S1034C/N1042D; clone DM) were generated by site-directed mutagenesis (26). Appropriate 1.6-kb SnaBIHindlIl fragments overlapping the mutations were reintroduced in pfindrl by homologous recombination (38).…”

mentioning

confidence: 99%

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RETRACTED: The pfmdr1 gene of Plasmodium falciparum confers cellular resistance to antimalarial drugs in yeast cells.

Ruetz

Delling²,

Brault³

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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The exact role of the pfmdr1 gene in the emergence of drug resistance in the malarial parasite Plasmodium falciparum remains controversial. pfmdr1 is a member of the ATP binding cassette (ABC) superfamily of transporters that includes the mammalian P-glycoprotein family. We have introduced wild-type and mutant variants of the pfmdr1 gene in the yeast Saccharomyces cerevisiae and have analyzed the effect of pfmdr1 expression on cellular resistance to quinoline-containing antimalarial drugs. Yeast transformants expressing either wild-type or a mutant variant of mouse P-glycoprotein were also analyzed. Dose-response studies showed that expression of wild-type pfmdr1 causes cellular resistance to quinine, quinacrine, mefloquine, and halofantrine in yeast cells. Using quinacrine as substrate, we observed that increased resistance to this drug in pfmdr1 transformants was associated with decreased cellular accumulation and a concomitant increase in drug release from preloaded cells. The introduction of amino acid polymorphisms in TM11 of Pgh-1 (pfmdr1 product) associated with drug resistance in certain field isolates of P. falciparum abolished the capacity of this protein to confer drug resistance. Thus, these findings suggest that Pgh-1 may act as a drug transporter in a manner similar to mammalian P-glycoprotein and that sequence variants associated with drug-resistance pfmdr1 alleles behave as loss of function mutations.

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confidence: 75%

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confidence: 82%

mentioning

confidence: 99%

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RETRACTED: The pfmdr1 gene of Plasmodium falciparum confers cellular resistance to antimalarial drugs in yeast cells.

Ruetz

Delling²,

Brault³

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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“…The functional relevance of these mutations in pfmdrl on chloroquine sensitivity was tested in another system. The pftndrl gene expressed in Chinese hamster ovary cells results in an increased sensitivity of these cells to chloroquine, and these same mutations inpjindrl at positions 1034 and 1042 abolish this increase in chloroquine sensitivity in this system (36). These data support the findings in this work which demonstrate that these genetic polymorphisms identified in a naturally occurring, chloroquine-resistant parasite (23) are associated with altered transport of substrate.…”

Section: Resultssupporting

confidence: 82%

Functional complementation of the ste6 gene of Saccharomyces cerevisiae with the pfmdr1 gene of Plasmodium falciparum.

Volkman

Cowman

Wirth

1995

Proc. Natl. Acad. Sci. U.S.A.

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The pfindrl gene has been associated with a drug-resistant phenotype in Plasmodiumfalkiparum, and overexpression of pfmidrl has been associated with mefloquineand halofantrine-resistant parasites, but little is known about the functional role of pfmdrl in this process. Here, we demonstrate that the pfmdrl gene expressed in a heterologous yeast system functions as a transport molecule and complements a mutation in ste6, a gene which encodes a mating pheromone a-factor export molecule. In addition, the pfmdrl gene containing two mutations which are associated with naturally occurring chloroquine resistance abolishes this mating phenotype, suggesting that these genetic polymorphisms alter this transport function. Our results support the functional role of pfmidrl as a transport molecule in the mediation of drug resistance and provide an assay system to address the nature of this transport function.

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“…En 1994, al expresar el tipo silvestre del gen pfmdrl en células CHO (células de ovario de hámster chino), se observó un aumento en la sensibilidad a cloroquina, ocasionada por un aumento en la acumulación del medicamento, a partir de lo cual se postuló que la P-glicoproteína producto del gen podría estar mediando la acumulación de cloroquina y no su eflujo (10). Aunque en otros organismos se ha observado que la proteína producto del gen pfmdrl puede actuar regulando el pH de organelos ácidos (11) y también como transportador de moléculas (12), su función en el parásito aun no se ha establecido.…”

Section: (7)unclassified

Expresión del gen asociado con la resistencia múltiple a medicamentos (pfmdrl) en cepas colombianas de Plasmodium falciparum

et al. 1999

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El tratamiento y control de la malaria ha sido obstaculizado por la capacidad del parásito para desarrollar resistencia a agentes antimaláricos. La cloroquina, que ha sido el principal agente antimalárico debido a su eficiencia, baja toxicidad y costo, ahora frecuentemente fracasa en el control de la enfermedad. El mecanismo por el cual los parásitos desarrollan resistencia a cloroquina no se ha establecido hasta el momento, aunque inicialmente la amplificación, sobre-expresión y mutaciones puntuales en un gen denominado pfmdrl (Plasmodium falciparum multidrug resistant gene) fueron asociadas con el fenotipo cloroquinorresistente (CQR); estudios posteriores suscitaron controversia acerca de esta asociación. En el trabajo se estudió la expresión del gen pfmdrl en las cepas colombianas de P falciparum y en dos cepas de referencia, una sensible (Haití 135) y una resistente (Palo Alto), mediante un ensayo de slot-blot Los resultados obtenidos permiten sugerir que la expresión del gen pfmdrl no está directamente relacionada con el fenotipo resistente.Palabras clave: Plasmodium, resistencia, fármacos, gen MDR, malaria.Expresion of the multiple drug resistance associated gene (pfMDR 1) in Colombian strains of Plasmodium falciparum AbstractThe treatment and control of malaria have confronted obstacles dueto the parasite's capacity to develop resistance to antimalarial agents. Chloroquine, which has been the main agent against malaria due to its efficiency, low toxicity and cost, is now failing in the control of the disease.The mechanism through which the parasite develops resistance to chloroquine has not been defined yet, although the amplification, over-expression and point mutationsfound in a gene called pfmdrl (Plasmodium falciparummultidrug resistance gene) were related to the chloroquine resistance phenotype (CQR). Nevertheless, later studies opened controversial discussion over such association.The present research work studied pfmdrl gene's expression in Colombian strains of P falciparum and in two reference strains: a sensitive one (Haiti 135) and a resistant one (Palo Alto), using a slot-blot test. The results obtained allow us to suggest that the pfmdrl gene's expression is not directly reiated to the resistant phenotype.

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Expression of the plasmodial pfmdr1 gene in mammalian cells is associated with increased susceptibility to chloroquine.

Cited by 78 publications

References 39 publications

RETRACTED: The pfmdr1 gene of Plasmodium falciparum confers cellular resistance to antimalarial drugs in yeast cells.

RETRACTED: The pfmdr1 gene of Plasmodium falciparum confers cellular resistance to antimalarial drugs in yeast cells.

Functional complementation of the ste6 gene of Saccharomyces cerevisiae with the pfmdr1 gene of Plasmodium falciparum.

Expresión del gen asociado con la resistencia múltiple a medicamentos (pfmdrl) en cepas colombianas de Plasmodium falciparum

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