School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, China.
Hum Exp Toxicol. 2019 May;38(5):598-609. doi: 10.1177/0960327119829527. Epub 2019 Feb 11.
The aim of this study was to identify biomarkers of zoledronate-induced nephrotoxicity and to further characterize the mechanisms underlying this process by analyzing urinary metabolites. Twenty-four rats were randomly divided into four groups containing four (two control groups) or eight rats (two zoledronate groups) per group. The rats were injected intravenously with saline or zoledronate (3 mg/kg) singly (single, 3 weeks) or repeatedly eight times (3 weeks/time, 24 weeks). Serum blood urea nitrogen, serum creatinine, creatinine clearance, and kidney injury observed by hematoxylin and eosin and immunohistochemical staining were changed only in the repeated zoledronate group (3 mg/kg, 3 weeks/time, 24 weeks). Urinary levels of S-adenosylmethionine, S-adenosylhomocysteine, l-cystathionine, l-γ-glutamylcysteine, and glutathione related to glutathione metabolism and fumaric acid and succinic acid related to the tricarboxylic acid cycle in the zoledronate-treated group (3 mg/kg, 3 weeks/time, 24 weeks) were significantly lower than those in the control group, suggesting that zoledronate may cause cellular oxidative stress. Besides, urinary levels of uracil and uridine related to pyrimidine metabolism also decreased after zoledronate treatment (3 mg/kg, 3 weeks/time, 24 weeks), while the levels of hypoxanthine related to purine metabolism, histamine related to histamine metabolism, and several amino acids were significantly increased. Moreover, zoledronate-induced enhanced oxidative stress and histamine overproduction were confirmed by reactive oxygen species (ROS) and histamine measurement in a human proximal tubular cell line. Taken together, zoledronate-induced nephrotoxicity may be attributed to it inducing perturbations in glutathione biosynthesis and the tricarboxylic acid cycle, further causing ROS overproduction, oxidative stress, and cellular inflammation, thereby leading to nephrotoxicity.
本研究旨在确定唑来膦酸诱导肾毒性的生物标志物，并通过分析尿液代谢物进一步探讨其作用机制。24 只大鼠随机分为四组，每组 4 只（两组对照组，两组唑来膦酸组）或 8 只（两组唑来膦酸组，每组 8 只）。大鼠单次静脉注射生理盐水或唑来膦酸（3mg/kg）（单次，3 周）或重复 8 次（3 周/次，24 周）。只有重复唑来膦酸组（3mg/kg，3 周/次，24 周）大鼠的血清尿素氮、血清肌酐、肌酐清除率和苏木精-伊红及免疫组织化学染色观察到的肾损伤发生变化。与谷胱甘肽代谢相关的 S-腺苷甲硫氨酸、S-腺苷同型半胱氨酸、l-胱硫醚、l-γ-谷氨酰半胱氨酸和谷胱甘肽以及与三羧酸循环相关的富马酸和琥珀酸在唑来膦酸处理组（3mg/kg，3 周/次，24 周）的尿水平显著低于对照组，表明唑来膦酸可能引起细胞氧化应激。此外，唑来膦酸处理后嘧啶代谢相关的尿嘧啶和尿苷水平也降低（3mg/kg，3 周/次，24 周），而嘌呤代谢相关的次黄嘌呤、组胺代谢相关的组氨酸和几种氨基酸水平显著升高。此外，通过人近端肾小管细胞系中活性氧（ROS）和组氨酸的测量，证实了唑来膦酸诱导的增强氧化应激和组氨酸过度产生。综上所述，唑来膦酸诱导的肾毒性可能与其诱导谷胱甘肽生物合成和三羧酸循环紊乱有关，进而导致 ROS 过度产生、氧化应激和细胞炎症，从而导致肾毒性。
