Effect of antifungal azoles on the heme detoxification system of malarial parasite.
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 heme-polymerization 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.
Huy
Nguyen Tien
NT
Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
Kamei
Kaeko
K
Kondo
Yoshiro
Y
Serada
Satoshi
S
Kanaori
Kenji
K
Takano
Ryo
R
Tajima
Kunihiko
K
Hara
Saburo
S
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology; D003022:Clotrimazole / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006418:Heme / Q000737:chemistry / Q000378:metabolism*; D006461:Hemolysis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D008825:Miconazole / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects*; D013057:Spectrum Analysis
D000935:Antifungal Agents; D000962:Antimalarials; D010455:Peptides; D006418:Heme; D008825:Miconazole; D003022:Clotrimazole; D005978:Glutathione; D007654:Ketoconazole