Article(id=1210517375212974371, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210517366081975259, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2022-0589, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1652630400000, receivedDateStr=2022-05-16, revisedDate=1660838400000, revisedDateStr=2022-08-19, acceptedDate=null, acceptedDateStr=null, onlineDate=1766539432575, onlineDateStr=2025-12-24, pubDate=1668182400000, pubDateStr=2022-11-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766539432575, onlineIssueDateStr=2025-12-24, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766539432575, creator=13701087609, updateTime=1766539432575, updator=13701087609, issue=Issue{id=1210517366081975259, tenantId=1146029695717560320, journalId=1189982191388893191, year='2022', volume='57', issue='11', pageStart='3259', pageEnd='3450', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1766539430399, creator=13701087609, updateTime=1766539608198, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1210518111875363690, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210517366081975259, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1210518111875363691, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210517366081975259, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=3371, endPage=3377, ext={EN=ArticleExt(id=1210517375758233924, articleId=1210517375212974371, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=HPLC-Q-TOF-MS/MS analysis of Danshen-Honghua herb pair in vivo metabolites in the intestinal flora, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Identification of metabolites of Danshen-Honghua herb pairs in isolated rat intestinal flora based on HPLC-Q-TOF-MS/MS technique. By incubating enterobacteria in isolated rats as well as inactivated enterobacteria in the incubation solution. The extracts of Danshen-Honghua herb pairs were added separately and co-incubated under anaerobic conditions. Animal experiments and protocols were approved by the Laboratory Animal Ethics Committee of Shaanxi University of Traditional Chinese Medicine (approval number: TCM-2020-030-E05). A total of 14 compounds, including 5 prototypes and 9 metabolites, were identified in the isolated rat intestinal incubation fluid. In contrast, no metabolites were detected in the inactivated enterobacterial fluid, except for the prototype component. The results showed that the main components of the Danshensu, salvianolic acid B, rosmarinic acid, lithospermic acid, and hydroxysafflor yellow A, could be metabolized by the intestinal flora, and these active ingredients were mainly metabolized in the rat intestinal flora in isolation by hydroxylation, decarboxylation, deoxygenation, decarboxylation and dehydration in phase Ⅰ, sulfate esterification and methylation in phase Ⅱ. This proved that the Danshen-Honghua herb pair could be transformed into various metabolites by the action of rat intestinal flora, further clarifying the role of intestinal flora in the metabolic transformation of the active ingredients of Chinese medicine and laying the foundation for perfecting the potent substances of the pair.

