Imidazole antifungals, but not triazole antifungals, increase membrane Zn2+ permeability in rat thymocytes Possible contribution to their cytotoxicity

• Published in: Toxicology (Amsterdam) 2008-06, Vol.248 (2-3), p.142-150
• Main Authors: MATSUI, Hiroko, SAKANASHI, Yoko, OYAMA, Tomohiro M, OYAMA, Yasuo, YOKOTA, Shin-Ichi, ISHIDA, Shiro, OKANO, Yoshiro, OYAMA, Toshihisa B, NISHIMURA, Yumiko
• Format: Article
• Language: English
• Subjects: Animals; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Biological and medical sciences; Cell Membrane Permeability - drug effects; Cell Survival - drug effects; Cells, Cultured; Chlorides - metabolism; Clotrimazole - chemistry; Clotrimazole - toxicity; Dose-Response Relationship, Drug; Fluconazole - chemistry; Fluconazole - toxicity; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazoles - toxicity; Itraconazole - chemistry; Itraconazole - toxicity; Male; Medical sciences; Rats; Rats, Wistar; Structure-Activity Relationship; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Thymus Gland - drug effects; Thymus Gland - metabolism; Thymus Gland - pathology; Toxicology; Triazoles - chemistry; Triazoles - pharmacology; Zinc Compounds - metabolism
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2008.03.022

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.