斑马鱼模型在药物研发早期肾脏毒性中的应用研究

摘要

Objective To evaluate the renal toxicity of vancomycin hydrochloride and irbesartan tablets using the zebrafish model. Methods After construction of AB zebrafish kidney model, the fish were treated with drug after fertilization 2 days (2 dpf) to 5 dpf. At the end of the experiment, the number of renal edema zebrafish was counted in each experimental group to evaluate the renal toxicity of drugs. Results The zebrafish development was normal and no obvious toxicity at the dose of 16�4 ng/fish (1/10 MNLD) for vancomycin, and zebrafish renal edema occurred rate was 3�3%, 10% and 10% respectively at the dose of 54�7 ng/fish (1/3 MNLD), 164 ng/fish (MNLD) and 273 ng/fish ( LD10 ) with the death rate of 0%, 0% and 16�7%, respectively, which indicated that there was significant renal toxicity of vancomycin at the dose of 54�7 ng/fish (1/3MNLD) to 273 ng/fish (LD10). Irbesartan didn’t induce renal toxicity at the dose of 8�3 μg/mL (1/10 MNLC) to 91 μg/mL (LC10). Conclusions The zebrafish model of renal toxicity can be used for the early evaluation of drug renal toxicity and we made evaluation of the renal toxicity of vancomycin and irbesartan with this model.%目的：利用斑马鱼模型评价注射用盐酸万古霉素和厄贝沙坦片的肾毒性。方法构建AB系斑马鱼肾脏模型，药物处理受精后2 d（2 dpf）的斑马鱼至5 dpf，统计各实验组斑马鱼肾性水肿发生率，判断药物是否具有肾毒性。结果万古霉素在注射剂量为16�4 ng／尾（1／10 MNLD）时，斑马鱼发育正常，未见明显的毒性；在注射剂量为54�7 ng／尾（1／3 MNLD）、164 ng／尾（MNLD）和273 ng／尾（LD10）时，斑马鱼肾性水肿发生率分别为3�3％、10％和10％，死亡率分别为0％、0％和16�7％，表明万古霉素在注射剂量54�7 ng／尾（1／3 MNLD）至273 ng／尾（LD10）的范围内，有明显的肾毒性。厄贝沙坦在浓度为8�3μg／mL（1／10 MNLC）至91μg／mL（LC10）范围内，斑马鱼肾脏均发育正常，未见肾毒性。结论斑马鱼肾毒性模型的建立，可用于药物肾毒性的早期评价，并且精确评价了万古霉素和厄贝沙坦的肾脏毒性。