, correspAuthors=Xiao-ping WANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2022 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Hui-hui ZHOU, Cheng HUAN, Zhi-peng XUE, Shao-bing DU, Jing LI, Yi MENG, Ji-qing BAI, Xiao-ping WANG), CN=ArticleExt(id=1210517376689369475, articleId=1210517375212974371, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=HPLC-Q-TOF-MS/MS分析丹参-红花药对在离体肠道菌群中的代谢产物, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

基于高效液相色谱-四极杆飞行时间质谱鉴别丹参-红花药对在离体大鼠肠道菌群中的代谢产物。通过在离体大鼠的肠菌孵育液以及灭活的肠菌孵育液中, 分别加入丹参-红花药对提取液, 厌氧条件下共孵育。动物实验和方案经陕西中医药大学实验动物伦理委员会批准(批准文号: TCM-2020-030-E05)。结果发现在离体大鼠肠道孵育液中共检测鉴定出14种化合物, 其中包括了5种原形成分以及9种代谢产物。而在灭活的肠菌液中除了原形成分外并未检测出代谢产物。结果表明丹参-红花药对中的主要成分丹参素、丹酚酸B、迷迭香酸、紫草酸、羟基红花黄色素A均可被肠道菌群代谢, 且这些有效成分在大鼠离体肠道菌群中主要发生羟基化反应、脱羧反应、去氧、脱羧以及脱水反应等Ⅰ相代谢、硫酸酯化反应和甲基化反应Ⅱ相代谢。从而证明丹参-红花药对能够在大鼠肠道菌群作用下转化为多种代谢产物, 进一步明确肠道菌群在中药有效成分代谢转化过程中的作用, 为完善该药对药效物质奠定了基础。

, correspAuthors=王小平, authorNote=null, correspAuthorsNote=
*王小平, Tel: 85-29-38185165, E-mail:
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Chin J Appl Chem (应用化学), 2021, 38: 323-330., articleTitle=In vitro biotransformation of protopanaxatriol saponin from red ginseng by intestinal flora and its effect on intestinal flora, refAbstract=null), Reference(id=1210517388190151442, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210517375212974371, doi=null, pmid=null, pmcid=null, year=2018, volume=34, issue=null, pageStart=20, pageEnd=23, url=null, language=null, rfNumber=[21], rfOrder=20, authorNames=Gao JX, Ding JX, Wang JY, journalName=J Harbin Univ Commerce Nat Sci Ed (哈尔滨商业大学学报·自然科学版), refType=null, unstructuredReference= Gao JX , Ding JX , Wang JY et al . Research on intestinal metabolism of chemical constituents in traditions Chinese medicine[J]. 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A: Danshen-Honghua extract; B: Mixed reference substance. 1: Danshensu; 2: Hydroxysafflor yellow A; 3: Rosmarinic acid; 4: Shikoric acid; 5: Salvianolic acid B , figureFileSmall=904Gt/ubDzG/1xT6LWEfWw==, figureFileBig=6wsLaoXf79w05tXNEY8sVg==, tableContent=null), ArticleFig(id=1210517384041984704, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210517375212974371, language=EN, label=null, caption=null, figureFileSmall=jLUp4ghPDLd7Ym6V+qJpmQ==, figureFileBig=Vrw7i4u2Vxp0TbUrd7Mhog==, tableContent=null), ArticleFig(id=1210517384104899266, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210517375212974371, language=CN, label=Figure 2, caption= Base peak intensity (BPI) chromatograms of metabolites of effective components of Danshen-Honghua pair in negative ion modes by UPLC-Q-TOF MS/MS analysis. 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No.tR/minm/zError /ppmFormulaFragment ionIdentification
ExperimentalTheoretical
M1a5.2197.045 8197.044 94.57C9H9O5135.037 5, 109.030 0Danshensu
M25.53627.155 1627.155 5-0.64C27H31O17627.155 0, 609.264 9, 509.091 2Hydroxylation product of HSYA
M35.55277.002 3277.001 23.97C9H9O8S197.010 7, 179.501 2, 135.037 5Sulfate danshensu
M45.84153.019 5153.018 28.50C7H5O4109.033 1Protocatechuic acid
M59.81165.055 8165.054 67.27C9H9O3121.030 63-Phenyl-2-hydroxypropanoic acid
M69.92181.050 8181.049 57.18C9H9O4135.037 5, 121.030 6, 109.050 2Deoxydanshensu
M7a10.72611.163 1611.160 64.09C27H31O16491.120 6, 403.104 3, 325.072 6HSYA
M811.26179.035 2179.033 87.82C9H7O4135.045 6Caffeic acid
M915.48551.114 3551.118 4-7.44C28H23O12551.284 2, 507.293 4, 353.121 5Methyl lithospermic acid
M10a23.2359.075 5359.076 1-1.67C18H15O8197.046 3, 179.035 4, 135.037 5Rosmarinic acid
