Daniel Kiboi1, 2, Beatrice Irungu2, Jennifer Orwa2, Luna Kamau2, Lynette Isabella Ochola-Oyier2, Joseph Ng�¡ng�¡1 and Alexis Nzila3
1Jomo Kenyatta University of Agriculture and Technology, Kenya 2Kenya Medical Research Institute ( KEMRI), Kenya 3King Fahd University of Petroleum and Minerals, Kingdom of Saudi Arabia
Posters-Accepted Abstracts: Pharmaceut Reg Affairs
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 analysed 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 Pbmdr-1 or in the mRNA transcript levels of Pbmdr-1. 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-Stransferase (gst) genes. These mechanisms are also known to contribute to chloroquine resistance in P. falciparum and rodent malaria parasites. The increase in �ggcs� and �gst� transcript levels were accompanied by high glutathione (GSH) levels and elevated activity of glutathione-S-transferase (GST) enzyme. Taken together, these results demonstrate that Pbcrt and Pbmdr-1 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.
Email: dmuthui@jkuat.ac.ke
Pharmaceutical Regulatory Affairs: Open Access received 533 citations as per Google Scholar report
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