Xia Shuang, Hu Zhi-Yu, Cao Rong, Guo Lin, Ma Jia-Ting, Xiao Ming-Xuan, Liu Jiayi, Zhai Bo-Wen, Fu Rao, Jiang Zhi-Chao, Gong Hui, Yan Miao
Department of Pharmacy, The Second Xiangya Hospital, Central South University, 139# Renmin Middle Road, Furong District, Changsha 410011, China.
International Research Center for Precision Medicine, Transformative Technology and Software Services, 139# Renmin Middle Road, Furong District, Changsha 410011, China.
Toxicol Res (Camb). 2025 Mar 26;14(2):tfaf024. doi: 10.1093/toxres/tfaf024. eCollection 2025 Apr.
Acetaminophen (N-acetyl-para-aminophenol, APAP) is the most widely used antipyretic and anti-inflammatory drug in the world. It is reported that APAP-induced liver damage accounts for about half of all liver failure patients in Europe and the United States. Magnesium isoglycyrrhizinate (MI) is the fourth-generation glycyrrhizic acid preparation developed in China. It has anti-inflammatory, hepatocyte membrane protection, and liver function recovery effects. This study aimed to investigate the effect of MI on alleviating APAP-induced liver injury and explore potential mechanisms. C57 BL/6 J mice were used to assess the efficacy of liver protection, by detecting ALT, AST, H&E and TUNEL staining. Liver samples from saline, APAP, APAP combined with MI group were selected for the transcriptomics analysis. MI significantly prevented the elevation of ALT, and AST. Hepatocyte necrosis was alleviated when MI was co-treated with APAP in TUNEL assay. There were no differences in total GSH levels or GSH/GSSG ration between APAP and MI group. Western Blot MI showed MI didn't affect the protein levels of CYP2E1 expression, mitochondrial p-JNK and cytosolic Endo G. GO analysis showed that mitochondria were the main target of MI in reducing APAP-induced liver injury. MI also significantly upregulated the expression of TFAM, NRF-1, PGC-1β and Sirt1. MI restored mRNA levels of oxidative phosphorylation genes and recovered mitochondrial membrane potential that fell after APAP administration. In conclusion, MI alleviated APAP-induced liver injury by promoting mitochondrial biogenesis.
对乙酰氨基酚（N - 乙酰 - 对氨基酚，APAP）是世界上使用最广泛的解热抗炎药。据报道，在欧美，APAP 引起的肝损伤约占所有肝衰竭患者的一半。异甘草酸镁（MI）是我国研制的第四代甘草酸制剂。它具有抗炎、保护肝细胞膜和恢复肝功能的作用。本研究旨在探讨 MI 对减轻 APAP 诱导的肝损伤的作用并探索其潜在机制。采用 C57 BL/6 J 小鼠，通过检测谷丙转氨酶（ALT）、谷草转氨酶（AST）、苏木精 - 伊红（H&E）染色和 TUNEL 染色来评估肝脏保护功效。选取生理盐水组、APAP 组、APAP 联合 MI 组的肝脏样本进行转录组学分析。MI 显著抑制了 ALT 和 AST 的升高。在 TUNEL 检测中，当 MI 与 APAP 联合处理时，肝细胞坏死得到缓解。APAP 组和 MI 组之间的总谷胱甘肽（GSH）水平或 GSH/GSSG 比值没有差异。蛋白质免疫印迹法显示 MI 不影响细胞色素 P450 2E1（CYP2E1）表达、线粒体磷酸化 c - 氨基末端激酶（p - JNK）和胞质内核酸内切酶 G（Endo G）的蛋白水平。基因本体（GO）分析表明，线粒体是 MI 减轻 APAP 诱导的肝损伤的主要靶点。MI 还显著上调了线粒体转录因子 A（TFAM）、核呼吸因子 - 1（NRF - 1）、过氧化物酶体增殖物激活受体γ共激活因子 - 1β（PGC - 1β）和沉默信息调节因子 1（Sirt1）的表达。MI 恢复了氧化磷酸化基因的 mRNA 水平，并恢复了 APAP 给药后下降的线粒体膜电位。总之，MI 通过促进线粒体生物合成减轻了 APAP 诱导的肝损伤。