M1123.68493.116 6493.112 97.50C26H21O10313.073 2, 295.062 0, 197.046 1Decarboxylation product of lithospermic acid
M12a23.70537.105 6537.102 75.40C27H21O12493.121 5, 295.062 3, 197.046 3Lithospermic acid
M13a24.43717.146 4717.145 01.95C36H29O16519.097 9, 339.054 1, 321.043 3Salvianolic acid B
M1425.44731.160 1731.160 7-0.82C37H31O16533.112 3, 353.063 2, 335.061 5Methyl salvianolic acid B
), ArticleFig(id=1210517384557884115, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210517375212974371, language=CN, label=Table 1, caption=

Metabolites of Danshen-Honghua herb pairs in normal rat intestinal bacterial fluid. HYSA: Hydroxysafflor yellow A. aPrototype component

, figureFileSmall=null, figureFileBig=null, tableContent=
No.tR/minm/zError /ppmFormulaFragment ionIdentification
ExperimentalTheoretical
M1a5.2197.045 8197.044 94.57C9H9O5135.037 5, 109.030 0Danshensu
M25.53627.155 1627.155 5-0.64C27H31O17627.155 0, 609.264 9, 509.091 2Hydroxylation product of HSYA
M35.55277.002 3277.001 23.97C9H9O8S197.010 7, 179.501 2, 135.037 5Sulfate danshensu
M45.84153.019 5153.018 28.50C7H5O4109.033 1Protocatechuic acid
M59.81165.055 8165.054 67.27C9H9O3121.030 63-Phenyl-2-hydroxypropanoic acid
M69.92181.050 8181.049 57.18C9H9O4135.037 5, 121.030 6, 109.050 2Deoxydanshensu
M7a10.72611.163 1611.160 64.09C27H31O16491.120 6, 403.104 3, 325.072 6HSYA
M811.26179.035 2179.033 87.82C9H7O4135.045 6Caffeic acid
M915.48551.114 3551.118 4-7.44C28H23O12551.284 2, 507.293 4, 353.121 5Methyl lithospermic acid
M10a23.2359.075 5359.076 1-1.67C18H15O8197.046 3, 179.035 4, 135.037 5Rosmarinic acid
M1123.68493.116 6493.112 97.50C26H21O10313.073 2, 295.062 0, 197.046 1Decarboxylation product of lithospermic acid
M12a23.70537.105 6537.102 75.40C27H21O12493.121 5, 295.062 3, 197.046 3Lithospermic acid
M13a24.43717.146 4717.145 01.95C36H29O16519.097 9, 339.054 1, 321.043 3Salvianolic acid B
M1425.44731.160 1731.160 7-0.82C37H31O16533.112 3, 353.063 2, 335.061 5Methyl salvianolic acid B
), ArticleFig(id=1210517384641770199, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210517375212974371, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No.tR/minm/zError /ppmFormulaFragment ionIdentification
ExperimentalTheoretical
U1a3.48197.046 1197.044 96.09C9H9O5135.045 8, 123.045 6, 109.029 6Danshensu
U2a8.50611.163 5611.160 74.75C27H31O16491.120 8, 403.104 5, 325.072 7HSYA
U3a22.89359.079 6359.076 19.75C18H15O8197.046 9, 179.036 0, 135.045 6Rosmarinic acid
U4a23.55537.105 0537.102 74.28C27H21O1493.121 3, 295.061 9, 197.045 9Lithospermic acid
U5a24.99717.148 2717.145 04.46C36H29O16519.094 3, 339.051 6, 321.041 1Salvianolic acid B
), ArticleFig(id=1210517384767599324, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210517375212974371, language=CN, label=Table 2, caption=

Metabolites of Danshen-Honghua herb pairs in inactivated intestinal fluids. aPrototype component

, figureFileSmall=null, figureFileBig=null, tableContent=
No.tR/minm/zError /ppmFormulaFragment ionIdentification
ExperimentalTheoretical
U1a3.48197.046 1197.044 96.09C9H9O5135.045 8, 123.045 6, 109.029 6Danshensu
U2a8.50611.163 5611.160 74.75C27H31O16491.120 8, 403.104 5, 325.072 7HSYA
U3a22.89359.079 6359.076 19.75C18H15O8197.046 9, 179.036 0, 135.045 6Rosmarinic acid
U4a23.55537.105 0537.102 74.28C27H21O1493.121 3, 295.061 9, 197.045 9Lithospermic acid
