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Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in Plasmodium falciparum

24 Nov 2008

Maristela Martins de Camargo and Marcia Triunfol

Source: Molecular Microbiology (see original article)

Citation: Sanchez CP, Rotmann A, Stein WD, Lanzer M (2008). Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in Plasmodium falciparum. Mol Microbiol; 70(4):786-798.

Human malaria parasites showing resistance to drugs have been associated with the expression of specialized proteins known as drug transporters. These transporters are found in the membrane of the parasite’s digestive vacuoles. The parasite expresses several proteins of the of drug transporter family. By doing so, it can modulate the concentration of drug that enters the vacuole and the cell’s cytoplasm.

The drug transporter expressed by malaria parasites is a homolog to the human P-glycoprotein, a protein that belongs to a family of drug transporters described in humans almost two decades ago. The human P-glycoprotein is expressed by anticancer drug-resistance cells that efflux the drug from the cells. P-glycoprotein is inhibited by verapamil, a drug that make cells that were resistant to drugs into sensitive ones.

In malaria parasites, the protein homolog to the human P-glycoprotein is called Pgh1. Pgh1is found in the digestive vacuole inside parasitized red cells. Its expression has been shown to be associated with increased resistance to three antimalarial drugs: mefloquine, quinine, and halofantrine.

Expression of Pgh1 has also been correlated with decreased sensitivity to the antimalarial drug artemisinin. Interestingly, some studies have suggested that Pgh1 acts by exporting drugs from the vacuole, which then causes an increase of the drug concentration in the red cell’s cytoplasm. Perhaps, a better strategy taken by the parasite would be trapping the drug inside the digestive vacuole, as increased concentrations of the drug in the cytoplasm should make cells more sensitive to its effects. Nevertheless, no system for measuring the transporter activity has been available to better investigate the behaviour of Pgh1 and the drug concentration in each cellular environment.

The work by Sanchez and collaborators aimed at developing a system that allowed for direct measurement of drugs transported by Pgh1. To do so, different variants of Pgh1 were injected into frogs’ eggs and expressed in their membranes. The authors followed the uptake and transport of radiolabelled drugs, which allow these drugs to be traced in the cell. They found that all mutant forms of Pgh1 correlated with decreased concentrations of vinblastine inside the cells, as compared to cells bearing wild-type transporters. Vinblastine is a known substrate of P-glycoprotein.

Next, they tested several antimalarial drugs. The results found with these drugs were more heterogeneous than those found with vinblastine. Pgh1 mutants showing resistance to antimalarial drugs correlated with decreased cellular accumulation of the drug halofantrine, while no effect on drug concentration was found when the wild-type transporter was expressed. In contrast, expression of wild-type Pgh1 correlated with efflux of chloroquine and quinine, while mutant forms were associated with decreased drug accumulation that could be reversed with P-glycoprotein inhibitors (such as verapamil).

The authors did not investigate why Pgh1 variants that transport halofantrine unexpectedly correlated with increased sensitivity to this drug. The expected result was for the variants to be associated with increased concentrations of this drug inside the digestive vacuole. But the data represents progress towards unravelling the mechanisms of antimalarial drug resistance. Knowing more about Pgh1 drug transporter expression may provide us with a better understanding of how to stop the appearance of drug-resistant strains of the parasite.