Universidad de Alcalá, Departamento de Química Analítica, Química Física e Ingeniería Química, Ctra. Madrid-Barcelona Km. 33.600, 28871 Alcalá de Henares, Madrid, Spain; Department of Biological and Chemical Engineering-Plastic and Plastic Engineering, Aarhus University, Aabogade 40, DK-8200 Aarhus N, Denmark.
Universidad de Alcalá, Departamento de Química Analítica, Química Física e Ingeniería Química, Ctra. Madrid-Barcelona Km. 33.600, 28871 Alcalá de Henares, Madrid, Spain.
Sci Total Environ. 2022 Sep 10;838(Pt 4):156617. doi: 10.1016/j.scitotenv.2022.156617. Epub 2022 Jun 9.
Ivabradine (S-ivabradine) is a contemporary antihypertensive drug designed and commercialized for cardiovascular diseases treatment over the world. In this work the enantiomer-specific stability and acute toxicity of ivabradine to the marine bacterium Vibrio fischeri as well as the potential mechanism of action were investigated for the first time. With this aim, real concentrations of ivabradine enantiomers under abiotic and biotic conditions were determined by Capillary Electrophoresis (CE) with cyclodextrins (CDs) as chiral selectors. A moderate chiral stability without enantiomeric interconversion was observed for ivabradine. The bioluminescence inhibition method revealed an enantioselective toxicity of ivabradine to marine bacterium. The order of ecotoxicity was R-ivabradine < racemic ivabradine < S-ivabradine with EC50 (t = 5 min) values about 75.98, 11.11 and 7.93 mg/L, respectively. Confocal Live/Dead stained images showed that bacterial envelops cells were seriously damaged after exposure to S-ivabradine. S-ivabradine also disturbed the esterase activity and significantly increased the ROS level compared with the control. Thus, oxidative stress originating membrane cells damage and enzymatic activity changes was shown to be the primary mechanism of S-ivabradine toxicity to marine bacterium. Our results highlight the need for more eco-toxicological evaluations of the cardiovascular drug S-ivabradine on other aquatic organisms to establish the risk on the environment.
依伐布雷定（S-依伐布雷定）是一种新型降压药，专为治疗心血管疾病而设计并在全球范围内商业化。本工作首次研究了依伐布雷定对海洋细菌发光菌的对映体选择性稳定性和急性毒性及其潜在作用机制。为此，采用环糊精（CDs）作为手性选择剂的毛细管电泳（CE），测定了非生物和生物条件下依伐布雷定对映体的真实浓度。结果表明，依伐布雷定具有中等的对映体稳定性，没有对映体相互转化。生物发光抑制法显示依伐布雷定对海洋细菌具有对映体选择性毒性。依伐布雷定的生态毒性顺序为 R-依伐布雷定<外消旋依伐布雷定<S-依伐布雷定，EC50（t=5 min）值分别约为 75.98、11.11 和 7.93mg/L。共聚焦活/死染色图像显示，与对照组相比，S-依伐布雷定暴露后细菌包膜细胞严重受损。S-依伐布雷定还干扰了酯酶活性，并显著增加了 ROS 水平。因此，起源于细胞膜损伤和酶活性变化的氧化应激被认为是 S-依伐布雷定对海洋细菌毒性的主要机制。我们的研究结果强调了需要对心血管药物 S-依伐布雷定对其他水生生物进行更多的生态毒理学评价，以确定其对环境的风险。
