title: Imidazole antifungals, but not triazole antifungals, increase membrane Zn2+ permeability in rat thymocytes Possible contribution to their cytotoxicity.
abstract: The use of zinc as a nutritional supplement has become common in many countries. Since zinc has diverse actions, it may be difficult to predict its synergistic and/or antagonistic action in simultaneous presence of drug(s). The combination of imidazole antifungals, but not triazole antifungals, with 3-30 microM ZnCl2 significantly increased the lethality of rat thymocytes. Since intracellular Zn2+ exerts various actions on the process of cell death, there is a possibility that imidazole antifungals, but not triazole antifungals, increases concentration of intracellular Zn2+ ([Zn2+]i). To test the possibility, we examined the effects of imidazole and triazole antifungals on [Zn2+]i of rat thymocytes in absence and presence of extracellular Zn2+ by the use of FluoZin-3, a fluorescent Zn2+ indicator. Imidazole antifungals (clotrimazole, econazole, and oxiconazole) increased the [Zn2+]i in the presence of extracellular Zn2+ while it was not the case for triazole antifungals (itraconazole and fluoconazole). Thus, it is suggested that imidazole antifungals increase the membrane permeability of Zn2+. The potency order in the augmentation of FluoZin-3 fluorescence by imidazole antifungals in the presence of extracellular Zn2+ was the same as that in their cytotoxic action. Therefore, the cytotoxic action of imidazole antifungals may be related to their action on membrane Zn2+ permeability.
authors.affiliation: Laboratory of Cellular Signaling, Faculty of Integrated Arts and Sciences, The University of Tokushima, Tokushima 770-8502, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Matsui
authors.forename: Yoko
authors.initials: Y
authors.lastname: Sakanashi
authors.forename: Tomohiro M
authors.initials: TM
authors.lastname: Oyama
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Oyama
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Yokota
authors.forename: Shiro
authors.initials: S
authors.lastname: Ishida
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Okano
authors.forename: Toshihisa B
authors.initials: TB
authors.lastname: Oyama
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D003022:Clotrimazole / Q000737:chemistry / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D015725:Fluconazole / Q000737:chemistry / Q000633:toxicity; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017964:Itraconazole / Q000737:chemistry / Q000633:toxicity; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D017967:Zinc Compounds / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D002712:Chlorides; D007093:Imidazoles; D014230:Triazoles; D017967:Zinc Compounds; D017964:Itraconazole; C016837:zinc chloride; D015725:Fluconazole; C022155:oxiconazole; D003022:Clotrimazole