U5a24.99717.148 2717.145 04.46C36H29O16519.094 3, 339.051 6, 321.041 1Salvianolic acid B
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HPLC-Q-TOF-MS/MS分析丹参-红花药对在离体肠道菌群中的代谢产物
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周慧慧 1 , 环诚 2 , 薛志鹏 1 , 杜少兵 1 , 李菁 1 , 孟祎 1 , 白吉庆 1 , 王小平 1, *
药学学报 | 研究论文 2022,57(11): 3371-3377
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药学学报 | 研究论文 2022, 57(11): 3371-3377
HPLC-Q-TOF-MS/MS分析丹参-红花药对在离体肠道菌群中的代谢产物
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周慧慧1, 环诚2, 薛志鹏1, 杜少兵1, 李菁1, 孟祎1, 白吉庆1, 王小平1, *
作者信息
  • 1.陕西中医药大学药学院/陕西省中药基础与新药研究重点实验室, 陕西 咸阳 712046
  • 2.陕西中医药大学医学技术学院, 陕西 咸阳 712046

通讯作者:

*王小平, Tel: 85-29-38185165, E-mail:
HPLC-Q-TOF-MS/MS analysis of Danshen-Honghua herb pair in vivo metabolites in the intestinal flora
Hui-hui ZHOU1, Cheng HUAN2, Zhi-peng XUE1, Shao-bing DU1, Jing LI1, Yi MENG1, Ji-qing BAI1, Xiao-ping WANG1, *
Affiliations
  • 1. College of Pharmacy and Shaanxi Provincial Key Laboratory for Chinese Medicine Basis & New Drugs Research, Shaanxi University of Chinese Medicine, Xianyang 712046, China
  • 2. Department of Medical Technology, Shaanxi University of Chinese Medicine, Xianyang 712046, China
出版时间: 2022-11-12 doi: 10.16438/j.0513-4870.2022-0589
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基于高效液相色谱-四极杆飞行时间质谱鉴别丹参-红花药对在离体大鼠肠道菌群中的代谢产物。通过在离体大鼠的肠菌孵育液以及灭活的肠菌孵育液中, 分别加入丹参-红花药对提取液, 厌氧条件下共孵育。动物实验和方案经陕西中医药大学实验动物伦理委员会批准(批准文号: TCM-2020-030-E05)。结果发现在离体大鼠肠道孵育液中共检测鉴定出14种化合物, 其中包括了5种原形成分以及9种代谢产物。而在灭活的肠菌液中除了原形成分外并未检测出代谢产物。结果表明丹参-红花药对中的主要成分丹参素、丹酚酸B、迷迭香酸、紫草酸、羟基红花黄色素A均可被肠道菌群代谢, 且这些有效成分在大鼠离体肠道菌群中主要发生羟基化反应、脱羧反应、去氧、脱羧以及脱水反应等Ⅰ相代谢、硫酸酯化反应和甲基化反应Ⅱ相代谢。从而证明丹参-红花药对能够在大鼠肠道菌群作用下转化为多种代谢产物, 进一步明确肠道菌群在中药有效成分代谢转化过程中的作用, 为完善该药对药效物质奠定了基础。

丹参-红花药对  /  肠道菌群  /  代谢产物  /  HPLC-Q-TOF-MS/MS  /  裂解途径  /  裂解规律

Identification of metabolites of Danshen-Honghua herb pairs in isolated rat intestinal flora based on HPLC-Q-TOF-MS/MS technique. By incubating enterobacteria in isolated rats as well as inactivated enterobacteria in the incubation solution. The extracts of Danshen-Honghua herb pairs were added separately and co-incubated under anaerobic conditions. Animal experiments and protocols were approved by the Laboratory Animal Ethics Committee of Shaanxi University of Traditional Chinese Medicine (approval number: TCM-2020-030-E05). A total of 14 compounds, including 5 prototypes and 9 metabolites, were identified in the isolated rat intestinal incubation fluid. In contrast, no metabolites were detected in the inactivated enterobacterial fluid, except for the prototype component. The results showed that the main components of the Danshensu, salvianolic acid B, rosmarinic acid, lithospermic acid, and hydroxysafflor yellow A, could be metabolized by the intestinal flora, and these active ingredients were mainly metabolized in the rat intestinal flora in isolation by hydroxylation, decarboxylation, deoxygenation, decarboxylation and dehydration in phase Ⅰ, sulfate esterification and methylation in phase Ⅱ. This proved that the Danshen-Honghua herb pair could be transformed into various metabolites by the action of rat intestinal flora, further clarifying the role of intestinal flora in the metabolic transformation of the active ingredients of Chinese medicine and laying the foundation for perfecting the potent substances of the pair.

