Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

Ginsburg, Hagaï; Demel, R.A.

doi:10.1016/0009-3084(84)90076-8

Cited by 42 publications

(25 citation statements)

References 36 publications

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“…The overall effects of heme reported here are reminiscent of those of Shiga toxin, a primary trigger of HUS, which induces P-selectin expression on endothelial cells, resulting in C3 binding and alternative pathway activation together with a vWF-mediated thrombus formation. 43 Heme also binds directly to the cell membrane phospholipids, 40,44 where it could activate complement as in the fluid phase ( Figure 7D, step 4). In addition, the endothelial cell retraction, which occurs after treatment with heme 45 and exposes the complement activating subendothelial matrix 46 may lead to hemedependent C3 deposition on the endothelium ( Figure 7D, step 5).…”

Section: Discussionmentioning

confidence: 99%

Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

Frimat

Tabarin

Dimitrov

et al. 2013

Blood

217

248

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Key Points• Heme activates complement alternative pathway in serum and on endothelial cell surfaces.• Heme-induced complement activation in the presence of complement mutations contributes as a secondary hit to the development of aHUS.Atypical hemolytic uremic syndrome (aHUS) is characterized by genetic and acquired abnormalities of the complement system leading to alternative pathway (AP) overactivation and by glomerular endothelial damage, thrombosis, and mechanical hemolysis. Mutations per se are not sufficient to induce aHUS, and nonspecific primary triggers are required for disease manifestation. We investigated whether hemolysis-derived heme contributes to aHUS pathogenesis. We confirmed that heme activates complement AP in normal human serum, releasing C3a, C5a, and sC5b9. We demonstrated that hemeexposed endothelial cells also activate the AP, resulting in cell-bound C3 and C5b9. This was exacerbated in aHUS by genetic abnormalities associated with AP overactivation. Heme interacted with C3 close to the thioester bond, induced homophilic C3 complexes, and promoted formation of an overactive C3/C5 convertase. Heme induced decreased membrane cofactor protein (MCP) and decay-accelerating factor (DAF) expression on endothelial cells, giving Factor H (FH) a major role in complement regulation. Finally, heme promoted a rapid exocytosis of Weibel-Palade bodies, with membrane expression of P-selectin known to bind C3b and trigger the AP, and the release of the prothrombotic von Willebrand factor. These results strongly suggest that hemolysis-derived heme represents a common secondary hit amplifying endothelial damage and thrombosis in aHUS. (Blood. 2013;122(2):282-292) IntroductionAtypical hemolytic uremic syndrome (aHUS) is a rare kidneypredominant thrombotic microangiopathy (TMA) associated with formation of fibrin-platelet clots in the glomerular microvasculature leading to mechanical hemolysis. 1 This disease is related to a dysregulation of the complement alternative pathway (AP), as shown by the identification of genetic or acquired abnormalities in AP regulators or activators in more than 60% of patients. 2 aHUS has an incomplete penetrance among mutation carriers, and a triggering event is presumably required for the disease manifestation. This primary hit can be an infection, pregnancy, drug, or other cell-activating event. Sera from aHUS patients carrying mutations deposit complement on endothelial cells activated by inflammatory cytokines, 3 suggesting continuous aggression on the endothelium. However, not all infections trigger aHUS in patients. It is frequently the second pregnancy postpartum period that is associated with the disease.4 Therefore, other factors appear to be necessary to exceed the threshold of tolerable endothelial stress leading to severe TMA lesions.In acute phase TMA, mechanical hemolysis induces the release of hemoglobin into the bloodstream. 5 This hemoglobin is readily oxidized to ferric hemoglobin (methemoglobin) which, in turn, liberates heme. In physiological conditions...

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Section: Discussionmentioning

confidence: 99%

Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

Frimat

Tabarin

Dimitrov

et al. 2013

Blood

217

248

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“…It is widely held that chloroquine mainly exerts its parasiticidal effects by binding to heme moieties released in the food vacuole by hemoglobin digestion, thus preventing sequestration of the heme in inert hemozoin crystals and producing toxic levels of free heme or chloroquine-heme complexes (5,23,38). The latter molecules are thought to be lipophilic and have detergent-like qualities which could cause significant vacuole membrane damage (14). Conceivably, such an alteration in the physical characteristics of the lipid bilayer of the vacuole or the fusion machinery associated with it could significantly inhibit the ability of this compartment to fuse with incoming endocytic transport vesicles.…”

