Zhang Y, Zhang Y, Li J, Chen Y, Han L, He Q, Chu J, Liu K
1 Key Laboratory for Drug Screening Technology, Shandong Provincial Engineering Laboratory for Biological Testing Technology, Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, People's Republic of China.
2 Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China.
Hum Exp Toxicol. 2019 Jan;38(1):36-44. doi: 10.1177/0960327118774873. Epub 2018 May 18.
Isopsoralen is the main component of the Chinese medicine psoralen, which has antitumour activity and can be used for the treatment of osteoporosis. However, the mechanism behind its hepatotoxicity has not yet been elucidated. In this study, the hepatotoxicity of isopsoralen was investigated using zebrafish. Isopsoralen treatment groups of 25, 50 and 100 μM were established. The mortality, liver morphology changes, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), liver histopathology and mRNA levels of liver injury-related genes in zebrafish larvae were measured. The results showed that isopsoralen resulted in the development of malformed zebrafish, dose-dependent increases in ALT and AST, decreased liver fluorescence and weakened fluorescence intensity. Histopathological examination showed that high-dose isopsoralen caused a large number of vacuolated structures in the larvae liver. The polymerase chain reaction results showed a significant decrease in the mRNA levels of genes related to antioxidant capacity ( lfabp, gstp2 and sod1) and drug transport ( mdr1, mrp1 and mrp2), indicating that isopsoralen significantly inhibited liver antioxidant capacity and drug efflux capacity in zebrafish larvae. Isopsoralen is hepatotoxic to zebrafish larvae via inhibition of drug transporter expression resulting in the accumulation of isopsoralen in the body and decreased antioxidant capacity, leading to liver injury.
异补骨脂素是中药补骨脂的主要成分，具有抗肿瘤活性，可用于治疗骨质疏松症。然而，其肝毒性背后的机制尚未阐明。在本研究中，使用斑马鱼研究了异补骨脂素的肝毒性。建立了25、50和100μM的异补骨脂素处理组。测量了斑马鱼幼体的死亡率、肝脏形态变化、丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平、肝脏组织病理学以及肝脏损伤相关基因的mRNA水平。结果表明，异补骨脂素导致斑马鱼发育畸形，ALT和AST呈剂量依赖性升高，肝脏荧光降低且荧光强度减弱。组织病理学检查显示，高剂量异补骨脂素导致幼体肝脏出现大量空泡结构。聚合酶链反应结果显示，与抗氧化能力相关的基因（lfabp、gstp2和sod1）以及药物转运相关的基因（mdr1、mrp1和mrp2）的mRNA水平显著降低，表明异补骨脂素显著抑制了斑马鱼幼体的肝脏抗氧化能力和药物外排能力。异补骨脂素通过抑制药物转运蛋白表达对斑马鱼幼体产生肝毒性，导致异补骨脂素在体内蓄积，抗氧化能力下降，从而导致肝脏损伤。
