Insights into the Role of Heme in the Mechanism of Action of Antimalarials
By using cell fractionation and measurement of Fe(III)heme-pyridine, the antimalarial chloroquine (CQ) has been shown to cause a dose-dependent decrease in hemozoin and concomitant increase in toxic free heme in cultured Plasmodium falciparum that is directly correlated with parasite survival. Tra...
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| Published in: | ACS chemical biology Vol. 8; no. 1; pp. 133 - 137 |
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| Main Authors: | , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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American Chemical Society
18-01-2013
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| Abstract | By using cell fractionation and measurement of Fe(III)heme-pyridine, the antimalarial chloroquine (CQ) has been shown to cause a dose-dependent decrease in hemozoin and concomitant increase in toxic free heme in cultured Plasmodium falciparum that is directly correlated with parasite survival. Transmission electron microscopy techniques have further shown that heme is redistributed from the parasite digestive vacuole to the cytoplasm and that CQ disrupts hemozoin crystal growth, resulting in mosaic boundaries in the crystals formed in the parasite. Extension of the cell fractionation study to other drugs has shown that artesunate, amodiaquine, lumefantrine, mefloquine, and quinine, all clinically important antimalarials, also inhibit hemozoin formation in the parasite cell, while the antifolate pyrimethamine and its combination with sulfadoxine do not. This study finally provides direct evidence in support of the hemozoin inhibition hypothesis for the mechanism of action of CQ and shows that other quinoline and related antimalarials inhibit cellular hemozoin formation. |
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| AbstractList | Using cell fractionation and measurement of Fe(III)heme-pyridine, the antimalarial chloroquine (CQ) has been shown to cause a dose-dependent decrease in hemozoin and concomitant increase in toxic “free” heme in cultured
Plasmodium falciparum
that is directly correlated with parasite survival. Transmission electron microscopy techniques have further shown that heme is redistributed from the parasite digestive vacuole to the cytoplasm and that CQ disrupts hemozoin crystal growth, resulting in mosaic boundaries in the crystals formed in the parasite. Extension of the cell fractionation study to other drugs has shown that artesunate, amodiaquine, lumefantrine, mefloquine and quinine, all clinically important antimalarials, also inhibit hemozoin formation in the parasite cell, while the antifolate pyrimethamine and its combination with sulfadoxine do not. This study finally provides direct evidence in support of the hemozoin inhibition hypothesis for the mechanism of action of CQ and shows that other quinoline and related antimalarials inhibit cellular hemozoin formation. By using cell fractionation and measurement of Fe(III)heme-pyridine, the antimalarial chloroquine (CQ) has been shown to cause a dose-dependent decrease in hemozoin and concomitant increase in toxic free heme in cultured Plasmodium falciparum that is directly correlated with parasite survival. Transmission electron microscopy techniques have further shown that heme is redistributed from the parasite digestive vacuole to the cytoplasm and that CQ disrupts hemozoin crystal growth, resulting in mosaic boundaries in the crystals formed in the parasite. Extension of the cell fractionation study to other drugs has shown that artesunate, amodiaquine, lumefantrine, mefloquine, and quinine, all clinically important antimalarials, also inhibit hemozoin formation in the parasite cell, while the antifolate pyrimethamine and its combination with sulfadoxine do not. This study finally provides direct evidence in support of the hemozoin inhibition hypothesis for the mechanism of action of CQ and shows that other quinoline and related antimalarials inhibit cellular hemozoin formation. By using cell fractionation and measurement of Fe(III)heme-pyridine, the antimalarial chloroquine (CQ) has been shown to cause a dose-dependent decrease in hemozoin and concomitant increase in toxic free heme in cultured Plasmodium falciparum that is directly correlated with parasite survival. Transmission electron microscopy techniques have further shown that heme is redistributed from the parasite digestive vacuole to the cytoplasm and that CQ disrupts hemozoin crystal growth, resulting in mosaic boundaries in the crystals formed in the parasite. Extension of the cell fractionation study to other drugs has shown that artesunate, amodiaquine, lumefantrine, mefloquine, and quinine, all clinically important antimalarials, also inhibit hemozoin formation in the parasite cell, while the antifolate pyrimethamine and its combination with sulfadoxine do not. This study finally provides direct evidence in support of the hemozoin inhibition hypothesis for the mechanism of action of CQ and shows that other quinoline and related antimalarials inhibit cellular hemozoin formation. |
| Author | Combrinck, Jill M Smith, Peter J Ncokazi, Kanyile K Taylor, Dale Ambele, Melvin A Hoppe, Heinrich C Egan, Timothy J Mabotha, Tebogo E |
| AuthorAffiliation | Department of Chemistry University of Cape Town Division of Pharmacology, Department of Medicine |
| AuthorAffiliation_xml | – name: – name: Department of Chemistry – name: Division of Pharmacology, Department of Medicine – name: University of Cape Town – name: 2 Division of Pharmacology, Department of Medicine, University of Cape Town, Private Bag, Rondebosch 7701 – name: 1 Department of Chemistry and University of Cape Town, Private Bag, Rondebosch 7701 |
| Author_xml | – sequence: 1 givenname: Jill M surname: Combrinck fullname: Combrinck, Jill M – sequence: 2 givenname: Tebogo E surname: Mabotha fullname: Mabotha, Tebogo E – sequence: 3 givenname: Kanyile K surname: Ncokazi fullname: Ncokazi, Kanyile K – sequence: 4 givenname: Melvin A surname: Ambele fullname: Ambele, Melvin A – sequence: 5 givenname: Dale surname: Taylor fullname: Taylor, Dale – sequence: 6 givenname: Peter J surname: Smith fullname: Smith, Peter J – sequence: 7 givenname: Heinrich C surname: Hoppe fullname: Hoppe, Heinrich C – sequence: 8 givenname: Timothy J surname: Egan fullname: Egan, Timothy J email: Timothy.Egan@uct.ac.za |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23043646$$D View this record in MEDLINE/PubMed |
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| Snippet | By using cell fractionation and measurement of Fe(III)heme-pyridine, the antimalarial chloroquine (CQ) has been shown to cause a dose-dependent decrease in... By using cell fractionation and measurement of Fe(III)heme-pyridine, the antimalarial chloroquine (CQ) has been shown to cause a dose-dependent decrease in... Using cell fractionation and measurement of Fe(III)heme-pyridine, the antimalarial chloroquine (CQ) has been shown to cause a dose-dependent decrease in... |
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| SubjectTerms | Antimalarials - pharmacology Chloroquine - pharmacology Dose-Response Relationship, Drug Heme - physiology Microscopy, Electron, Transmission Plasmodium falciparum - drug effects Trophozoites - drug effects |
| Title | Insights into the Role of Heme in the Mechanism of Action of Antimalarials |
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