Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
Chem Biol Interact. 2023 Sep 25;383:110693. doi: 10.1016/j.cbi.2023.110693. Epub 2023 Aug 31.
Voriconazole (VOR) - induced liver injury is a common adverse reaction, and can lead to serious clinical outcomes. It is of great significance to describe the metabolic characteristics of VOR - induced liver injury and to elucidate the potential mechanisms. This study investigated the changes of plasma metabolic profiles in a rat model of VOR - induced liver injury by non - targeted metabolomics. Correlation analysis was performed between differentially expressed metabolites and plasma liver function indexes. The metabolites with strong correlation were determined for their predictive performance for liver injury using receiver operating characteristic (ROC) curve analysis. Potential biomarkers were then screened combined with liver pathological scores. Finally, the expression level of genes that involved in lipid metabolism were determined in rat liver to verify the mechanism of VOR - induced liver injury we proposed. VOR - induced liver injury in rats was characterized by plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, the lipid droplets accumulation in liver, as well as inflammation and fibrosis. Significant changes of plasma metabolites were observed, with a decrease in lipid metabolites accounting for over 50% of all changed metabolites, and alterations of cholesterol and bile acids metabolites. The decrease of 3 phosphatidylcholine (PC) in plasma could indicate the occurrence of VOR - induced liver injury. Decreased fatty acids (FA) oxidation and bile acid excretion might be the potential mechanisms of VOR - induced liver injury. This study provided new insights into the molecular characterization of VOR - induced liver injury.
伏立康唑（VOR）诱导的肝损伤是一种常见的不良反应，可导致严重的临床后果。描述 VOR 诱导的肝损伤的代谢特征并阐明潜在机制具有重要意义。本研究通过非靶向代谢组学研究了 VOR 诱导的肝损伤大鼠模型中血浆代谢谱的变化。对差异表达的代谢物与血浆肝功能指标进行相关性分析。使用受试者工作特征（ROC）曲线分析对与肝损伤具有强相关性的代谢物进行预测性能分析。然后结合肝病理评分筛选潜在生物标志物。最后，通过测定大鼠肝中参与脂质代谢的基因的表达水平，验证我们提出的 VOR 诱导肝损伤的机制。VOR 诱导的大鼠肝损伤表现为血浆丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）升高、肝内脂质滴积聚以及炎症和纤维化。观察到血浆代谢物发生显著变化，脂质代谢物减少占所有变化代谢物的 50%以上，胆固醇和胆汁酸代谢物也发生变化。血浆中 3 种磷脂酰胆碱（PC）的减少可能表明发生了 VOR 诱导的肝损伤。脂肪酸（FA）氧化和胆汁酸排泄减少可能是 VOR 诱导肝损伤的潜在机制。本研究为 VOR 诱导肝损伤的分子特征提供了新的见解。