Danshen-Honghua herb pair  /  intestinal flora  /  metabolite  /  HPLC-Q-TOF-MS/MS  /  cleavage pathway  /  cleavage law
周慧慧, 环诚, 薛志鹏, 杜少兵, 李菁, 孟祎, 白吉庆, 王小平. HPLC-Q-TOF-MS/MS分析丹参-红花药对在离体肠道菌群中的代谢产物. 药学学报, 2022 , 57 (11) : 3371 -3377 . DOI: 10.16438/j.0513-4870.2022-0589
Hui-hui ZHOU, Cheng HUAN, Zhi-peng XUE, Shao-bing DU, Jing LI, Yi MENG, Ji-qing BAI, Xiao-ping WANG. HPLC-Q-TOF-MS/MS analysis of Danshen-Honghua herb pair in vivo metabolites in the intestinal flora[J]. Acta Pharmaceutica Sinica, 2022 , 57 (11) : 3371 -3377 . DOI: 10.16438/j.0513-4870.2022-0589
肠道菌群是中药有效成分代谢的重要环节之一[1]。肠道菌群中有多种药物代谢酶, 不同种类的细菌产生不同的代谢酶, 而不同的药物代谢酶又会参与到不同类型的药物代谢中[2]。药物在口服进入消化道后, 会与大量的细菌接触, 使药物在发生肝脏的首过效应之前就进行了生物转化[3], 从而转化为各种代谢产物。
丹参-红花药对是我国具有活血化瘀作用的传统中药组合, 两者合用已被广泛用于治疗心血管疾病中[4]。丹参-红花配伍用药多见于近现代的许多中药方剂中, 比如丹红注射液、中风回春片、丹红化瘀口服液、丹桂香颗粒、心宁片等[5]。本文以丹参-红花药对为研究对象, 通过体外肠道菌群代谢实验, 鉴定其活性成分及代谢产物的结构, 从而阐明丹参-红花发挥药效的物质基础以及肠道菌群对药物代谢的转化作用。
仪器  Ultimate 3000型超高效液相色谱系统和Q Exactive Focus型质谱仪(美国Thermo Fisher Scientific公司); 电热恒温水浴锅(HX-25, 上海宜昌仪器纱筛厂); Direct-Q3 UV纯水超纯水一体机(美国Millipore公司); 101-2型电热鼓风干燥箱(北京科伟永兴仪器设备有限公司); 离心机(TG16-MW, 湖南赫西仪器装备有限公司); QL-861型涡旋混合仪(江苏海门市其林贝尔仪器制造); 全自动高压灭菌器(MLS-3780, 日本SANYO公司); 洁净工作台(BBS-SDC, 济南鑫贝西生物技术有限公司); 恒温培养箱(DUP-25, 江苏金怡仪器科技有限公司)。
试剂与试药  丹参采自山东省菏泽市鄄城县, 红花采自新疆维吾尔自治区塔城市裕民县, 均经陕西中医药大学中药鉴定教研室白吉庆教授鉴定, 丹参为唇形科植物丹参Salvia miltiorrhiza Bge.的干燥根和根茎, 红花为菊科植物红花Carthamus tinctorius L.的干燥花。盐酸异丙肾上腺素(批号: P1794259, 美国Sigma公司); 丹酚酸B对照品(批号: 111562-201716, 99.8%)、丹参素对照品(批号: DST170420-015, 98.0%) 均由成都德思特生物技术有限公司提供; 紫草酸对照品(批号: 19053003, 99.8%) 购自江西森岚科技有限公司; 迷迭香酸对照品(批号: BZP0004, 98.0%)、原儿茶酸(批号: 250088-85-5, 98%) 均由江西佰草源生物科技有限公司提供; 羟基红花黄色素A对照品(批号: 111637-201810, 93.1%), 购自中国食品药品检定研究院; 厌氧产气包、GAM培养基(批号: 20210616)、维生素K1 (批号: 20210518)、氯化血红素(批号: 20210512) 均购自青岛海博生物技术有限公司; 甲醇、乙腈(色谱纯, 美国默克公司)。
动物  SD雄性大鼠, 体重180~220 g, 购自成都达硕有限公司, 合格证号SCXK (川) 2020-030。动物实验和方案经陕西中医药大学实验动物伦理委员会批准(批准文号: TCM-2020-030-E05)。
