基于斑马鱼模型的柴胡皂苷a保肝作用与肝毒性研究
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摘要
柴胡既有保肝作用又有肝毒性。皂苷类成分是柴胡中的主要药效和毒性物质,其"量-毒-效"关系不明确。该文以柴胡皂苷a(SSa)为例,基于健康和酒精性脂肪肝斑马鱼模型,建立"量-时-毒"曲线,评价相同浓度SSa对斑马鱼生理模型和病理模型的毒性差异,及其对酒精性脂肪肝的保护作用。实验结果显示1. 77μmol·L-1SSa对酒精性脂肪肝具有保护作用,且对健康幼鱼无毒性作用; 5. 30μmol·L-1SSa对酒精性脂肪肝幼鱼无肝毒性且具有肝保护作用,对健康幼鱼具有肝毒性;5. 62μmol·L-1SSa对生理和病理模型均具有肝毒性。该文阐述了柴胡皂苷a"量-毒-效"关系,符合"有故无殒"理论,为柴胡及柴胡皂苷a的临床用药安全提供参考。
Bupleuri Radix has both liver protection and hepatotoxicity. Saponins are the main pharmacodynamic and toxic components of Bupleuri Radix. Based on zebrafish physical model and the model of alcoholic fatty liver( AFL) pathology,the liver toxic and protective effect of saikosaponin a( SSa) were assessed. The results indicated that 1. 77 μmol·L-1 SSa showed protective effect to AFL zebrafish. 5. 30 μmol·L-1 SSa was hepatotoxic to healthy zebrafish,but it showed protective effect to AFL zebrafish. 5. 62 μmol·L-1 SSa was hepatotoxic to healthy and AFL zebrafish. This study is benefit for clinical safety of saikosaponin a.
Bupleuri Radix has both liver protection and hepatotoxicity. Saponins are the main pharmacodynamic and toxic components of Bupleuri Radix. Based on zebrafish physical model and the model of alcoholic fatty liver( AFL) pathology,the liver toxic and protective effect of saikosaponin a( SSa) were assessed. The results indicated that 1. 77 μmol·L-1 SSa showed protective effect to AFL zebrafish. 5. 30 μmol·L-1 SSa was hepatotoxic to healthy zebrafish,but it showed protective effect to AFL zebrafish. 5. 62 μmol·L-1 SSa was hepatotoxic to healthy and AFL zebrafish. This study is benefit for clinical safety of saikosaponin a.
引文
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[13] Xia Q,Wei L,Zhang Y,et al. Psoralen induces developmental toxicity in zebrafish embryos/larvae through oxidative stress,apoptosis,and energy metabolism disorder[J]. Front Pharmacol,2018,9:1457.
[14] Kanungo J,Cuevas E,Ali S F,et al. Zebrafish model in drug safety assessment[J]. Curr Pharm Design,2014,20(34):5416.
[15]林艳.小柴胡汤合理应用常见问题及对策分析[J].海峡药学,2018,219(4):224.
[16]刘旭,刘振华,仲华,等.柴胡注射液致药品不良反应/药品不良事件的分析及防治[J].中国医院用药评价与分析,2018,18(6):840.
[17]杨印军,郑伟,郭佳琪,等.北柴胡、竹叶柴胡、藏柴胡与小叶黑柴胡化学成分比较研究[J].中国中药杂志,2019,44(2):332.
[2] Fude Y,Xiaoxv D,Xingbin Y,et al. Radix Bupleuri:a review of traditional uses,botany,phytochemistry,pharmacology,and toxicology[J]. Biomed Res Int,2017,2017:1.
[3] Yuan B,Yang R,Ma Y,et al. A systematic review of the active saikosaponins and extracts isolated from Radix Bupleuri and their applications[J]. Pharm Biol,2017,55(1):620.
[4]刘亚,刘新民,潘瑞乐.柴胡毒性作用研究进展[J].中成药,2012,34(6):1148.
[5]黄伟,孙蓉,张作平.柴胡总皂苷粗提物多次给药对大鼠肝毒性的“量-时-毒”关系研究[J].中国中药杂志,2010,35(24):3344.
[6] Chen C H,Chen M F,Huang S J,et al. Saikosaponin a induces apoptosis through mitochondria-dependent pathway in hepatic stellate cells[J]. Am J Chin Med,2017,45(2):351.
[7]李晓宇,李晓骄阳,孙蓉.柴胡皂苷a对人肝细胞L-02的体外肝毒性机制研究[C].南宁:中国药学大会暨中国药师周,2013.
[8] Hinton D E,Couch J A. Architectural pattern,tissue and cellular morphology in livers of fishes:relationship to experimentally-induced neoplastic responses[J]. Experientia(Suppl),1998,86:141.
[9] Zhang Y,Liu K,Hassan H M,et al. L-FABP-deficiency provoked oxidative stress,inflammation and apoptosis-mediated hepatotoxicity induced by pyrazinamide on zebrafish larvae[J]. Antimicrob Agents Chemother,2016,60(12):7347.
[10] Zhang Y,Han L,He Q,et al. A rapid assessment for predicting drug-induced hepatotoxicity using zebrafish[J]. J Pharmacol Toxicol,2016,84:102.
[11] Clark M D,Hennig S,Herwig R,et al. An oligonucleotide fingerprint normalized and expressed sequence tag characterized zebrafish c DNA library[J]. Genome Res,2001,11(9):1594.
[12] Li C,Luo L,Awerman J,et al. Whole zebrafish cytochrome P450 assay for assessing drug metabolism and safety[M]//Zebrafish:methods for assessing drug safety and toxicity. New York:John Wiley&Sons Inc.,2011:103.
[13] Xia Q,Wei L,Zhang Y,et al. Psoralen induces developmental toxicity in zebrafish embryos/larvae through oxidative stress,apoptosis,and energy metabolism disorder[J]. Front Pharmacol,2018,9:1457.
[14] Kanungo J,Cuevas E,Ali S F,et al. Zebrafish model in drug safety assessment[J]. Curr Pharm Design,2014,20(34):5416.
[15]林艳.小柴胡汤合理应用常见问题及对策分析[J].海峡药学,2018,219(4):224.
[16]刘旭,刘振华,仲华,等.柴胡注射液致药品不良反应/药品不良事件的分析及防治[J].中国医院用药评价与分析,2018,18(6):840.
[17]杨印军,郑伟,郭佳琪,等.北柴胡、竹叶柴胡、藏柴胡与小叶黑柴胡化学成分比较研究[J].中国中药杂志,2019,44(2):332.