药学学报, 2017, 52(7): 1041-1047
引用本文:
张乐, 柏兆方, 李春雨, 胡黄婉茵, 沙孟晨, 刘振兴, 何琴, 李雨萌, 刘友平, 肖小河, 王伽伯. 制首乌中顺式二苯乙烯苷转化量与特异质肝损伤的相关性研究[J]. 药学学报, 2017, 52(7): 1041-1047.
ZHANG Le, BAI Zhao-fang, LI Chun-yu, HU Huang-wan-yin, SHA Meng-chen, LIU Zhen-xing, HE Qin, LI Yu-meng, LIU You-ping, XIAO Xiao-he, WANG Jia-bo. Study on idiosyncratic liver injury and content of cis-2,3,5,4'-tetrahy­droxystilbene-2-O-β-D-glucoside in radix Polygoni multiflori Preparata[J]. Acta Pharmaceutica Sinica, 2017, 52(7): 1041-1047.

制首乌中顺式二苯乙烯苷转化量与特异质肝损伤的相关性研究
张乐1,2, 柏兆方2, 李春雨2,4, 胡黄婉茵1,2, 沙孟晨2, 刘振兴2, 何琴2, 李雨萌2, 刘友平1, 肖小河2,3, 王伽伯2
1. 成都中医药大学药学院, 四川 成都 611137;
2. 解放军302医院全军中医药研究所, 北京 100039;
3. 解放军302医院中西医结合肝病诊疗与研究中心, 北京 100039;
4. 中国医学科学院肿瘤医院, 北京 100021
摘要:
考察制首乌中易感物质顺式二苯乙烯苷(顺式-2,3,5,4'-四羟基二苯乙烯-2-O-β-D-葡萄糖苷,cis-SG)转化量与特异质肝损伤的相关性,并探讨其可能的安全限度。通过光照将制首乌50%乙醇提取液中反式二苯乙烯苷(反式-2,3,5,4'-四羟基二苯乙烯-2-O-β-D-葡萄糖苷,trans-SG)转化为cis-SG,得到不同转化量的样品,分别在正常大鼠和内毒素(2.8 mg·kg-1,iv)复制的易感性模型大鼠上给药(7.56 g·kg-1,ig),考察血浆生化指标、炎症因子及组织病理的改变等,比较大鼠肝损伤作用的差异。结果表明,所有制首乌样品在正常大鼠上均未引起肝损伤;在内毒素模型上,未光照、光转化cis-SG含量0.10% 的制首乌样品均未见明显的肝损伤,而光转化cis-SG含量0.35% 和0.70% 的制首乌样品均引起明显肝脏病理改变,表现为肝细胞肿胀坏死、大量炎症细胞浸润,肝组织核转录因子-κB(NF-κB)p65表达量、细胞凋亡率均显著增加(P <0.05),同时血浆ALT、AST、TNF-α和IL-6含量均显著增加(P <0.05),过氧化物酶体增殖物激活受体-γ(PPAR-γ)含量显著降低(P <0.05)。同时,临床上制首乌引起肝损伤患者的余留药物含量分析发现,其cis-SG含量(>0.40%)均高于产地收集饮片(<0.10%)。综合实验评价和临床分析结果提示,易感物质cis-SG含量与制首乌特异质肝损伤存在一定的量-毒关系;为降低临床用药风险,初步建议可将cis-SG含量0.10% 作为何首乌生产炮制过程的质控限度。
关键词:    制首乌      特异质肝损伤      内毒素模型      顺式二苯乙烯苷      限度     
Study on idiosyncratic liver injury and content of cis-2,3,5,4'-tetrahy­droxystilbene-2-O-β-D-glucoside in radix Polygoni multiflori Preparata
ZHANG Le1,2, BAI Zhao-fang2, LI Chun-yu2,4, HU Huang-wan-yin1,2, SHA Meng-chen2, LIU Zhen-xing2, HE Qin2, LI Yu-meng2, LIU You-ping1, XIAO Xiao-he2,3, WANG Jia-bo2
1. School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China;
2. China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing 100039, China;
3. Integrative Medicine Center, 302 Military Hospital, Beijing 100039, China;
4. Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China
Abstract:
This study was designed to investigate the correlation between idiosyncratic liver injury and content of cis-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside(cis-SG)in radix Polygoni multiflori Preparata(RPMP). In order to compare the effect of hepatotoxicity of different cis-SG contents in RPMP, rats were administered with 50% alcohol extracts of RPMP(7.56 g·kg-1, via intragastric administration)alone or co-treated with lipopolysaccharide(LPS, 2.8 mg·kg-1, via tail vein injection). The results showed that no significant alterations of plasma ALT and AST activities were observed in the normal rats. In the LPS treated rats, the group without light treatment and the group with 0.10% cis-SG after light treatment did not exhibit obvious injury in liver. The group with 0.35% cis-SG after light treatment and the group with 0.70% cis-SG after light treatment showed significant increases in ALT, AST, TNF-α, IL-6, NF-κB p65 and apoptosis rate(P < 0.05), causing pathological changes in the liver tissue. Through the content analysis of drug in patients with liver injury, we found that the content of cis-SG(> 0.40%)was generally higher than that of pieces collected from different origins(< 0.10%). The comparative analysis of experiments and clinical data showed that there was a relationship between the content of cis-SG and idiosyncratic liver injury. In order to reduce the risk of clinical medication, the content of cis-SG of 0.10% should be a limit of quality control in the production processing of Polygonum multiflorum.