丹参-红花药对提取液的制备  取丹参30 g, 加水320 mL, 室温浸泡60 min, 加入红花10 g, 50 ℃浸泡提取120 min, 取出放至室温, 滤过, 滤渣加8倍量的水再50 ℃温浸提取2次, 每次120 min, 滤液合并减压浓缩至每毫升含1.44 g生药材。
肠菌孵育液的制备  称取GAM培养基49.0 g于烧杯中, 加入1 000 mL纯化水加热溶解后, 于120 ℃高压灭菌25 min, 冷却至50 ℃左右时, 加入无菌0.1%维生素K1溶液1 mL和氯化血红素(5 mg·mL-1) 1 mL, 混匀, 备用。
取大鼠的盲肠内容物与无菌生理盐水按1 g∶4 mL的比例混合, 涡旋3 min, 10 000 r·min-1离心10 min, 取上清液按1∶9 mL比例加入到已灭菌的厌氧培养基中, 混匀后, 置厌氧培养袋中, 于37 ℃恒温培养箱中预孵育12 h, 使肠菌培养液中的肠道菌充分成长。以肠菌培养液再次加热灭菌, 使培养系统中的菌群失活, 作为阴性对照, 以消除培养基等环境因素的干扰。
体外共孵育  取正常肠菌孵育液、灭活的肠菌孵育液各2 mL分别置于培养瓶中, 再分别加入0.1 mL丹参-红花提取液(0.288 g·mL-1), 混合均匀后。将培养瓶置于厌氧培养袋中, 于37 ℃恒温培养箱中孵育24 h后取样。
样品预处理  上述取得的样品中, 分别加入1 mL甲醇, 终止反应后涡旋振摇3 min, 在13 000 r·min-1条件下离心10 min, 取上清液经0.22 μm无菌微孔滤膜滤过, 采用UPLC-Q-TOF /MS进行分析。
色谱条件  色谱柱为Thermo Hypersil Syncronis C18色谱柱(100 mm × 2.1 mm, 1.7 μm); 保护柱Syncronis C18 (100 mm × 2.1 mm, 1.7 μm); 流动相为0.1%甲酸水溶液(A)-乙腈溶液(B), 梯度洗脱程序为0 min, 6% B; 0~5 min, 6%~10% B; 5~20 min, 10%~21% B; 20~27 min, 21%~48% B; 27~30 min, 48%~100% B; 30~35 min, 100% B; 35~38min, 100%~6% B; 38 min, 6% B。柱温35 ℃; 体积流量为0.3 mL·min-1, 进样量1 μL。
质谱条件  离子源为加热电喷雾离子源(HESI), 喷雾电压3.5 kV, 鞘气(N2) 流量40 arb, 辅助气流量10 arb, 辅助加热器温度350 ℃, 毛细管温度320 ℃, S-lens射频水平50, 自动增益控制(AGC) 106。扫描方式采用正、负离子Full MS/dd-MS2模式, Full MS分辨率17 500, dd-MS2分辨率35 000; 扫描范围m/z 100~1 500, 碰撞能量30 eV。
本研究采用HPLC-UVD法对丹参-红花药对中主要活性成分进行定性鉴别, 结果如图 1显示。
利用UPLC-ESI-Q-TOF-MS/MS技术对大鼠肠道孵育液样品进行检测, 获得了不含药物的空白肠菌液、灭活的肠菌液以及正常大鼠的肠菌液谱图, 见图 2
对各成分的质谱图进行质谱谱库检索、查阅文献以及人工图谱解析, 从而推测代谢产物的化学式, 见表 12
tR为5.20 min时, 化合物M1在负离子模式下出现准分子离子峰[M-H]- m/z 197.045 8 (C9H9O5), 误差为4.57, 碎片离子[M-H-CO2-H2O]- m/z 135.037 5 (C8H7O2), 经与对照品核对, 结合文献[6]确认化合物M1为丹参素; 在tR为5.55 min时, 化合物M3的[M-H]-分子离子峰是m/z 277.002 3 (C9H9O8S), 比丹参素的分子量多了80 Da, 其碎片离子[M-H-SO3]- m/z 197.010 7 (C8H7O2), 结合文献[7]确认化合物M3为丹参素硫酸盐; 化合物M5的[M-H]-分子离子峰是m/z 165.055 8 (C9H9O3), 碎片离子[M-H-CO2]- m/z 121.030 6 (C8H9O), 其相对分子质量较丹参素减少了32 Da (-2O), 据参考文献[8], 推测化合物M5为丹参素的去氧产物(羟基苯基丙酸); 在tR为9.92 min时, 负离子模式下出现准分子离子峰[M-H]- m/z 181.050 8 (C9H9O4), 误差为7.18, 碎片离子[M-H-H2CO2]- m/z 135.037 5 (C8H7O2), 其相对分子质量较丹参素减少了16 Da (-O), 据参考文献[9], 推测化合物M6为丹参素的去氧产物。