Section: Discussionmentioning

confidence: 99%

“…Chloroquine interferes with the crystallization of the free heme monomers released during hemoglobin proteolysis by binding to them, causing a buildup of toxic heme and chloroquine-heme complexes (5,7,23) that can potentially inhibit key enzymes as well as bind to the membrane and compromise membrane integrity (14,36). Less certainty exists about the action of mefloquine, but studies suggest that it also has the ability to interfere with hemozoin formation, resulting in free heme accumulation (44).…”

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confidence: 99%

Antimalarial Quinolines and Artemisinin Inhibit Endocytosis in Plasmodium falciparum

Hoppe

Schalkwyk²,

Wiehart³

et al. 2004

Antimicrob Agents Chemother

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Endocytosis is a fundamental process of eukaryotic cells and fulfills numerous functions, most notably, that of macromolecular nutrient uptake. Malaria parasites invade red blood cells and during their intracellular development endocytose large amounts of host cytoplasm for digestion in a specialized lysosomal compartment, the food vacuole. In the present study we have examined the effects of artemisinin and the quinoline drugs chloroquine and mefloquine on endocytosis in Plasmodium falciparum. By using novel assays we found that mefloquine and artemisinin inhibit endocytosis of macromolecular tracers by up to 85%, while the latter drug also leads to an accumulation of undigested hemoglobin in the parasite. During 5-h incubations, chloroquine inhibited hemoglobin digestion but had no other significant effect on the endocytic pathway of the parasite, as assessed by electron microscopy, the immunofluorescence localization of hemoglobin, and the distribution of fluorescent and biotinylated dextran tracers. By contrast, when chloroquine was added to late ring stage parasites, followed by a 12-h incubation, macromolecule endocytosis was inhibited by more than 40%. Moreover, there is an accumulation of transport vesicles in the parasite cytosol, possibly due to a disruption in vacuole-vesicle fusion. This fusion block is not observed with mefloquine, artemisinin, quinine, or primaquine but is mimicked by the vacuole alkalinizing agents ammonium chloride and monensin. These results are discussed in the light of present theories regarding the mechanisms of action of the antimalarials and highlight the potential use of drugs in manipulating and studying the endocytic pathway of malaria parasites.

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“…It has been shown previously that chloroquine enhances the association of haem with phospholipid monolayers [38] and promotes haem-catalysed lipid peroxidation [39]. We have therefore examined the ability of chloroquine and other drugs to affect the level of binding of haem to lipid bilayers, using the erythrocyte membrane as a convenient model system.…”

Section: Antimalarial Drugs Inhibit the Peroxidative Decomposition Ofmentioning

confidence: 99%

Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials

Loria

Miller

Foley

et al. 1999

Biochemical Journal

192

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The malaria parasite feeds by degrading haemoglobin in an acidic food vacuole, producing free haem moieties as a by-product. The haem in oxyhaemoglobin is oxidized from the Fe(II) state to the Fe(III) state with the consequent production of an equimolar concentration of H2O2. We have analysed the fate of haem molecules in Plasmodium falciparum-infected erythrocytes and have found that only about one third of the haem is polymerized to form haemozoin. The remainder appears to be degraded by a non-enzymic process which leads to an accumulation of iron in the parasite. A possible route for degradation of the haem is by reacting with H2O2, and we show that, under conditions designed to resemble those found in the food vacuole, i.e., at pH 5.2 in the presence of protein, free haem undergoes rapid peroxidative decomposition. Chloroquine and quinacrine are shown to be efficient inhibitors of the peroxidative destruction of haem, while epiquinine, a quinoline compound with very low antimalarial activity, has little inhibitory effect. We also show that chloroquine enhances the association of haem with membranes, while epiquinine inhibits this association, and that treatment of parasitized erythrocytes with chloroquine leads to a build-up of membrane-associated haem in the parasite. We suggest that chloroquine exerts its antimalarial activity by causing a build-up of toxic membrane-associated haem molecules that eventually destroy the integrity of the malaria parasite. We have further shown that resistance-modulating compounds, such as chlorpromazine, interact with haem and efficiently inhibit its degradation. This may explain the weak antimalarial activities of these compounds.

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Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

Cited by 42 publications

References 36 publications

Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

Antimalarial Quinolines and Artemisinin Inhibit Endocytosis in Plasmodium falciparum

Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials

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