Effect of Antifungal Azoles on the Heme Detoxification System of Malarial Parasite.
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概要
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The antimalarial activities of some antifungal azole agents (ketoconazole, miconazole, and clotrimazole) have been known for several years, however, their antimalarial mechanism remains equivocal. Our recent study showed that clotrimazole has a relative high affinity for heme, inhibits reduced glutathione-dependent heme catabolism, and enhances heme-induced hemolysis. In the present study, we have found that clotrimazole can remove heme from histidine rich peptide-heme complex, which initiates hemepolymerization in malaria. In addition, we show that two other azoles (ketoconazole and miconazole) behave similarly to clotrimazole in binding to heme: they bind to heme with similar affinities, remove heme from the histidine rich peptide-heme complex and from the reduced glutathione-heme complex to form stable heme-azole complexes with two nitrogenous ligands derived from the imidazole moieties of two azole molecules. We have also revealed that clotrimazole and miconazole have stronger promoting activities for heme-induced hemolysis than ketoconazole, implying that the stronger antimalarial activities of clotrimazole and miconazole might arise from their stronger ability to promote heme-induced hemolysis of clotrimazole and clotrimazole than that of ketoconazole. These results also suggest that ketoconazole and miconazole, like clotrimazole, might possess an antimalarial mechanism relating to their inhibition of heme polymerization and the degradation of reduced glutathione-dependent heme.
- 社団法人 日本生化学会の論文
著者
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Huy Nguyen
Department Of Applied Biology Kyoto Institute Of Technology:department Of Immunogenetics Institute O
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Takano Ryo
Department Of Applied Biology Kyoto Institute Of Technology
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SERADA Satoshi
Department of Applied Biology, Kyoto Institute of Technology
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KONDO Yoshiro
Department of Applied Biology, Kyoto Institute of Technology
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Kanaori Kenji
Department Of Applied Biology Kyoto Institute Of Technology
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Tajima Kunihiko
Department Of Applied Biology Kyoto Institute Of Technology
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Hara Saburo
Department Of Applied Biology Kyoto Institute Of Technology
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Kamei Kaeko
Department of Applied Biology, Kyoto Institute of Technology
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Kamei Kaeko
Department fo Chemistry and Materials Technology, Faculty of Engineering and Design, Kyoto Institute of Technology
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Huy Nguyen
Department of Applied Biology, Kyoto Institute of Technology
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