化合物M8在负离子模式下出现准分子离子峰[M-H]- m/z 179.035 2 (C9H7O4), 碎片离子[M-H-CO2]- m/z 135.045 6 (C8H7O2), 其相对分子质量较丹参素减少了18 Da (-H2O), 经与对照品核对, 结合参考文献[10], 推测化合物M8为咖啡酸。
tR为23.2 min时, 化合物M10的准分子离子峰[M-H]- m/z 359.075 5, 分子式为C18H15O8, 碎片离子[M-H-C9H5O3]- m/z 197.046 3 (C9H9O5)、[M-H-H2O-C9H5O3]- m/z 179.035 4 (C9H7O4), 根据其质谱信息及二级碎片离子, 与对照品核对, 结合参考文献[11], 推测化合物M10为迷迭香酸; 在tR为5.84 min时, 化合物M4负离子模式下出现准分子离子峰[M-H]- m/z 153.019 5 (C7H5O4), 误差为8.50, 碎片离子[M-H-CO2]- m/z 109.033 1 (C6H5O2)、[M-CO2-H2O]- m/z 91.022 5 (C6H3O), 经与对照品核对并结合文献[12], 推测化合物M4为原儿茶酸; 化合物M13负离子模式下出现准分子离子峰[M-H]- m/z 717.146 4 (C36H29O16), 误差为1.95, 碎片离子[M-H-C9H10O5]- m/z 519.097 9 (C27H19O11), [M-H-C9H10O5-C9H8O4]- m/z 339.054 1 (C18H11O7)、[M-H-2C9H10O5]- m/z 321.043 3 (C18H9O6), 与丹酚酸B对照品一致, 推测化合物M13为丹酚酸; 化合物M14在负离子模式下出现准分子离子峰[M-H]- m/z 731.160 1 (C37H31O16), 误差为-0.82, 碎片离子[M-H-C9H10O5]- m/z 533.112 3 (C28H21O11), 其精确分子量比丹酚酸B增加了14 Da (+CH3), 为1分子甲基的相对分子质量, 根据其质谱信息及二级碎片离子, 结合参考文献[13], 推测化合物M14为甲基丹酚酸B。
化合物M7在负离子模式下出现准分子离子峰[M-H]- m/z 611.163 1 (C27H31O16), 误差为4.09, 碎片离子[M-H-C4H8O4]- m/z 491.120 6 (C23H23O12)、[M-H-C6H10O5-H2O-CO]- m/z 403.104 3 (C20H19O9), 经与对照品核对, 结合参考文献[14], 推测化合物M7为羟基红花黄色素A; 化合物M2的准分子离子峰[M-H]- m/z 627.155 1, 分子式为C27H31O17, 误差为-0.64, 碎片离子[M-H-H2O]- m/z 609.264 9 (C27H28O16), 其相对分子质量较羟基红花黄色素A增加了16 Da (+O), 与文献[15]报道一致, 推测化合物M2为羟基红花黄色素A的羟基化产物。
化合物M12的准分子离子峰[M-H]- m/z 537.105 6 (C27H21O12), 碎片离子[M-H]- m/z 537.105 6 (C27H21O12)、[M-H-CO2]- m/z 493.121 5 (C26H21O10)、[M-H-CO2-C9H10O5]- m/z 295.062 3 (C17H11O5), 经与对照品核对, 且根据其质谱信息及二级碎片离子, 结合参考文献[16], 推测化合物M12为紫草酸; 在tR为15.48 min时, 化合物M9的负离子模式下出现准分子离子峰[M-H]- m/z 551.114 3, 分子式为C28H23O12, 碎片离子[M-H-H2O]- m/z 533.284 5 (C28H21O11)、[M-H-CO2]- m/z 507.293 4 (C27H23O10), 根据其质谱信息及二级碎片离子, 与文献[17]报道一致, M9的相对分子质量比紫草酸增加了14, 鉴定其为紫草酸的甲基化后产物; 在tR为23.68 min时, 化合物M11在负离子模式下出现准分子离子峰[M-H]- m/z 493.116 6 (C26H21O10), 误差为7.50, 碎片离子[M-H-C9H10O5]- m/z 295.062 0 (C17H11O5), 根据其质谱信息及二级碎片离子, 结合参考文献[18], 推测化合物M11为紫草酸脱羧产物。
