Modulation of Nitrated Lipid Signaling by Multidrug Resistance Protein 1 (MRP1):  Glutathione Conjugation and MRP1-Mediated Efflux Inhibit Nitrolinoleic Acid-Induced, PPARγ-Dependent Transcription Activation†

Biochemistry ◽  
2006 ◽  
Vol 45 (25) ◽  
pp. 7889-7896 ◽  
Author(s):  
Richard L. Alexander ◽  
Darcy J. P. Bates ◽  
Marcus W. Wright ◽  
S. Bruce King ◽  
Charles S. Morrow
Keyword(s):  
Multidrug Resistance ◽  
Transcription Activation ◽  
Lipid Signaling ◽  
Multidrug Resistance Protein ◽  
Multidrug Resistance Protein 1 ◽  
Glutathione Conjugation ◽  
Resistance Protein ◽  
Nitrolinoleic Acid

scholarly journals Multidrug resistance protein 1 regulates lipid asymmetry in erythrocyte membranes

2000 ◽  
Vol 350 (2) ◽  
pp. 531-535 ◽  
Author(s):  
David W. C. DEKKERS ◽  
Paul COMFURIUS ◽  
Rein G. J. VAN GOOL ◽  
Edouard M. BEVERS ◽  
Robert F. A. ZWAAL
Keyword(s):  
Multidrug Resistance ◽  
Erythrocyte Membrane ◽  
Erythrocyte Membranes ◽  
Multidrug Resistance Protein ◽  
Multidrug Resistance Protein 1 ◽  
Lipid Asymmetry ◽  
Appreciable Change ◽  
Outer Leaflet ◽  
Resistance Protein ◽  
Phospholipid Distribution

The role of multidrug resistance protein 1 (MRP1) in the maintenance of transbilayer lipid asymmetry in the erythrocyte membrane was investigated. The transbilayer distribution of endogenous phospholipids and [(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]hexanoyl (NBD)-labelled lipid analogues was compared in the absence and the presence of inhibitors of MRP1. At equilibrium the transbilayer distribution of the NBD analogues (in the absence of MRP1 inhibitors) was very similar to that of the endogenous lipids. Inhibition of MRP1 by verapamil or indomethacin resulted in a shift in the amount of probe that was internalized: approx. 50% of NBD-labelled phosphatidylcholine (PtdCho) and 9% of NBD-sphingomyelin (NBD-Spm) were no longer extractable by BSA in cells treated with inhibitor, in comparison with 25% and 3% for control cells respectively. To verify whether inhibition of MRP1 also affected the distribution of the endogenous phospholipids, phospholipase A2 and sphingomyelinase were used to assess the amount of each of the various lipid classes present in the membrane outer leaflet. No shift in phospholipid distribution was observed after 5h of incubation with verapamil or indomethacin. However, after 48h of incubation with these inhibitors, significantly smaller amounts of PtdCho and Spm were present in the outer membrane leaflet. No appreciable change was observed in the distribution of phosphatidylethanolamine or phosphatidylserine. Decreased hydrolysis of PtdCho and Spm was not due to endovesicle formation, as revealed by electron microscopy. This is the first report to show that MRP1 has a role in the maintenance of the outwards orientation of endogenous choline-containing phospholipids in the erythrocyte membrane.

scholarly journals Expansion of a Specific Plasmodium falciparum PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Carla Calçada ◽  
Miguel Silva ◽  
Vitória Baptista ◽  
Vandana Thathy ◽  
Rita Silva-Pedrosa ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Southeast Asia ◽  
Gene Copy ◽  
Multidrug Resistance Protein ◽  
Combination Therapies ◽  
Transport Capacity ◽  
Multidrug Resistance Protein 1 ◽  
Content Type ◽  
Resistance Protein

ABSTRACT Artemisinin-based combination therapies (ACTs) have been vital in reducing malaria mortality rates since the 2000s. Their efficacy, however, is threatened by the emergence and spread of artemisinin resistance in Southeast Asia. The Plasmodium falciparum multidrug resistance protein 1 (PfMDR1) transporter plays a central role in parasite resistance to ACT partner drugs through gene copy number variations (CNV) and/or single nucleotide polymorphisms (SNPs). Using genomic epidemiology, we show that multiple pfmdr1 copies encoding the N86 and 184F haplotype are prevalent across Southeast Asia. Applying genome editing tools on the Southeast Asian Dd2 strain and using a surrogate assay to measure transporter activity in infected red blood cells, we demonstrate that parasites harboring multicopy N86/184F PfMDR1 have a higher Fluo-4 transport capacity compared with those expressing the wild-type N86/Y184 haplotype. Multicopy N86/184F PfMDR1 is also associated with decreased parasite susceptibility to lumefantrine. These findings provide evidence of the geographic selection and expansion of specific multicopy PfMDR1 haplotypes associated with multidrug resistance in Southeast Asia. IMPORTANCE Global efforts to eliminate malaria depend on the continued success of artemisinin-based combination therapies (ACTs) that target Plasmodium asexual blood-stage parasites. Resistance to ACTs, however, has emerged, creating the need to define the underlying mechanisms. Mutations in the P. falciparum multidrug resistance protein 1 (PfMDR1) transporter constitute an important determinant of resistance. Applying gene editing tools combined with an analysis of a public database containing thousands of parasite genomes, we show geographic selection and expansion of a pfmdr1 gene amplification encoding the N86/184F haplotype in Southeast Asia. Parasites expressing this PfMDR1 variant possess a higher transport capacity that modulates their responses to antimalarials. These data could help tailor and optimize antimalarial drug usage in different regions where malaria is endemic by taking into account the regional prevalence of pfmdr1 polymorphisms.

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