ABCMdb

ABCC1 p.Ser1034Cys

Predicted by SNAP2:	A: N (61%), C: D (59%), D: D (71%), E: D (71%), F: D (75%), G: N (61%), H: D (71%), I: D (71%), K: D (75%), L: D (80%), M: D (66%), N: N (57%), P: D (85%), Q: D (59%), R: D (85%), T: N (78%), V: D (53%), W: D (80%), Y: D (80%),
Predicted by PROVEAN:	A: N, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: N, P: D, Q: D, R: D, T: N, V: D, W: D, Y: D,

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[hide] Atorvastatin is a promising partner for antimalari... Antimicrob Agents Chemother. 2009 Jun;53(6):2248-52. Epub 2009 Mar 23. Parquet V, Briolant S, Torrentino-Madamet M, Henry M, Almeras L, Amalvict R, Baret E, Fusai T, Rogier C, Pradines B
Atorvastatin is a promising partner for antimalarial drugs in treatment of Plasmodium falciparum malaria.
Antimicrob Agents Chemother. 2009 Jun;53(6):2248-52. Epub 2009 Mar 23., [PMID:19307369]

Abstract [show]
Atorvastatin (AVA) is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. AVA exposure resulted in the reduced in vitro growth of 22 Plasmodium falciparum strains, with the 50% inhibitory concentrations (IC(50)s) ranging from 2.5 microM to 10.8 microM. A significant positive correlation was found between the strains' responses to AVA and mefloquine (r = 0.553; P = 0.008). We found no correlation between the responses to AVA and to chloroquine, quinine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone, or doxycycline. These data could suggest that the mechanism of AVA uptake and/or the mode of action of AVA is different from those for other antimalarial drugs. The IC(50)s for AVA were unrelated to the occurrence of mutations in the transport protein genes involved in quinoline antimalarial drug resistance, such as the P. falciparum crt, mdr1, mrp, and nhe-1 genes. Therefore, AVA can be ruled out as a substrate for the transport proteins (CRT, Pgh1, and MRP) and is not subject to the pH modification induced by the P. falciparum NHE-1 protein. The absence of in vitro cross-resistance between AVA and chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone, and doxycycline argues that these antimalarial drugs could potentially be paired with AVA as a treatment for malaria. In conclusion, the present observations suggest that AVA is a good candidate for further studies on the use of statins in association with drugs known to have activities against the malaria parasite.

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No. Sentence Comment
99 The following mutations were identified in at least one strain: Pfcrt M74I, N75E, K76T, A220S, Q271(E/V), N326S, I356T, and I371R; Pfmrp H191Y and S437A; and Pfmdr1 N86Y, Y184F, S1034C, N1042D, and D1246Y (Table 2). Login to comment

[hide] Pleiotropic resistance to diverse antimalarials in... Biochem Pharmacol. 2000 May 1;59(9):1123-32. Abrahem A, Certad G, Pan X, Georges E
Pleiotropic resistance to diverse antimalarials in actinomycin D-resistant Plasmodium falciparum.
Biochem Pharmacol. 2000 May 1;59(9):1123-32., [PMID:10704942]

Abstract [show]
The development and spread of multidrug-resistant Plasmodium falciparum are major health concerns. The molecular mechanisms of multidrug resistance, including resistance to many quinoline-based antimalarials, are largely unknown. In this study, we report on the isolation and partial characterization of actinomycin D (actD)-resistant P. falciparum (3D7(R)/actD2.3) from a chloroquine-susceptible strain, 3D7. The stepwise selection of an actD-resistant clone (3D7(R)/actD2.3) led to the isolation and cloning of P. falciparum that grew in the presence of 2 ng/mL of actD. The parental isolate (3D7) did not grow in the presence of a 10-fold lower drug concentration (0.2 ng/mL). The latter estimate of parasite growth was determined by direct counting of parasites in infected red blood cells. Estimates of drug resistance levels to actD, using a [(3)H]hypoxanthine uptake and incorporation method, showed a 3-fold difference in the IC(50) between 3D7 and 3D7(R)/actD2.3. Interestingly, 3D7(R)/actD2.3 P. falciparum parasites were less sensitive to several antimalarials (chloroquine, mefloquine, quinidine, and artemisinin) and to the mitochondrial specific dye Rhodamine 123. Drug transport studies using [(3)H]actD showed that 3D7(R)/actD2.3 accumulated less drug than 3D7. Moreover, the accumulation of [(3)H]actD was energy dependent. To determine if Pfmdr1 expression, previously implicated in drug resistance to certain antimalarials, mediated the resistance phenotype of 3D7(R)/actD2.3, Pfmdr1 levels in 3D7 and 3D7(R)/actD2.3 were compared by Southern and northern blot analyses. Our results revealed no differences in Pfmdr1 copy number or mRNA levels between 3D7 and 3D7(R)/actD2.3. Furthermore, comparison of Pfmdr1 sequences between 3D7 and 3D7(R)/actD2.3 showed no differences. In addition, verapamil, which reverses P-glycoprotein-mediated drug resistance in mammalian cells, did not reverse the resistance of 3D7(R)/actD2.3 to actD or chloroquine. Taken together, the findings of this study demonstrated that in vitro selection of P. falciparum for resistance to actD leads to decreased sensitivity to diverse drugs and that this pleiotropic drug resistance is associated with reduced drug accumulation not mediated by Pfmdr1.

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185 Although these results point to the lack of involvement of Pfmdr1 in actD resistance, earlier reports have suggested that several point mutations in Pfmdr1 (Asn86Tyr, Ser1034Cys, Asn1042Asp, and Asp1246Tyr) may be important to chloroquine or mefloquine resistance [38]. Login to comment

[hide] The pfmdr1 gene of Plasmodium falciparum confers c... Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9942-7. Ruetz S, Delling U, Brault M, Schurr E, Gros P
The pfmdr1 gene of Plasmodium falciparum confers cellular resistance to antimalarial drugs in yeast cells.
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9942-7., [PMID:8790436]

Abstract [show]
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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38 Mutant variants ofpftndrl 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). Login to comment
88 The expression of the wild-type P. falciparum Pgh-1 protein (A) and mutant variants bearing single S1034C (B) or N1042D (C) mutations or both (D) in permeabilized yeast S. cerevisiae spheroplasts is shown by immunofluorescence using a specific antiserum (rabbit anti-Pgh-1) at a 1:100 dilution, followed by an fluorescein isothiocyanate-coupled goat anti-rabbit antibody at a dilution of 1:800. Login to comment
94 Time-dependent cell growth in absence (solid symbols) or presence (open symbols) of MFQ at 150 ,ug/ml was established for JPY201 transformants expressing wild-type Pgh-1, wild-type Mdr3 (Mdr3S), or Pgh-1 variants bearing single S1034C (M1034) or single N1042D (M1042) mutations or both mutations (S1034C/N1042D; DM) in predicted TM11 or a mutant variant of Mdr3 (S939F; Mdr3F). Login to comment
97 JPY201 cells expressing wild-type Pgh-1, wild-type Mdr3 (Mdr3S), or mutant Pgh-1 variants bearing single S1034C (M1034), single N1042D M1042) mutations, or both mutations (S1034C/N1042D; DM) were evaluated for growth in increasing concentrations of MFQ. Login to comment
133 JPY201 cells expressing either wild-type Pgh-1 or a double mutant Pgh-1 variant (S1034C/ N1042D; DM) were incubated with QA. Login to comment