title: Zinc-related actions of sublethal levels of benzalkonium chloride: Potentiation of benzalkonium cytotoxicity by zinc.
abstract: Benzalkonium chloride (BZK) is a common preservative used in pharmaceutical and personal care products. ZnCl2was recently reported to significantly potentiate the cytotoxicity of some biocidal compounds. In the present study, therefore, we compared the cytotoxic potency of BZK and then further studied the Zn2+-related actions of the most cytotoxic agent among BZK, using flow cytometric techniques with appropriate fluorescent probes in rat thymocytes. Cytotoxicity of benzylcetyldimethylammonium (BZK-C16) was more potent that those of benzyldodecyldimethylammonium and benzyldimethyltetradecylammonium. ZnCl2(1-10 μM) significantly potentiated the cytotoxicity of BZK-C16 at a sublethal concentration (1 μM). The co-treatment of cells with 3 μM ZnCl2and 1 μM BZK-C16 increased the population of both living cells with phosphatidylserine exposed on membrane surfaces and dead cells. BZK-C16 at 0.3-1.0 μM elevated intracellular Zn2+levels by increasing Zn2+influx, and augmented the cytotoxicity of 100 μM H2O2. Zn2+is concluded to facilitate the toxicity of BZK. We suggest that the toxicity of BZK is determined after taking extracellular (plasma) and/or environmental Zn2+levels into account.
authors.affiliation: Faculty of Integrated Arts and Sciences, Tokushima University, Tokushima 770-8502, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Mitani
authors.affiliation: Graduate School of Integrated Arts and Sciences, Tokushima University, Tokushima 770-8502, Japan.
authors.forename: Ahmed Ibrahim Elhossany
authors.initials: AI
authors.lastname: Elmarhomy
authors.affiliation: Graduate School of Integrated Arts and Sciences, Tokushima University, Tokushima 770-8502, Japan.
authors.forename: Luvsandorj
authors.initials: L
authors.lastname: Dulamjav
authors.affiliation: Graduate School of Integrated Arts and Sciences, Tokushima University, Tokushima 770-8502, Japan.
authors.forename: Enkhtumur
authors.initials: E
authors.lastname: Anu
authors.affiliation: Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Saitoh
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8512, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ishida
authors.affiliation: Graduate School of Integrated Arts and Sciences, Tokushima University, Tokushima 770-8502, Japan; Faculty of Bioscience and Bioindustry, Tokushima University, Tokushima 770-8513, Japan. Electronic address: oyamay@tokushima-u.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Oyama
mesh_terms: D000818:Animals; D001548:Benzalkonium Compounds / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002712:Chlorides / Q000633:toxicity*; D004347:Drug Interactions; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010718:Phosphatidylserines / Q000378:metabolism; D011310:Preservatives, Pharmaceutical / Q000633:toxicity*; D051381:Rats; D060168:Thymocytes / Q000166:cytology / Q000187:drug effects; D017967:Zinc Compounds / Q000633:toxicity*
chemical_list: D001548:Benzalkonium Compounds; D002712:Chlorides; D010718:Phosphatidylserines; D011310:Preservatives, Pharmaceutical; D017967:Zinc Compounds; C000617644:benzylcetyldimethylammonium; C005883:zephiramine; C016837:zinc chloride; D005978:Glutathione; C015163:dimethyldodecylbenzylammonium
keywords: Benzalkonium chloride; Cytotoxicity; Lymphocytes; Zinc