Polymorphisms of the oxidant enzymes glutathione S–transferase and glutathione reductase and their association with resistance of Plasmodium falciparum isolates to antimalarial drugs

Wisedpanichkij, Raewadee; Chaicharoenkul, Wanna; Mahamad, Poonuch; Prompradit, Prapichaya; Na‐Bangchang, Kesara

doi:10.1016/s1995-7645(10)60163-0

Cited by 9 publications

(1 citation statement)

References 26 publications

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“…Several reports support the hypothesis that blood group A represents a risk factor for high chance of rosette, which is usually characterized by high P. falciparum parasitaemia during malaria infection and a reducing effect of blood group 'O' on rosette [37][38][39][40][41][42][43][44][45] . The presence of several glycosylated adhesion molecules such as intracellular adhesion molecule 1 [38] , complement receptor 1 [37] , heparin sulfate-like glycosaminoglycan [40,41] , platelet glycoprotein CD36 [46][47][48][49][50][51][52][53][54] , high level von Willebrand factor [43] , low arginine and nitrate levels [42] , presence of cellular micro-particles [44] and the nature of sugar molecules (trisacchrides) [55] in blood group 'A' cells promote a high chance of binding with the rosette-forming surface molecules of the P. falciparum such as Duffy binding-like domain 1 alpha of P. falciparum erythrocyte membrane protein-1 [21,56] , rifs [57,58] . On the other hand, blood group 'O' cells show deficiency of most of the above adhesive molecules and contain disaccharides sugar molecules which reduce the rate, size and stability of rosette formed during P. falciparum infection [44,55] .…”

Section: Discussionmentioning

confidence: 99%

Association of ABO blood group and Plasmodium falciparum malaria in Dore Bafeno Area, Southern Ethiopia

Zerihun

Degarege

Erko

2011

Asian Pacific Journal of Tropical Biomedicine

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Section: Discussionmentioning

confidence: 99%

Association of ABO blood group and Plasmodium falciparum malaria in Dore Bafeno Area, Southern Ethiopia

Zerihun

Degarege

Erko

2011

Asian Pacific Journal of Tropical Biomedicine

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A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine

Haynes

Cheu

et al. 2011

ChemMedChem

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Artemisinins rapidly oxidize leucomethylene blue (LMB) to methylene blue (MB); they also oxidize dihydroflavins such as the reduced conjugates RFH₂ of riboflavin (RF), and FADH₂ of the cofactor flavin adenine dinucleotide (FAD), to the corresponding flavins. Like the artemisinins, MB oxidizes FADH₂, but unlike artemisinins, it also oxidizes NAD(P)H. Like MB, artemisinins are implicated in the perturbation of redox balance in the malaria parasite by interfering with parasite flavoenzyme disulfide reductases. The oxidation of LMB by artemisinin is inhibited by chloroquine (CQ), an inhibition that is abruptly reversed by verapamil (VP). CQ also inhibits artemisinin-mediated oxidation of RFH₂ generated from N-benzyl-1,4-dihydronicotinamide (BNAH)-RF, or FADH₂ generated from NADPH or NADPH-Fre, an effect that is also modulated by verapamil. The inhibition likely proceeds by the association of LMB or dihydroflavin with CQ, possibly involving donor-acceptor or π complexes that hinder oxidation by artemisinin. VP competitively associates with CQ, liberating LMB or dihydroflavin from their respective CQ complexes. The observations explain the antagonism between CQ-MB and CQ-artemisinins in vitro, and are reconcilable with CQ perturbing intraparasitic redox homeostasis. They further suggest that a VP-CQ complex is a means by which VP reverses CQ resistance, wherein such a complex is not accessible to the putative CQ-resistance transporter (PfCRT).

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Interactions between Artemisinins and other Antimalarial Drugs in Relation to the Cofactor Model—A Unifying Proposal for Drug Action

et al. 2012

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Artemisinins are proposed to act in the malaria parasite cytosol by oxidizing dihydroflavin cofactors of redox-active flavoenzymes, and under aerobic conditions by inducing their autoxidation. Perturbation of redox homeostasis coupled with the generation of reactive oxygen species (ROS) ensues. Ascorbic acid-methylene blue (MB), N-benzyl-1,4-dihydronicotinamide (BNAH)-MB, BNAH-lumiflavine, BNAH-riboflavin (RF), and NADPH-FAD-E. coli flavin reductase (Fre) systems at pH 7.4 generate leucomethylene blue (LMB) and reduced flavins that are rapidly oxidized in situ by artemisinins. These oxidations are inhibited by the 4-aminoquinolines piperaquine (PPQ), chloroquine (CQ), and others. In contrast, the arylmethanols lumefantrine, mefloquine (MFQ), and quinine (QN) have little or no effect. Inhibition correlates with the antagonism exerted by 4-aminoquinolines on the antimalarial activities of MB, RF, and artemisinins. Lack of inhibition correlates with the additivity/synergism between the arylmethanols and artemisinins. We propose association via π complex formation between the 4-aminoquinolines and LMB or the dihydroflavins; this hinders hydride transfer from the reduced conjugates to the artemisinins. The arylmethanols have a decreased tendency to form π complexes, and so exert no effect. The parallel between chemical reactivity and antagonism or additivity/synergism draws attention to the mechanism of action of all drugs described herein. CQ and QN inhibit the formation of hemozoin in the parasite digestive vacuole (DV). The buildup of heme-Fe(III) results in an enhanced efflux from the DV into the cytosol. In addition, the lipophilic heme-Fe(III) complexes of CQ and QN that form in the DV are proposed to diffuse across the DV membrane. At the higher pH of the cytosol, the complexes decompose to liberate heme-Fe(III) . The quinoline or arylmethanol reenters the DV, and so transfers more heme-Fe(III) out of the DV. In this way, the 4-aminoquinolines and arylmethanols exert antimalarial activities by enhancing heme-Fe(III) and thence free Fe(III) concentrations in the cytosol. The iron species enter into redox cycles through reduction of Fe(III) to Fe(II) largely mediated by reduced flavin cofactors and likely also by NAD(P)H-Fre. Generation of ROS through oxidation of Fe(II) by oxygen will also result. The cytotoxicities of artemisinins are thereby reinforced by the iron. Other aspects of drug action are emphasized. In the cytosol or DV, association by π complex formation between pairs of lipophilic drugs must adversely influence the pharmacokinetics of each drug. This explains the antagonism between PPQ and MFQ, for example. The basis for the antimalarial activity of RF mirrors that of MB, wherein it participates in redox cycling that involves flavoenzymes or Fre, resulting in attrition of NAD(P)H. The generation of ROS by artemisinins and ensuing Fenton chemistry accommodate the ability of artemisinins to induce membrane damage and to affect the parasite SERCA PfATP6 Ca(2+) transporter. Thus, the effect exerted by ...

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Polymorphisms of the oxidant enzymes glutathione S–transferase and glutathione reductase and their association with resistance of Plasmodium falciparum isolates to antimalarial drugs

Cited by 9 publications

References 26 publications

Association of ABO blood group and Plasmodium falciparum malaria in Dore Bafeno Area, Southern Ethiopia

Association of ABO blood group and Plasmodium falciparum malaria in Dore Bafeno Area, Southern Ethiopia

A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine

Interactions between Artemisinins and other Antimalarial Drugs in Relation to the Cofactor Model—A Unifying Proposal for Drug Action

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