药学学报, 2021, 56(4): 1079-1085
叶铉玲, 姜凯元, 杨莉, 熊爱珍, 王峥涛. 丹酚酸B对千里光碱致小鼠肝损伤的保护作用[J]. 药学学报, 2021, 56(4): 1079-1085.
YE Xuan-ling, JIANG Kai-yuan, YANG Li, XIONG Ai-zhen, WANG Zheng-tao. The protective effect of salvianolic acid B against senecionine-induced hepatotoxicity in mice[J]. Acta Pharmaceutica Sinica, 2021, 56(4): 1079-1085.

叶铉玲1, 姜凯元1, 杨莉1,2*, 熊爱珍1,2*, 王峥涛1,2
1. 上海中医药大学, 中药研究所, 中药标准化教育部重点实验室暨国家中医药管理局中药新资源与质量评价重点实验室, 上海 201203;
2. 上海中药标准化研究中心, 上海 201203
近年来,我国由于误服含吡咯里西啶生物碱(pyrrolizidine alkaloids,PAs)的中草药而导致药源性肝损伤的报道逐年增多。丹酚酸B(salvianolic acid B,Sal B)是丹参(Salvia miltiorrhiza Bge.)中的主要水溶性有效成分,具有抗凝血和抗氧化等作用。本研究旨在研究丹酚酸B对千里光碱(senecionine,SEN)肝毒性的保护作用及其可能的作用机制。实验方案经上海中医药大学动物实验伦理委员会批准,所有程序均严格按照动物使用和护理的伦理原则进行。实验采用SEN(50 mg·kg-1)单次灌胃造成小鼠急性肝损伤模型,使用Sal B(10 mg·kg-1)进行干预。结果表明,Sal B能显著改善SEN致小鼠肝损伤,降低血清谷丙转氨酶和谷草转氨酶活力,并明显改善肝窦内出血、肝细胞坏死等病理状况,血清PAs毒性标志物吡咯蛋白加合物的含量也明显减少。进一步检测凝血、氧化应激和纤维化等相关通路关键因子,发现Sal B可降低纤溶酶原激活物抑制因子1的表达以抑制凝血系统,可调节谷胱甘肽及超氧化物歧化酶水平等改善机体的抗氧化应激能力,还可以通过影响基质金属蛋白酶9、转化生长因子-β1、信号传导蛋白和转录激活物3、趋化因子1等肝纤维化相关因子改善细胞外基质的过度沉积及延缓肝纤维化进程。本研究表明,丹酚酸B对千里光碱肝毒性的保护作用与调控凝血系统、改善氧化应激以及调控肝纤维化相关因子等有关,为临床上应用丹酚酸B治疗PAs肝损伤提供了理论依据。
关键词:    丹参      丹酚酸B      吡咯里西啶生物碱      千里光碱      药源性肝损伤      纤溶酶原激活物抑制因子1     
The protective effect of salvianolic acid B against senecionine-induced hepatotoxicity in mice
YE Xuan-ling1, JIANG Kai-yuan1, YANG Li1,2*, XIONG Ai-zhen1,2*, WANG Zheng-tao1,2
1. The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;
2. Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
In recent years, there has been an increase in the incidence of herbal-induced liver injury due to the accidental ingestion of herbal medicines containing pyrrolizidine alkaloids (PAs) in domestic. Salvianolic acid B (Sal B), a hydrophilic component in Salvia miltiorrhiza Bge., shows activities of anticoagulation, antioxidation, and other pharmacological activities. This research aims to investigate the protective effect of Sal B on hepatotoxicity induced by senecionine (SEN) and its potential mechanism. The animal experiment was approved by the Experimental Animal Ethical Committee of Shanghai University of Traditional Chinese Medicine, and all mice have received humane care in compliance with the institutional animal care guidelines. Mice were treated with Sal B (10 mg·kg-1) 3 days before and 1 day after SEN (50 mg·kg-1) treatment. The animals were sacrificed 48 h after SEN administration. As a result, Sal B effectively ameliorated SEN-induced liver injury. The mice in the group treated with Sal B showed lower serum activities of alanine aminotransferase and aspartate aminotransferase, less hepatic sinusoidal hemorrhage, and reduced hepatocyte necrosis. Besides, contents of pyrrole-protein adducts, the marker for PA-induced toxicity, were also decreased in serum. The key factors related to coagulation, oxidative stress, and liver fibrosis were further analyzed. It was found that Sal B inhibited the coagulant system by reducing the expression of plasminogen activator inhibitor-1. Sal B also modulated glutathione and superoxide dismutase levels and improved the anti-oxidative defense system. In addition, Sal B decreased the excessive deposition of extracellular matrix and inhibited the progression of liver fibrosis via down-regulating several key factors related to liver fibrosis, including matrix metalloproteinase 9, transforming growth factor-β1, signal transducer and activator of transcription 3, and chemokine 1. In conclusion, Sal B ameliorated SEN-induced liver injury in mice by regulating the blood coagulation system, improving oxidative stress, and modulating liver fibrosis-related factors. Our present study pointed to the possibility of utilizing salvianolic acid B for protection against PA-induced liver injury clinically.
Key words:    Salvia miltiorrhiza Bge.    salvianolic acid B    pyrrolizidine alkaloid    senecionine    drug-induced liver injury    plasminogen activator inhibitor-1   
收稿日期: 2020-10-26
DOI: 10.16438/j.0513-4870.2020-1663
基金项目: 上海市自然科学基金资助项目(20ZR1473300);上海市进一步加快中医药事业发展三年行动计划[ZY(2018-2020)-CCCX-5002];上海市人才发展资金;上海中医药大学“杏林学者”计划;上海中医药大学“研究生创新培养专项”科研项目(Y2020031).
