Wang Qiyi, Cheng Weina, He Tianmu, Li Shan, Ao Jingwen, He Yanmei, Duan Cancan, Li Xiaofei, Zhang Jianyong
Department of Pharmacy, Zunyi Medical University, Zunyi, 563000, China.
Department of Pharmacy, Zunyi Medical University, Zunyi, 563000, China; Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, 563000, China.
Chem Biol Interact. 2025 Jan 5;405:111314. doi: 10.1016/j.cbi.2024.111314. Epub 2024 Nov 17.
The hepatotoxicity mechanism of cantharidin (CTD), a major active component of Mylabris was explored based on liver lipidome alterations and spatial distributions in female and male rats using lipidomics and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). After oral CTD exposure, the livers of female rats were screened for 104 differential lipids including lysophosphatidylethanolamine(LysoPE)(20:2/0:0) and diacylglycerol(DG)(18:2/22:4), whereas the livers of male rats were screened for 76 differential lipids including fatty acid(FA)(24:6) and DG(18:0/22:4). According to the MALDI-MSI results, female rats exhibited 12 differential lipids with alteration in the abundance and spatial distribution of phosphatylcholine(PC), phosphatidylethanolamine(PE), lysophosphatidylcholine(LysoPC), and LysoPE in the liver lesion area. On the other hand, male rats exhibited 8 differential lipids with changes in the abundance and spatial distribution of PC, PE, and FA in the liver lesion area. The lipidomics- and MALDI-MSI-detected differential lipids strongly disrupted glycerophospholipid metabolism in both female and male rats. Additionally, phosphatidate phosphatase (Lipin1), choline/ethanolamine phosphotransferase 1 (CEPT1), and phosphatidylethanolamine N-methyltransferase (PEMT) were screened to distinguish CTD hepatoxicity in female and male rats. Western blotting analysis demonstrated a significant elevation in Lipin1 expression in female and male rat livers, accompanied by a decrease in PEMT expression. Furthermore, CEPT1 expression increased significantly in female rat livers and decreased significantly in male rat livers. These findings suggested that CTD could disrupt lipid metabolism in a gender-specific manner. Moreover, the combination of lipidomics and MALDI-MSI could offer valuable insights into CTD-induced hepatotoxicity in rats.
基于脂质组学和基质辅助激光解吸/电离质谱成像（MALDI-MSI）技术，通过观察肝脏脂质组变化和空间分布情况，对斑蝥主要活性成分斑蝥素（CTD）在雌性和雄性大鼠中的肝毒性机制进行了研究。口服CTD后，在雌性大鼠肝脏中筛选出104种差异脂质，包括溶血磷脂酰乙醇胺（LysoPE）（20:2/0:0）和二酰基甘油（DG）（18:2/22:4）；而在雄性大鼠肝脏中筛选出76种差异脂质，包括脂肪酸（FA）（24:6）和DG（18:0/22:4）。根据MALDI-MSI结果，雌性大鼠在肝脏损伤区域有12种差异脂质，其磷脂酰胆碱（PC）、磷脂酰乙醇胺（PE）、溶血磷脂酰胆碱（LysoPC）和LysoPE的丰度和空间分布发生改变。另一方面，雄性大鼠在肝脏损伤区域有8种差异脂质，其PC、PE和FA的丰度和空间分布发生变化。脂质组学和MALDI-MSI检测到的差异脂质严重扰乱了雌性和雄性大鼠的甘油磷脂代谢。此外，筛选了磷脂酸磷酸酶（Lipin1）、胆碱/乙醇胺磷酸转移酶1（CEPT1）和磷脂酰乙醇胺N-甲基转移酶（PEMT）以区分CTD对雌性和雄性大鼠的肝毒性。蛋白质免疫印迹分析表明，雌性和雄性大鼠肝脏中Lipin1表达显著升高，同时PEMT表达降低。此外，CEPT1在雌性大鼠肝脏中表达显著增加，在雄性大鼠肝脏中表达显著降低。这些发现表明，CTD可能以性别特异性方式扰乱脂质代谢。此外，脂质组学和MALDI-MSI的结合可为CTD诱导的大鼠肝毒性提供有价值的见解。
