School of Pharmacy, Lanzhou University, Lanzhou, 730000, China; Engineering Research Centre of Prevention and Control for Clinical Medication Risk, Gansu Province, China.
Engineering Research Centre of Prevention and Control for Clinical Medication Risk, Gansu Province, China.
Food Chem Toxicol. 2024 Oct;192:114949. doi: 10.1016/j.fct.2024.114949. Epub 2024 Aug 23.
Acute kidney injury (AKI) is a worldwide public health problem with high morbidity and mortality. Cisplatin is a widely used chemotherapeutic agent for treating solid tumors, but the induction of AKI restricts its clinical application. In this study, the effect of cisplatin on the expression of organic ion transporters was investigated through in vivo and in vitro experiments. Targeted metabolomics techniques were used to measure the levels of selected endogenous substances in serum. Transmission electron microscopy was used to observe the microstructure of renal tubular epithelial cells. Our results show that the toxicity of cisplatin on HK-2 cells or HEK-293 cells was time- and dose-dependent. Administration of cisplatin decreased the expression of OAT1/3 and OCT2 and increased the expression of MRP2/4. Mitochondrial damage induced by cisplatin lead to renal tubular epithelial cell injury. In addition, administration of cisplatin resulted in significant changes in endogenous substance levels in serum, including amino acids, carnitine, and fatty acids. These serum amino acids and metabolites (α-aminobutyric acid, proline, and alanine), carnitines (tradecanoylcarnitine, hexanylcarnitine, octanoylcarnitine, 2-methylbutyroylcarnitine, palmitoylcarnitine, and linoleylcarnitine) and fatty acids (9E-tetradecenoic acid) represent endogenous substances with diagnostic potential for cisplatin-induced AKI.
急性肾损伤 (AKI) 是一个全球性的公共健康问题，具有高发病率和死亡率。顺铂是一种广泛用于治疗实体瘤的化疗药物，但 AKI 的诱导限制了其临床应用。在这项研究中，通过体内和体外实验研究了顺铂对有机离子转运体表达的影响。靶向代谢组学技术用于测量血清中选定内源性物质的水平。透射电子显微镜用于观察肾小管上皮细胞的微观结构。我们的结果表明，顺铂对 HK-2 细胞或 HEK-293 细胞的毒性是时间和剂量依赖性的。顺铂给药降低了 OAT1/3 和 OCT2 的表达，增加了 MRP2/4 的表达。顺铂诱导的线粒体损伤导致肾小管上皮细胞损伤。此外，顺铂给药导致血清内源性物质水平发生显著变化，包括氨基酸、肉碱和脂肪酸。这些血清氨基酸和代谢物（α-氨基丁酸、脯氨酸和丙氨酸）、肉碱（十六烷酰肉碱、己烷肉碱、辛烷肉碱、2-甲基丁酰肉碱、棕榈酰肉碱和亚油酰肉碱）和脂肪酸（9E-十四碳烯酸）代表了顺铂诱导 AKI 的潜在诊断内源性物质。
