Ferriprotoporphyrin IX Fulfills the Criteria for Identification as the Chloroquine Receptor of Malaria Parasites.

Chou, Albert C.; Chevli, Rekha; Fitch, Coy D.

doi:10.1021/bi00549a600

Cited by 363 publications

(196 citation statements)

References 24 publications

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“…2 Glaser et al are to be commended for their systematic study, but does it improve our understanding of the pathophysiology of cerebral edema or provide new guidelines for therapy? The authors note that cerebral edema was associated with higher serum urea nitrogen concentrations and lower partial pressures of arterial carbon dioxide at the time of diagnosis; they argue that this finding supports the hypothesis, first proposed by Dillon et al, 6 that cerebral edema is the result of reduced blood volume, aggravated by a reduced partial pressure of arterial carbon dioxide and leading to cerebral vasoconstriction, cerebral ischemia, and hypoxia. The reduced partial pressure of arterial carbon dioxide at presentation in children with cerebral edema may imply an increased respiratory drive in response to acidosis.…”

Section: Predicting Cerebral Edema During Diabetic Ketoacidosissupporting

confidence: 63%

“…Ferriprotoporphyrin IX, which is detached from globin during digestion, is normally detoxified in the parasite's lysosome. The weak base chloroquine accumulates in the acidic lysosome 5 and binds to ferriprotoporphyrin IX, 6 thereby preventing its detoxification and thus destroying the parasite (Fig. 1).…”

Section: A M Olecular M Arker For C Hloroquine -R Esistant F Alciparumentioning

confidence: 99%

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A Molecular Marker for Chloroquine-Resistant Falciparum Malaria

Warhurst¹

2001

N Engl J Med

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areas raises the specter of delayed oncogenesis in neighboring soft tissue and has been implicated in the constriction of vessels at the margins of irradiated stents -the so-called "candy wrapper" or "edge" effect. These issues must be resolved with carefully crafted clinical trials, the results of which could justify the evidence-based expansion of indications for a promising therapy for coronary and other vascular disease. Nevertheless, at this time, brachytherapy appears to provide a valuable addition to the armamentarium of the interventional cardiologist.

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Section: Predicting Cerebral Edema During Diabetic Ketoacidosissupporting

confidence: 63%

Section: A M Olecular M Arker For C Hloroquine -R Esistant F Alciparumentioning

confidence: 99%

A Molecular Marker for Chloroquine-Resistant Falciparum Malaria

Warhurst¹

2001

N Engl J Med

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“…The 9-aminoacridine, quinacrine, was an effective inhibitor suggesting that this drug acts via a similar mechanism of action to chloroquine. This drug has previously been shown to interact with haem [35] and to act as an efficient inhibitor of haem polymerization [22]. The quinolinemethanol antimalarial drug, mefloquine, also showed some inhibition of the destruction of haem, but was less effective than chloroquine ( Figure 1B).…”

Section: Antimalarial Drugs Inhibit the Peroxidative Decomposition Ofmentioning

confidence: 91%

“…Chloroquine forms a complex with haem with a 1 : 2 stoichiometry [33,34] (Scheme 1B, reaction d) and an estimated affinity ranging from 10 −' M to 10 −* M depending on the conditions of analysis [33,35]. The interaction of chloroquine with haem has previously been shown to inhibit haem polymerization [4][5][6].…”

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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“…Fresh GSH stock solution (200 mM) was prepared in isotonic standard buffer (50 mM sodium phosphate containing 68 mM NaCl, 4.8 mM KCl, and 1.2 mM MgSO 4 , pH 7.4) (24,25). Heme (final concentration, 3 M) and GSH (final concentration, 2 mM) were mixed in isotonic standard buffer (pH 7.4) and incubated at 37°C.…”

Section: Gsh-dependent Heme Degradation and Its Inhibition By Clt Ormentioning

confidence: 99%

Clotrimazole Binds to Heme and Enhances Heme-dependent Hemolysis

Huy

Kamei

Yamamoto

et al. 2002

Journal of Biological Chemistry

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Two recent studies have demonstrated that clotrimazole, a potent antifungal agent, inhibits the growth of chloroquine-resistant strains of the malaria parasite, Plasmodium falciparum, in vitro. We explored the mechanism of antimalarial activity of clotrimazole in relation to hemoglobin catabolism in the malaria parasite. Because free heme produced from hemoglobin catabolism is highly toxic to the malaria parasite, the parasite protects itself by polymerizing heme into insoluble nontoxic hemozoin or by decomposing heme coupled to reduced glutathione. We have shown that clotrimazole has a high binding affinity for heme in aqueous 40% dimethyl sulfoxide solution (association equilibrium constant: K a ‫؍‬ 6.54 ؋ 10 8 M ؊2 ). Even in water, clotrimazole formed a stable and soluble complex with heme and suppressed its aggregation. The results of optical absorption spectroscopy and electron spin resonance spectroscopy revealed that the heme-clotrimazole complex assumes a ferric low spin state (S ‫؍‬ 1 ⁄2), having two nitrogenous ligands derived from the imidazole moieties of two clotrimazole molecules. Furthermore, we found that the formation of heme-clotrimazole complexes protects heme from degradation by reduced glutathione, and the complex damages the cell membrane more than free heme. The results described herein indicate that the antimalarial activity of clotrimazole might be due to a disturbance of hemoglobin catabolism in the malaria parasite.

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Ferriprotoporphyrin IX Fulfills the Criteria for Identification as the Chloroquine Receptor of Malaria Parasites.

Cited by 363 publications

References 24 publications

A Molecular Marker for Chloroquine-Resistant Falciparum Malaria

A Molecular Marker for Chloroquine-Resistant Falciparum Malaria

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

Clotrimazole Binds to Heme and Enhances Heme-dependent Hemolysis

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