灭活条件下的大鼠肠道孵育液的代谢除了检测出丹参素、紫草酸、迷迭香酸、羟基红花黄色素A、丹酚酸B 5种原形成分之外, 并未检测出主要成分的代谢产物。
丹参-红花药对中的大部分原形成分及代谢产物为酚酸类成分, 而酚酸类化合物主要含有羟基、羰基以及羧基, 根据实验以及文献总结的质谱规律, 发现在负离子条件下, 酚酸类成分在质谱碰撞中易丢失CO、CO2、H2O等中性碎片。各化合物裂解途径见图 3
传统中草药的使用, 绝大多数以方剂的形式通过口服给药从而发挥药效作用, 口服药物在进入肠道后会不可避免地与肠道菌群发生接触[19], 药物中的某些成分通过肠道菌群发生生物转化, 而使这些化学成分的结构发生改变, 从而导致药物的活性以及生物利用度的改变[20]
本研究以UPLC-ESI-Q-TOF-MS/MS技术为基础, 结合化合物的质谱信息、色谱保留时间、相对分子质量以及国内外文献, 对丹参-红花药对中的主要有效成分及其代谢产物进行分析及鉴定, 在正常大鼠肠道孵育液中共检测鉴定出14种代谢产物, 其中包括了5种原形成分, 而在灭活的大鼠肠道孵育液中并未检测出代谢产物。通过实验推测正常大鼠的肠道菌群的生物转化途径主要包括了Ⅰ相代谢: 羟基化反应、脱羧反应、去氧、脱羧以及脱水反应等。Ⅱ相代谢: 硫酸酯化反应和甲基化反应。
目前, 肠道代谢的方法主要包括了体内法、在体法以及体外法[21], 而体外法是研究药物在肠内代谢的主要方法, 该方法简单易行, 重复性高, 可以排除体内的干扰因素, 从而更好地控制某些代谢条件, 其中肠道菌群实验中的粪便厌氧温孵法, 目前应用比较广泛。本实验通过将正常大鼠的肠道菌群进行体外培养, 从而比较丹参-红花有效成分在不同环境中的代谢产物, 对代谢产物进行分析, 进一步明确肠道菌群在中药有效成分代谢转化过程中的作用。
作者贡献: 周慧慧负责实验的设计、实施及论文撰写; 环诚、薛志鹏和周慧慧负责体外孵育实验与液质数据的处理; 李菁、孟祎负责动物实验部分; 白吉庆和王小平负责基金获得、实验监督以及论文审阅。
利益冲突: 所有作者均声明不存在利益冲突。
  • 国家自然科学基金资助项目(81974544)
  • 陕西省教育厅重点实验室项目(18JS025)
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2022年第57卷第11期
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doi: 10.16438/j.0513-4870.2022-0589
  • 接收时间:2022-05-16
  • 首发时间:2025-12-24
  • 出版时间:2022-11-12
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  • 收稿日期:2022-05-16
  • 修回日期:2022-08-19
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国家自然科学基金资助项目(81974544)
陕西省教育厅重点实验室项目(18JS025)
作者信息
    1.陕西中医药大学药学院/陕西省中药基础与新药研究重点实验室, 陕西 咸阳 712046
    2.陕西中医药大学医学技术学院, 陕西 咸阳 712046

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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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