Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
Academician Workstation, Jiangxi University of Chinese Medicine, Nanchang 330004, China.
Pharmacol Ther. 2022 Sep;237:108256. doi: 10.1016/j.pharmthera.2022.108256. Epub 2022 Jul 25.
Small molecule tyrosine kinase inhibitors (TKIs) are widely used as anticancer drugs approved by U.S. FDA. However, the toxicities of TKIs to multiple organs have greatly limited their clinical applications. The metabolism of TKIs generates several potentially toxic metabolites in vivo, that can disturb the endogenous metabolism as well as cellular function, leading to organ damage. Therefore, it is essential to identify the toxic metabolites and elucidate the underlying mechanism of TKI-induced toxicity. Metabolomics is a powerful tool for the identification of the xenobiotic metabolites and metabolic derangement associated with xenobiotic exposure, that is helpful to understand the toxicity of TKIs. The study using metabolomics approach has revealed that the reactive metabolites/intermediates (e.g., N-oxide metabolite, primary amine metabolite, 1,4-benzoquinone intermediate) and adducts with glutathione, cysteine and mercapturic acid can be derived from TKIs. Fourteen metabolic pathways could be affected following the TKI treatment, including lipid metabolism, bile acid metabolism, and gut microbiota-related pathway. Modulation of xenobiotic receptor signaling, inhibition of xenobiotic metabolism, and supplementation of endogenous metabolites are potential strategies to protect against TKI-induced toxicity. In this review, studies on the metabolism of TKIs and the alterations of endogenous metabolism are discussed, and the potential preventions against TKI-induced toxicity are summarized.
小分子酪氨酸激酶抑制剂（TKI）作为美国 FDA 批准的抗癌药物被广泛应用。然而，TKI 对多种器官的毒性极大地限制了其临床应用。TKI 的代谢在体内产生几种潜在有毒的代谢物，这些代谢物可以干扰内源性代谢和细胞功能，导致器官损伤。因此，识别 TKI 诱导毒性的有毒代谢物并阐明其潜在机制至关重要。代谢组学是一种用于鉴定与外源性物质暴露相关的外源代谢物和代谢紊乱的有力工具，有助于了解 TKI 的毒性。使用代谢组学方法的研究表明，TKI 可产生反应性代谢物/中间产物（如 N-氧化物代谢物、伯胺代谢物、1,4-苯醌中间产物）和与谷胱甘肽、半胱氨酸和硫尿酸的加合物。TKI 治疗后可能会影响 14 条代谢途径，包括脂质代谢、胆汁酸代谢和肠道微生物群相关途径。外源性受体信号转导的调节、外源性物质代谢的抑制和内源性代谢物的补充是预防 TKI 诱导毒性的潜在策略。本文综述了 TKI 的代谢以及内源性代谢物的变化，并总结了预防 TKI 诱导毒性的潜在策略。
