Wan Meiqi, Gao Hua, Liu Xiaoyan, Zhang Youbo
State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of State Administration of Traditional Chinese Medicine for Compatibility Toxicology, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Toxics. 2024 Jul 18;12(7):515. doi: 10.3390/toxics12070515.
In this study, we investigated whether rutaecarpine could aggravate acetaminophen-induced acute liver damage in vivo and in vitro. CCK-8 and apoptosis assays were performed to verify the cytotoxicity of acetaminophen to L02 cells with or without rutaecarpine. The expression levels of the target proteins and genes were determined using Western blotting and qRT-PCR. The liver pathological changes were evaluated with hematoxylin and eosin staining, while the aspartate aminotransferase (AST) and alanine aminotransferase (AST) levels in plasma were measured to assess the liver damage. Our results revealed that pretreatment of the cell and mice with rutaecarpine significantly aggravated the acetaminophen-induced liver damage. Mechanistically, rutaecarpine induces the CYP1A2 protein, which accelerates the metabolism of acetaminophen to produce a toxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI), leading to severe liver inflammation. Rutaecarpine exacerbated the liver damage by upregulating CYP1A2 and proinflammatory factors. These findings highlight the importance of carefully considering the dosage of rutaecarpine when combined with acetaminophen in drug design and preclinical trials.
在本研究中，我们调查了吴茱萸次碱是否会在体内和体外加重对乙酰氨基酚诱导的急性肝损伤。进行CCK-8和凋亡检测，以验证对乙酰氨基酚在有或没有吴茱萸次碱的情况下对L02细胞的细胞毒性。使用蛋白质免疫印迹法和qRT-PCR测定靶蛋白和基因的表达水平。用苏木精和伊红染色评估肝脏病理变化，同时测量血浆中天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平以评估肝损伤。我们的结果显示，用吴茱萸次碱预处理细胞和小鼠会显著加重对乙酰氨基酚诱导的肝损伤。机制上，吴茱萸次碱诱导CYP1A2蛋白，加速对乙酰氨基酚的代谢以产生有毒中间体N-乙酰对苯醌亚胺（NAPQI），导致严重的肝脏炎症。吴茱萸次碱通过上调CYP1A2和促炎因子加重肝损伤。这些发现凸显了在药物设计和临床试验中将吴茱萸次碱与对乙酰氨基酚联合使用时仔细考虑其剂量的重要性。
