草乌与生半夏、法半夏配伍的急性毒性及其毒性成分分析
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摘要
目的探索草乌与生半夏、法半夏配伍反与不反及其化学实质。方法采用Bliss法分别计算草乌提取液、草乌与生半夏合煎液、草乌与法半夏合煎液的LD50;利用超高效液相串联四级杆飞行时间质谱(UPLC-Q-TOF-MS)分析两合煎液的成分,通过主成分分析(PCA)与正交偏最小二乘判别分析法(OPLS-DA)进行数据统计,寻找两合煎液中毒性成分差异。结果草乌提取液、草乌与生半夏合煎液、草乌与法半夏合煎液的半数致死量(LD50)分别为7.96、4.40、12.20 g·kg~(-1)。两合煎液化学成分比较,草乌与生半夏合煎液中去氧乌头碱、新乌头碱、次乌头碱、北草乌碱、10-脱乙酰乌头碱(双脂型)和10-OH-苯甲酰新乌头原碱、苯甲酰新乌头原碱、苯甲酰次乌头原碱(单脂型)含量均明显增加,中乌头胺和阿克他林(醇胺型)等含量稍微上升,但尼奥林(醇胺型)含量有所减小。结论急性毒性显示,与单用草乌相比,草乌与生半夏配伍后LD50减小,毒性增大;草乌与法半夏配伍后LD50增大,毒性减小。草乌与生半夏、法半夏配伍毒性增大或者减小与酯型生物碱含量相关。
Objective To investigate the compatibility or incompatibility and the chemistry mechanism of Aconite kusnezoffii Radix(Aconiti kusnezoffii radix,CW)combined with the raw Pinelliae rhizome(Pinelliae rhizome,SBX)and processed Pinelliae rhizoma(Pinelliae rhizoma praeparatum,FBX).Methods LD50 of the extraction of CW,the decoction of CW and SBX,the decoction of CW and FBX was calculated by Bliss method.Then the toxic components of two decoctions were analyzed by UPLC/Q-TOF-MS.The difference was found by orthogonal partial least squares discriminant analysis(OPLS-DA)and principal component analysis(PCA).Results The LD50 of CW extract was 7.96 g?kg~(-1),the decoction of CW and SBX was 4.40 g?kg~(-1),the decoction of CW and FBX was12.20 g?kg~(-1).Comparing the two decoctions,only the content of neoline(amine alkaloids)was reduced,the contents of beiwutine,deacetyl-10-OH-aconitine,deoxyaconitine,aconitine,hypaconitine(diester alkaloids)and 14-benzoyl-10-mesaconine,benzoylaconitine and benzoyl-aconitum(monoester alkaloids),actaline and mesaconine(amine alkaloids)were all increased in the decoction of CW and SBX.Conclusion The LD50 of CW and SBX decoction is reduced,which means the acute toxicity is increased;the LD50 of CW and FBX decoction is raised,which means the acute toxicity is decreased.The increase or decrease of compatibilities of CW and SBX,FBX are related to the contents of ester alkaloids.
Objective To investigate the compatibility or incompatibility and the chemistry mechanism of Aconite kusnezoffii Radix(Aconiti kusnezoffii radix,CW)combined with the raw Pinelliae rhizome(Pinelliae rhizome,SBX)and processed Pinelliae rhizoma(Pinelliae rhizoma praeparatum,FBX).Methods LD50 of the extraction of CW,the decoction of CW and SBX,the decoction of CW and FBX was calculated by Bliss method.Then the toxic components of two decoctions were analyzed by UPLC/Q-TOF-MS.The difference was found by orthogonal partial least squares discriminant analysis(OPLS-DA)and principal component analysis(PCA).Results The LD50 of CW extract was 7.96 g?kg~(-1),the decoction of CW and SBX was 4.40 g?kg~(-1),the decoction of CW and FBX was12.20 g?kg~(-1).Comparing the two decoctions,only the content of neoline(amine alkaloids)was reduced,the contents of beiwutine,deacetyl-10-OH-aconitine,deoxyaconitine,aconitine,hypaconitine(diester alkaloids)and 14-benzoyl-10-mesaconine,benzoylaconitine and benzoyl-aconitum(monoester alkaloids),actaline and mesaconine(amine alkaloids)were all increased in the decoction of CW and SBX.Conclusion The LD50 of CW and SBX decoction is reduced,which means the acute toxicity is increased;the LD50 of CW and FBX decoction is raised,which means the acute toxicity is decreased.The increase or decrease of compatibilities of CW and SBX,FBX are related to the contents of ester alkaloids.
