Liu Peipei, Wu Jing, Yu Xinyue, Guo Linling, Zhao Ling, Ban Tao, Huang Yin
Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing 210009, China.
Pharmaceuticals (Basel). 2023 May 26;16(6):797. doi: 10.3390/ph16060797.
The chemotherapy drug doxorubicin (DOX) is an anthracycline with over 30% incidence of liver injury in breast cancer patients, yet the mechanism of its hepatotoxicity remains unclear. To identify potential biomarkers for anthracycline-induced hepatotoxicity (AIH), we generated clinically-relevant mouse and rat models administered low-dose, long-term DOX. These models exhibited significant liver damage but no decline in cardiac function. Through untargeted metabolic profiling of the liver, we identified 27 differential metabolites in a mouse model and 28 in a rat model. We then constructed a metabolite-metabolite network for each animal model and computationally identified several potential metabolic markers, with particular emphasis on aromatic amino acids, including phenylalanine, tyrosine, and tryptophan. We further performed targeted metabolomics analysis on DOX-treated 4T1 breast cancer mice for external validation. We found significant ( < 0.001) reductions in hepatic levels of phenylalanine and tyrosine (but not tryptophan) following DOX treatment, which were strongly correlated with serum aminotransferases (ALT and AST) levels. In summary, the results of our study present compelling evidence supporting the use of phenylalanine and tyrosine as metabolic signatures of AIH.
化疗药物阿霉素（DOX）是一种蒽环类药物，在乳腺癌患者中肝损伤发生率超过30%，但其肝毒性机制仍不清楚。为了确定蒽环类药物诱导的肝毒性（AIH）的潜在生物标志物，我们建立了给予低剂量、长期DOX的临床相关小鼠和大鼠模型。这些模型表现出明显的肝损伤，但心脏功能没有下降。通过对肝脏进行非靶向代谢谱分析，我们在小鼠模型中鉴定出27种差异代谢物，在大鼠模型中鉴定出28种。然后，我们为每个动物模型构建了代谢物-代谢物网络，并通过计算确定了几个潜在的代谢标志物，特别关注芳香族氨基酸，包括苯丙氨酸、酪氨酸和色氨酸。我们进一步对DOX处理的4T1乳腺癌小鼠进行靶向代谢组学分析以进行外部验证。我们发现DOX处理后肝脏中苯丙氨酸和酪氨酸（而非色氨酸）水平显著降低（<0.001），这与血清转氨酶（ALT和AST）水平密切相关。总之，我们的研究结果提供了有力证据，支持将苯丙氨酸和酪氨酸用作AIH的代谢特征。
