title: Micromolar Zn(2+) potentiates the cytotoxic action of submicromolar econazole in rat thymocytes: possible disturbance of intracellular Ca(2+) and Zn(2+) homeostasis.
abstract: Econazole, one of imidazole antifungals, has been reported to exhibit an inhibitory action on Mycobacterium tuberculosis and its multidrug-resistant strains under in vitro and ex vivo conditions. There is a chemotherapeutic potential of econazole against tuberculosis. We have revealed that Zn(2+) at micromolar concentrations potentiates the cytotoxicity of imidazole antifungals by increasing membrane Zn(2+) permeability. It is reminiscent of a possibility that econazole exhibits harmful action on human in the presence of Zn(2+) at a physiological range when the agent is systemically administered. Because it is necessary to characterize the cytotoxic action of econazole in the presence of Zn(2+), we have cytometrically examined the effects of econazole, ZnCl(2), and their combination on rat thymocytes. ZnCl(2) at concentrations ranging from 1 microM to 30 microM significantly increased the lethality induced by 10 microM econazole in a concentration-dependent manner. Econazole at a sublethal concentration of 1 microM significantly augmented the intensity of side scatter in the presence of micromolar ZnCl(2), suggesting the change in an intracellular circumstance by the combination of econazole and ZnCl(2). Econazole at 0.3 microM or more in the presence of ZnCl(2) increased the intensity of Fluo-3 fluorescence, an indicator for intracellular Ca(2+). Furthermore, the intensity of FluoZin-3 fluorescence, an indicator for intracellular Zn(2+), was also augmented by econazole at 0.1 microM or more in the presence of ZnCl(2). Results suggest that the combination of submicromolar econazole with micromolar ZnCl(2) may increase the intracellular concentration of Ca(2+) and Zn(2+), leading to disturbance of intracellular Ca(2+) and Zn(2+) homeostasis that triggers cytotoxic action.
authors.affiliation: Department of Pharmaceutical Care and Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Kinazaki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Sakanashi
authors.forename: Tomohiro M
authors.initials: TM
authors.lastname: Oyama
authors.forename: Haruka
authors.initials: H
authors.lastname: Shibagaki
authors.forename: Kohei
authors.initials: K
authors.lastname: Yamashita
authors.forename: Erika
authors.initials: E
authors.lastname: Hashimoto
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Shiro
authors.initials: S
authors.lastname: Ishida
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Okano
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Oyama
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004464:Econazole / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D008051:Lipid Bilayers / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D008051:Lipid Bilayers; D004464:Econazole; D015032:Zinc; D002118:Calcium