通讯作者: 熊爱珍,Tel:86-21-51322506,Fax:86-21-51322519,E-mail:a.z.xiong@hotmail.com;杨莉,E-mail:yl7@shutcm.edu.cn
Email: a.z.xiong@hotmail.com;yl7@shutcm.edu.cn
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姜凯元  在本刊中的所有文章
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王峥涛  在本刊中的所有文章

[1] Li N, Xia QS, Ruan JQ, et al. Hepatotoxicity and tumorigenicity induced by metabolic activation of pyrrolizidine alkaloids in herbs[J]. Curr Drug Metab, 2011, 12:823-834.
[2] Tang J, Hattori M. Pyrrolizidine alkaloids-containing Chinese medicines in the Chinese Pharmacopoeia and related safety concerns[J]. Acta Pharm Sin (药学学报), 2011, 46:762-772.
[3] Ruan JQ, Yang MB, Fu P, et al. Metabolic activation of pyrrolizidine alkaloids:insights into the structural and enzymatic basis[J]. Chem Res Toxicol, 2014, 27:1030-1039.
[4] Liu ZL, Fan ZP, Guo YS, et al. Clinical features, pathogenesis, and diagnosis and treatment of different types of hepatic sinusoidal obstruction syndrome[J]. J Clin Hepatol (临床肝胆病杂志), 2019, 35:208-212.
[5] Zhuge YZ, Wang Y, Zhang F, et al. Clinical characteristics and treatment of pyrrolizidine alkaloid-related hepatic vein occlusive disease[J]. Liver Int, 2018, 38:1867-1874.
[6] Lin M, Zhai XH, Wang GZ, et al. Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase Ⅱ detoxification gene expression via activation of the PI3K and PKC signaling pathways[J]. J Pharmacol Sci, 2015, 127:203-210.
[7] Wang R, Yu XY, Guo ZY, et al. Inhibitory effects of salvianolic acid B on CCl4-induced hepatic fibrosis through regulating NF-κB/IκBα signaling[J]. J Ethnopharmacol, 2012, 144:592-598.
[8] Yang L, Huo JR, Zhu HY, et al. Observation of Salvia miltiorrhiza on the prevention and treatment of Tusanqi-induced hepatic veno-occlusive disease in mice[J]. Chin Hepatol (肝脏), 2013, 18:105-107.
[9] Chen Y, Xiong F, Wang WQ, et al. The long persistence of pyrrolizidine alkaloid-derived pyrrole-protein adducts in vivo:kinetic study following multiple exposures of a pyrrolizidine alkaloid containing extract of Gynura japonica[J]. Toxicol Lett, 2020, 323:41-47.
[10] Chen Y, Wang XJ, Xiong F, et al. Kinetic study of pyrrolizidine alkaloid-derived pyrrole-protein adducts in rats after intragastric administration of Gynura japonica[J]. Acta Pharm Sin (药学学报), 2020, 55:473-477.
[11] Lee JH, Lee KH, Lee JH, et al. Plasminogen activator inhibitor-1 is an independent diagnostic marker as well as severity predictor of hepatic veno-occlusive disease after allogeneic bone marrow transplantation in adults conditioned with busulphan and cyclophosphamide[J]. Br J Haematol, 2002, 4:1087-1094.
[12] Liang QN, Sheng YC, Jiang P, et al. The gender-dependent difference of liver GSH antioxidant system in mice and its influence on isoline-induced liver injury[J]. Toxicology, 2011, 280:61-69.
[13] Huang ZL, Jing XQ, Sheng YC, et al. (-)-Epicatechin attenuates hepatic sinusoidal obstruction syndrome by inhibiting liver oxidative and inflammatory injury[J]. Redox Biol, 2019, 22:101117.
[14] Zhang F, Zhou Y, Yang X, et al. Gynura Rhizoma containing pyrrolizidine alkaloids induces the hepatic sinusoidal obstruction syndrome in mice via upregulating fibrosis-related factors[J]. Acta Pharmacol Sin, 2019, 40:781-789.
[15] Expert consensus on diagnosis and treatment of pyrrolidine alkaloids-related sinusoidal obstruction syndrome (2017, Nanjing)[J]. J Clin Hepatol (临床肝胆病杂志), 2017, 33:1627-1637.
[16] Pihusch V, Pihusch M, Penovici M, et al. Transforming growth factor beta-1 released from platelets contributes to hypercoagulability in veno-occlusive disease following hematopoetic stem cell transplantation[J]. Thromb Res, 2005, 116:233-240.
[17] Smith LH, Dixon JD, Stringham JR, et al. Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis[J]. Blood, 2006, 107:132-134.
[18] Shi CS, Huang HC, Wu HL, et al. Salvianolic acid B modulates hemostasis properties of human umbilical vein endothelial cells[J]. Thromb Res, 2007, 119:769-775.
[19] Origassa CS, Camara NO. Cytoprotective role of heme oxygenase-1 and heme degradation derived end products in liver injury[J]. World J Hepatol, 2013, 5:541-549.
[20] Robinson SM, Mann J, Vasilaki A, et al. Pathogenesis of FOLFOX induced sinusoidal obstruction syndrome in a murine chemotherapy model[J]. J Hepatol, 2013, 59:318-326.
[21] Hilscher MB, Sehrawat T, Arab JP, et al. Mechanical stretch increases expression of CXCL1 in liver sinusoidal endothelial cells to recruit neutrophils, generate sinusoidal microthombi, and promote portal hypertension[J]. Gastroenterology, 2019, 157:193-209.
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