Tryptophan Pathway-Targeted Metabolomics Study on the Mechanism and Intervention of Cisplatin-Induced Acute Kidney Injury in Rats,Chemical Research in Toxicology

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Tryptophan Pathway-Targeted Metabolomics Study on the Mechanism and Intervention of Cisplatin-Induced Acute Kidney Injury in Rats
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2021-06-10 , DOI: 10.1021/acs.chemrestox.1c00110
Bei Tan ₁ , Jie Chen ₁ , Siyuan Qin ₁ , Chuyao Liao ₁ , Ying Zhang ₁ , Di Wang ₁ , Siqi Li ₁ , Zunjian Zhang ₁ , Pei Zhang ₁ , Fengguo Xu ₁

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Cisplatin is a chemotherapeutic agent widely employed in the treatment of various solid tumors. However, its use is often restricted by acute kidney injury (AKI) which is the dose-limiting adverse effect of cisplatin. While numerous studies aiming to alleviate the AKI have been conducted, there are no effective remedies in clinical practice. In this paper, a targeted metabolomics study was performed to reveal the potential relationship between tryptophan metabolism and cisplatin-induced AKI. A chemical derivatization integrated liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) approach was utilized to quantify 29 metabolites in the tryptophan pathway in rat kidney medulla and cortex after cisplatin administration. Results showed that tryptophan metabolism was remarkably disturbed both in the medulla and cortex after cisplatin administration. We also found that the tryptophan pathway in the medulla was more sensitive to cisplatin exposure compared with the cortex. Among these metabolites, indoxyl sulfate was focused for further study because it accumulated most significantly in the kidney cortex and medulla in a dose-dependent manner. A function verification study proved that chlormethiazole, a widely used CYP2E1 inhibitor, could reduce the production of indoxyl sulfate in the liver and attenuate cisplatin-induced AKI in rats. In conclusion, our study depicted the tryptophan pathway in cisplatin-induced AKI for the first time and demonstrated tryptophan metabolism is closely associated with the renal toxicity caused by cisplatin, which can be of great use for the discovery of renal toxicity attenuating remedies.

中文翻译：

色氨酸通路靶向代谢组学研究顺铂致大鼠急性肾损伤的机制及干预

顺铂是一种广泛用于治疗各种实体瘤的化学治疗剂。然而，它的使用通常受到急性肾损伤 (AKI) 的限制，这是顺铂的剂量限制性副作用。虽然已经进行了许多旨在减轻 AKI 的研究，但在临床实践中没有有效的补救措施。在本文中，进行了一项靶向代谢组学研究，以揭示色氨酸代谢与顺铂诱导的 AKI 之间的潜在关系。使用化学衍生化集成液相色谱耦合串联质谱 (LC-MS/MS) 方法对顺铂给药后大鼠肾髓质和皮质中色氨酸途径中的 29 种代谢物进行定量。结果表明，顺铂给药后，髓质和皮质中的色氨酸代谢显着紊乱。我们还发现，与皮质相比，髓质中的色氨酸通路对顺铂暴露更敏感。在这些代谢物中，硫酸吲哚酚以剂量依赖性方式在肾皮质和髓质中积累最为显着，因此被重点关注以进行进一步研究。一项功能验证研究证明，氯甲噻唑是一种广泛使用的CYP2E1抑制剂，可以减少肝脏中硫酸吲哚酚的产生，并减轻顺铂诱导的大鼠AKI。总之，我们的研究首次描述了顺铂诱导的 AKI 中的色氨酸途径，并证明色氨酸代谢与顺铂引起的肾毒性密切相关，

更新日期：2021-07-19

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