引文
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[19]ZHANG Z H,ZHAO Y Y,CHENG X L,et al.Metabonomic study of biochemical changes in the rat urine induced by Pinellia ternata(Thunb.)Berit[J].Journal of pharmaceutical&biomedical analysis,2013,85(1):186-193.
[20]杨威,肖百全,喻祥,等.《中华人民共和国药典》收录毒性中药材生殖毒性研究进展[J].中国药理学与毒理学杂志,2018,32(5):355-363.
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[22]刘文龙,宋凤瑞,刘志强,等.川乌与半夏配伍禁忌的化学研究[J].化学通报,2008,71(6):435-438.
[23]张鲁,李遇伯,李利新,等.制川乌与法半夏不同比例配伍组合对乌头类生物碱的影响[J].中草药,2013,44(6):681-685.
[2]祝瑞德.乌头伍半夏治疗风寒湿痹症的临床运用[J].浙江中医杂志,2010,45(7):530.
[3]孙世晓,许蔚,王凤,等.生附子-生半夏配伍后急性毒性的实验研究[J].中医药信息,2011,28(2):104-106.
[4]李玲,马瑜红,欧阳静萍,等.附子配伍半夏对大鼠影响的实验研究[J].中国现代药物应用,2009,3(5):5-7.
[5]王为民.对乌头反贝母、瓜蒌、半夏的探讨[J].时珍国医国药,2004,15(3):183-184.
[6]李新莉,赵华.半夏配伍川乌产生相反作用的物质基础研究[J].中医药导报,2012,18(2):82-84.
[7]朱日然,李启艳,张学顺,等.附子与半夏不同炮制品种配伍应用的ESI-MSn研究[J].中国实验方剂学杂志,2011,17(18):62-67.
[8]陈奇.中药药理研究方法学[M].北京:人民卫生出版社,2006:67-68.
[9]许庆轩,王勇,刘志强,等.草乌中二萜类生物碱的电喷雾串联质谱研究[J].高等学校化学学报,2005,26(4):638-641.
[10]王勇,刘淑莹.乌头碱类生物碱的质谱研究进展[J].质谱学报,2002,23(2):112-119.
[11]夏烨,杨春华,刘静涵,等.乌头属药材特征成份二萜生物碱的电喷雾质谱研究进展[J].海峡药学,2009,21(3):1-5.
[12]YAN G,SUN H,SUN W,et al.Rapid and global detection and characterization of aconitum alkaloids in Yin Chen Si Ni Tang,a traditional Chinese medical formula,by ultra performance liquid chromatography-high resolution mass spectrometry and automated data analysis[J].Journal of pharmaceutical&biomedical analysis,2010,53(3):421-431.
[13]HAO Y,PI Z F,SONG F R,et al.Studies on the aconitine-type alkaloids in the roots of Aconitum Carmichaeli Debx.by HPLC/ESIMS/MS[J].Talant,2009,77(5):1800-1807.
[14]王勇,刘志强,宋凤瑞,等.草乌花及其煎煮液中二萜生物碱的电喷雾串联质谱研究[J].药学学报,2003,38(4):290-293.
[15]郑琴,陆浩伟,郝伟伟,等.乌头类双酯型生物碱水解转化规律及含量计算方法研究[J].中国药学杂志,2011,46(9):652-656.
[16]CSUPOR D,FORGO P,WENZIG E M,et al.Bisnorditerpene,norditerpene and lipo-alkaloids from Aconitum toxicum[J].Journal of natural products,2008,71(10):1779-1782.
[17]LIU M,ZHANG H,ZHAO L,et al.LC separation and determination of fivediester-diterpenoid alkaloids in the unprocessed and processed aconiteroots[J].Chromatographia,2008,67(11-12):1003-1006.
[18]杨守业,叶文华,吴子伦,等.半夏炮制前后对小白鼠急性、亚急性和蓄积性毒性的研究[J].中成药,1988(7):18-19.
[19]ZHANG Z H,ZHAO Y Y,CHENG X L,et al.Metabonomic study of biochemical changes in the rat urine induced by Pinellia ternata(Thunb.)Berit[J].Journal of pharmaceutical&biomedical analysis,2013,85(1):186-193.
[20]杨威,肖百全,喻祥,等.《中华人民共和国药典》收录毒性中药材生殖毒性研究进展[J].中国药理学与毒理学杂志,2018,32(5):355-363.
[21]杜贵友,方文贤.有毒中药现代研究与合理应用[M].北京:中国中医药出版社,2000:413.
[22]刘文龙,宋凤瑞,刘志强,等.川乌与半夏配伍禁忌的化学研究[J].化学通报,2008,71(6):435-438.
[23]张鲁,李遇伯,李利新,等.制川乌与法半夏不同比例配伍组合对乌头类生物碱的影响[J].中草药,2013,44(6):681-685.
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