Zhao Dong-Sheng, Jiang Li-Long, Fan Ya-Xi, Dong Lei-Chi, Ma Jiang, Dong Xin, Xu Xiao-Jun, Li Ping, Li Hui-Jun
State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing, 210009, China.
State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing, 210009, China.
Food Chem Toxicol. 2017 Oct;108(Pt B):532-542. doi: 10.1016/j.fct.2017.02.030. Epub 2017 Feb 24.
Polygoni Multiflori Radix (PMR) has been widely used as a tonic for centuries. However, hepatotoxicity cases linked to PMR have been frequently reported and appropriate biomarkers for clinical diagnosis are currently lacking. Here, an approach using UPLC-QqQ/MS-based targeted metabolomics of bile acids (BAs) complemented with biochemistry and histopathology was applied to characterize the development and recovery processes of PMR-induced hepatotoxicity in rats and to identify biomarkers. The expression of bile salt export pump (Bsep) and sodium taurocholate cotransporting polypeptide (Ntcp) were evaluated to investigate the underlying mechanism. Steatosis and inflammatory cell infiltration were observed in PMR-treated rats, which were accompanied by the elevation of serum biochemistry. The metabolic profiles of BAs were analyzed by Principal Component Analysis, hyodeoxycholic acid (HDCA) in serum and tauro-β-muricholic acid (TβMCA) in urine were identified as potential biomarkers for PMR-induced hepatotoxicity. The elevated expression of Bsep and decreased expression of Ntcp in the liver of PMRtreated rats indicated that hepatotoxicity was related to the disorders of BAs metabolism. Our study demonstrated that BAs may be used for clinical diagnosis of PMR-induced hepatotoxicity. Urine TβMCA was identified as a promising biomarker to facilitate the clinical monitoring of PMR-induced hepatotoxicity and may serve as potential therapeutic target.
何首乌（PMR）数百年来一直被广泛用作滋补品。然而，与PMR相关的肝毒性病例屡有报道，目前缺乏用于临床诊断的合适生物标志物。在此，采用基于超高效液相色谱-四极杆飞行时间串联质谱（UPLC-QqQ/MS）的胆汁酸（BAs）靶向代谢组学方法，并结合生物化学和组织病理学，来表征PMR诱导的大鼠肝毒性的发展和恢复过程，并鉴定生物标志物。评估胆盐输出泵（Bsep）和牛磺胆酸钠共转运多肽（Ntcp）的表达，以探究潜在机制。在PMR处理的大鼠中观察到脂肪变性和炎性细胞浸润，同时伴有血清生化指标升高。通过主成分分析对BAs的代谢谱进行分析，血清中的猪去氧胆酸（HDCA）和尿液中的牛磺-β-鼠胆酸（TβMCA）被鉴定为PMR诱导肝毒性的潜在生物标志物。PMR处理的大鼠肝脏中Bsep表达升高和Ntcp表达降低表明肝毒性与BAs代谢紊乱有关。我们的研究表明，BAs可用于PMR诱导肝毒性的临床诊断。尿液TβMCA被鉴定为一种有前景的生物标志物，有助于临床监测PMR诱导的肝毒性，并且可能作为潜在的治疗靶点。
