Cheng Weina, Feng Wenzhong, Tian Guanghuan, Liu Jingxian, Bai Zhixun, Yu Ming, Yan Rong, Liu Liu, He Yanmei, Li Xiaofei, Zhang Jianyong
School of Pharmacy, Zunyi Medical University, Zunyi, China.
School of Basic Medical Sciences, Zunyi Medical University, Zunyi, China.
J Appl Toxicol. 2025 May;45(5):736-754. doi: 10.1002/jat.4743. Epub 2024 Dec 15.
The clinical application of cantharidin (CTD) is seriously limited due to its nephrotoxicity. Therefore, this study aims to investigate sensitive biomarkers for the evaluation and prediction of nephrotoxicity induced by CTD in rat. A total of 80 rats were randomly divided into four groups: control group and three doses of CTD groups. After 0, 1, 5, 15, and 28 days of intragastric administration, rat serum and urine were collected for biochemical indexes, then serum was used for metabolomic analyses, and rat kidney was collected for pathological and ultrastructural observation. The levels of serum crea (Scr), blood urea nitrogen (BUN), urea, urine crea (Ucrea), and urinary microalbumin (UmALB) were significantly increased after administration of different doses of CTD (p < 0.05). Additionally, histopathology and cell ultrastructure observation of kidney showed significant cell inflammatory infiltration and glomerular edema. Seven metabolic biomarkers including 6-hydroxymelatonin were significantly disturbed by CTD. The CatBoost Classifier prediction model was used to establish the CTD nephrotoxicity prediction model, and the prediction accuracy and precision were 0.645 and 0.640, respectively. Moreover, 6-hydroxymelatonin was found to be most useful biomarkers for evaluating the CTD nephrotoxicity. Finally, the seven metabolic biomarkers were found mainly involved in pyruvate metabolism, pantothenate and CoA biosynthesis.
斑蝥素（CTD）因其肾毒性，临床应用受到严重限制。因此，本研究旨在探究敏感生物标志物，用于评估和预测CTD诱导的大鼠肾毒性。总共80只大鼠被随机分为四组：对照组和三个CTD剂量组。在灌胃给药0、1、5、15和28天后，收集大鼠血清和尿液用于生化指标检测，然后将血清用于代谢组学分析，并收集大鼠肾脏用于病理和超微结构观察。给予不同剂量的CTD后，血清肌酐（Scr）、血尿素氮（BUN）、尿素、尿肌酐（Ucrea）和尿微量白蛋白（UmALB）水平显著升高（p < 0.05）。此外，肾脏的组织病理学和细胞超微结构观察显示明显的细胞炎症浸润和肾小球水肿。包括6-羟基褪黑素在内的七种代谢生物标志物受到CTD的显著干扰。使用CatBoost分类器预测模型建立CTD肾毒性预测模型，预测准确率和精确率分别为0.645和0.640。此外，发现6-羟基褪黑素是评估CTD肾毒性最有用的生物标志物。最后，发现这七种代谢生物标志物主要参与丙酮酸代谢、泛酸和辅酶A生物合成。
