Henan Key Laboratory of Rehabilitation Medicine, Henan Joint International Research Laboratory of Chronic Liver Injury, Henan Workshop of Chronic Liver Injury for Outstanding Overseas Scientists, Zhengzhou Key Laboratory of Metabolic-dysfunction-associated Fatty Liver Disease, Department of Pharmacy, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
Phytomedicine. 2024 Dec;135:156106. doi: 10.1016/j.phymed.2024.156106. Epub 2024 Sep 29.
The hepatotoxicity induced by acetaminophen (APAP), a commonly used antipyretic, analgesic and anti-inflammatory drug in clinical practice, has received accumulated attention. Artemisia argyi essential oil (AAEO), a volatile oil component extracted from traditional Chinese medicine Artemisia argyi H.Lév. & Vaniot, has great hepatoprotective effects. However, the potential role of AAEO in APAP-induced hepatotoxicity has not been characterized. The present study aimed to investigate the effects of AAEO on hepatic metabolic changes in mice exposed to APAP.
In this study, 300.00 mg/kg acetaminophen was used to establish liver injury model in C57BL/6 J mice. Hepatoprotective effect of AAEO on APAP-induced hepatotoxicity in mice was investigated by detecting liver function enzymes and histopathological examination. Secondly, UPLC-MS/MS was used to analyze the to analyze the small molecule metabolites and metabolic pathways induced by AAEO treatment; In addition, the effect of AAEO on APAP-induced oxidative stress and inflammation were evaluated by detecting the levels of glutathione peroxidase 4, malondialdehyde, reactive oxygen species and inflammatory factors. Finally, the active components of AAEO were preliminarily screened by cellular assays. The hepatoprotective effect of AAEO against APAP-induced hepatotoxicity was examined through the Western blotting, after the CYP2E1 gene was knocked down in AML12 cells by siRNA transfection.
Compared with the APAP group, AAEO could reduce the abnormal increase in the levels of liver function enzymes caused by APAP. AAEO could enhance the antioxidant capacity by down-regulating the biosynthesis pathway of unsaturated fatty acids and promoting the activity of antioxidant enzymes SOD and CAT in liver tissue induced by APAP. Our study revealed that AAEO promoted GSH synthesis and covalently combined to form APAP-GSH conjugates to reduce the accumulation of APAP in liver tissue. In addition, the chemical constituents in AAEO were analyzed by GC-MS/MS, and it was determined to identify that dihydro-beta-ionone and (-)-verbenone in AAEO might have a significant protective effect on hepatocyte survival after APAP exposure. Further studies on the hepatoprotective mechanism of AAEO indicated that it might reduce the production of toxic metabolites by regulating CYP2E1 levels.
AAEO exerted hepatoprotective effects on acetaminophen-induced hepatotoxicity in mice via regulating the activity of CYP2E1 and regulating the γ-glutamyl cycle pathway.
醋氨酚（APAP）是一种常用的解热、镇痛和抗炎药物，在临床实践中已引起人们对其肝毒性的关注。艾蒿精油（AAEO）是从传统中药艾蒿 H.Lév. 和 Vaniot 中提取的挥发性油成分，具有很好的保肝作用。然而，AAEO 在 APAP 诱导的肝毒性中的潜在作用尚未得到描述。本研究旨在探讨 AAEO 对 APAP 暴露小鼠肝代谢变化的影响。
本研究采用 300.00mg/kg 醋氨酚建立 C57BL/6 J 小鼠肝损伤模型。通过检测肝功能酶和组织病理学检查，研究 AAEO 对 APAP 诱导的小鼠肝毒性的保护作用。其次，采用 UPLC-MS/MS 分析 AAEO 处理诱导的小分子代谢物和代谢途径；此外，通过检测谷胱甘肽过氧化物酶 4、丙二醛、活性氧和炎症因子的水平，评估 AAEO 对 APAP 诱导的氧化应激和炎症的影响。最后，通过细胞实验初步筛选 AAEO 的活性成分。通过 siRNA 转染使 AML12 细胞中 CYP2E1 基因敲低后，通过 Western blot 检测 AAEO 对 APAP 诱导的肝毒性的保护作用。
与 APAP 组相比，AAEO 可降低 APAP 引起的肝功能酶异常升高。AAEO 通过下调 APAP 诱导的肝组织中不饱和脂肪酸生物合成途径和促进抗氧化酶 SOD 和 CAT 的活性，增强抗氧化能力。我们的研究表明，AAEO 促进 GSH 的合成，并与 APAP 形成共价结合的 APAP-GSH 缀合物，以减少肝组织中 APAP 的积累。此外，通过 GC-MS/MS 分析 AAEO 的化学成分，确定 AAEO 中的二氢-β-紫罗兰酮和（-）马鞭草烯酮可能对 APAP 暴露后肝细胞的存活有显著的保护作用。进一步研究 AAEO 的保肝机制表明，它可能通过调节 CYP2E1 水平来减少有毒代谢物的产生。
AAEO 通过调节 CYP2E1 活性和调节γ-谷氨酰环途径，对 APAP 诱导的小鼠肝毒性发挥保护作用。