Key words:    radix Polygoni multiflori Preparata    idiosyncratic liver injury    endotoxin model    cis-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside    limit   
收稿日期: 2017-04-04
DOI: 10.16438/j.0513-4870.2017-0307
基金项目: 国家“重大新药创制”科技重大专项资助项目(2015ZX09501-004-001-008);国家公益性行业专项资助项目(201507004-04);北京市科技新星计划项目(Z16111000490000)
通讯作者: 王伽伯,Tel/Fax:86-10-66933325,E-mail:wjb0128@126.com
Email: wjb0128@126.com
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参考文献:
[1] China Pharmacopoeia Committee. Chinese Pharmacopoeia(中国药典)[M]. Beijing: China Medical Science Press, 2015: 175.
[2] Lei X, Chen J, Ren J, et al. Liver damage associated with Polygonum multiflorum Thunb.: a systematic review of case reports and case series [J]. Evid Based Complement Alternat Med, 2015, 2015: 459749.
[3] Li CY, Li YF, Tu C, et al. The idiosyncratic hepatotoxicity of Polygonum multiflorum based on endotoxin model [J]. Acta Pharm Sin(药学学报), 2015, 50: 28-33.
[4] Kong WJ, Wang JB, Zhang QC, et al. A novel "target con­stituent knock-out" strategy coupled with TLC, UPLC-ELSD and microcalorimetry for preliminary screening of antibacterial constituents in Calculus bovis [J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2011, 879: 3565-3573.
[5] Meng YK, Li CY, Li RY, et al. Mechanism of Polygonum multiflorum induced liver injury: cis-stilbene glucoside induces immunological idiosyncratic hepatotoxicity by suppressing PPAR-γ in a lipopolysaccharide model [J]. Acta Pharmacol Sin, 2017. DOI: 10.1038/aps.2017.32.
[6] Li CY, Niu M, Bai ZF, et al. Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb Polygonum multiflorum [J]. Front Med, 2017. DOI: 10.1007/s11684-017-0508-9.
[7] China Pharmacopoeia Committee. Chinese Pharmacopoeia(中国药典)[M]. Beijing: China Medical Science Press, 2010: 122.
[8] Beijing Food and Drug Administration. Beijing Standardized Processing of Chinese Herbal Pieces(北京市中药饮片炮制规范·上册)[M]. Beijing: Chemical Industry Press, 2008: 139.
[9] Lü Y, Wang JB, Ji Y, et al. Influence of extracting solvent on hepatocytes toxicity of Polygonum multiflorum [J]. Chin J Exp Tradit Med Form(中国实验方剂学杂志), 2013, 20: 268-272.
[10] Li XF, Li N, Tu C, et al. Comparison of crude and prepared Polygonum multiflorum-induced idiosyncratic hepatotoxicity based on lipopolysaccharide model [J]. Chin Tradit Herbal Drugs(中草药), 2015, 46: 1481-1486.
[11] Yee SB, Hanumegowda UM, Copple BL, et al. Endothelial cell injury and coagulation system activation during synergistic hepatotoxicity from monocrotaline and bacterial lipopolysac­charide coexposure [J]. Toxicol Sci, 2003, 74: 203-214.
[12] Zhu Y, Niu M, Chen J, et al. Comparison between Chinese herbal medicine and Western medicine-induced liver injury of 1985 patients [J]. J Gastroenterol Hepatol, 2016, 31: 1476.
[13] Zhu Y, Liu SH, Wang JB, et al. Clinical analysis of drug-induced liver injury caused by Polygonum multiflorum and its preparations [J]. Chin J Integr Tradit West Med(中国中西医结合杂志), 2015, 35: 1442-1447.
[14] Wang JB, Cui HR, Bai ZF, et al. Precision medicine-oriented safety assessment strategy for traditional Chinese medicines: disease-syndrome-based toxicology [J]. Acta Pharm Sin(药学学报), 2016, 51: 1681-1688.
[15] Krueger W, Boelsterli UA, Rasmussen TP. Stem cell strate­gies to evaluate idiosyncratic drug-induced liver injury [J]. J Clin Transl Hepatol, 2014, 2: 143-152.
[16] Wang Q, Mei H, Zhang YL, et al. The associations between idiosyncratic adverse drug reactions and HLA alleles and their underlying mechanism [J]. Acta Pharm Sin(药学学报), 2013, 48: 799-808.
[17] Roth RA, Ganey PE. Animal models of idiosyncratic drug-induced liver injury—current status [J]. Crit Rev Toxicol, 2011, 41: 723-739.
[18] Waring JF, Liguori MJ, Luyendyk JP, et al. Microarray analysis of lipopolysaccharide potentiation of trovafloxacin-induced liver injury in rats suggests a role for proinflammatory chemokines and neutrophils [J]. J Pharmacol Exp Ther, 2006, 316: 1080-1087.
[19] Luyendyk JP, Lehman-Mckeeman LD, Nelson DM, et al. Coagulation-dependent gene expression and liver injury in rats given lipopolysaccharide with ranitidine but not with famo­tidine [J]. J Pharmacol Exp Ther, 2006, 317: 635-643.
[20] Li RF, Feng WW, Li XF, et al. Influence of metal ions on stability of 2,3,5,4'-tetrahydroxy stilbene-2-O-β-D-glucoside contained in Polygoni Multiflori radix [J]. Acta Pharm Sin(药学学报), 2016, 51: 116-121.
相关文献:
1.张乐, 柏兆方, 李春雨, 胡黄婉茵, 沙孟晨, 刘振兴, 何琴, 李雨萌, 刘友平, 肖小河, 王伽伯.制首乌中顺式二苯乙烯苷转化量与特异质肝损伤的相关性研究[J]. 药学学报,