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Piperaquine and Lumefantrine resistance in Plasmodium berghei ANKA associated with increased expression of Ca2+/H+ antiporter and glutathione associated enzymes
- Source :
- Experimental Parasitology. 147:23-32
- Publication Year :
- 2014
- Publisher :
- Elsevier BV, 2014.
-
Abstract
- We investigated the mechanisms of resistance of two antimalarial drugs piperaquine (PQ) and lumefantrine (LM) using the rodent parasite Plasmodium berghei as a surrogate of the human parasite, Plasmodium falciparum. We analyzed the whole coding sequence of Plasmodium berghei chloroquine resistance transporter (Pbcrt) and Plasmodium berghei multidrug resistance gene 1(Pbmdr-1) for polymorphisms. These genes are associated with quinoline resistance in Plasmodium falciparum. No polymorphic changes were detected in the coding sequences of Pbcrt and Pbmdr1 or in the mRNA transcript levels of Pbmdr1. However, our data demonstrated that PQ and LM resistance is achieved by multiple mechanisms that include elevated mRNA transcript levels of V-type H+ pumping pyrophosphatase (vp2), Ca2+/H+ antiporter (vcx1), gamma glutamylcysteine synthetase (ggcs) and glutathione-S-transferase (gst) genes, mechanisms also known to contribute to chloroquine resistance in P. falciparum and rodent malaria parasites. The increase in ggcs and gst transcript levels was accompanied by high glutathione (GSH) levels and elevated activity of glutathione-S-transferase (GST) enzyme. Taken together, these results demonstrate that Pbcrt and Pbmdr1 are not associated with PQ and LM resistance in P. berghei ANKA, while vp2, vcx1, ggcs and gst may mediate resistance directly or modulate functional mutations in other unknown genes.
- Subjects :
- Male
Plasmodium berghei
Antiporter
Immunology
Real-Time Polymerase Chain Reaction
Lumefantrine
Article
Antiporters
Gene Expression Regulation, Enzymologic
Antimalarials
Mice
chemistry.chemical_compound
Parasitic Sensitivity Tests
Piperaquine
parasitic diseases
Animals
Coding region
Cloning, Molecular
Cation Transport Proteins
Gene
Glutathione Transferase
Genetics
Fluorenes
Glutathione Peroxidase
biology
Plasmodium falciparum
Sequence Analysis, DNA
General Medicine
Glutathione
DNA, Protozoan
biology.organism_classification
Molecular biology
Drug Resistance, Multiple
Glutathione Reductase
Infectious Diseases
chemistry
Ethanolamines
Quinolines
Parasitology
Subjects
Details
- ISSN :
- 00144894
- Volume :
- 147
- Database :
- OpenAIRE
- Journal :
- Experimental Parasitology
- Accession number :
- edsair.doi.dedup.....379b7634d49b23136ef18457eeccd1d4