基于体外实验技术评价芫花素肝毒性风险
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摘要
目的:考察芫花素对UGT1A1酶活性的影响,为阐明其肝毒性作用机制提供依据。方法:采用计算机分子对接技术考察芫花素与UGT1A1酶的结合方式及亲和作用强弱;采用体外人肝微粒体抑制实验评价芫花素对人源UGT1A1酶抑制作用强弱。结果:分子对接显示芫花素对接进入UGT1A1酶蛋白F活性区,亲和作用较强,体外抑制实验提示芫花素对UGT1A1酶具有较强抑制作用,抑制类型为竞争型抑制,与分子对接结果一致。结论:芫花素可与胆红素竞争性结合UGT1A1酶,抑制酶活性,具有潜在肝毒性风险。
Objective:To investigate the inhibition of genkwanin on UGT1 A1 activities of human liver microsomes,and predict the toxicity mechanism of genkwanin.Methods:The binding mode and affinity of genkwanin to UGT1 A1 enzyme was studied by using computer molecular docking technology.The inhibitory effect of genkwanin on human UGT1 A1 enzyme was evaluated by using in vitro human liver microsome inhibition test.Results:Molecular docking showed that genkwanin docked into the active region F of UGT1 A1 enzyme protein,and the affinity was strong.The inhibition experiments indicated that genkwanin had strong inhibitory effect on UGT1 A1 enzyme,and the inhibition type was competitive,which was consistent with molecular docking results.Conclusion:Genkwanin can compete with bilirubin for UGT1 A1 enzyme in order to inhibit enzyme activity,so it prompted genkwanin has potential hepatotoxicity and it should be pay a close attention.
Objective:To investigate the inhibition of genkwanin on UGT1 A1 activities of human liver microsomes,and predict the toxicity mechanism of genkwanin.Methods:The binding mode and affinity of genkwanin to UGT1 A1 enzyme was studied by using computer molecular docking technology.The inhibitory effect of genkwanin on human UGT1 A1 enzyme was evaluated by using in vitro human liver microsome inhibition test.Results:Molecular docking showed that genkwanin docked into the active region F of UGT1 A1 enzyme protein,and the affinity was strong.The inhibition experiments indicated that genkwanin had strong inhibitory effect on UGT1 A1 enzyme,and the inhibition type was competitive,which was consistent with molecular docking results.Conclusion:Genkwanin can compete with bilirubin for UGT1 A1 enzyme in order to inhibit enzyme activity,so it prompted genkwanin has potential hepatotoxicity and it should be pay a close attention.
引文
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[12] 汪祺,戴忠,张玉杰,等.何首乌中二蒽酮类成分肝毒性研究[J].药物分析杂志,2018,38(2):268.
[13] 汪祺,戴忠,张玉杰,等.基于二相代谢酶介导胆红素代谢考察不同体系UGT1A1酶动力学参数[J].中国药学杂志,2015,50(19):56.
[14] 汪祺,戴忠,张玉杰,等.基于UGT1A1酶介导的胆红素代谢考察大黄素在肝微粒体体系中的肝毒性[J].中国中药杂志,2016,41(23):4424.
[15] 汪祺,王亚丹,文海若,等.基于UGT1A1酶抑制探讨何首乌中顺(反)式二苯乙烯苷体外肝微粒体中潜在毒性作用[J].中国现代中药,2019,21(3):291-295.
[16] WANG Q,DAI Z,WEN B,et al.Estimating the differences of UGT1A1 activity in recombinant UGT1A1 enzyme,human liver microsomes and rat liver microsomes incubation systems in vitro[J].J Biol Pharm Bull,2015,38(12):1910.
[2] 李灵芝,宋少江,高品一.芫花的化学成分及药理作用研究进展[J].沈阳药科大学学报,2007,24(9):587.
[3] 郑维发,王莉,石枫.芫花根乙醇提取物的抗炎活性[J].中草药,2004,35(11):1262.
[4] HONG J Y,NAM J W,SEO E K,et al.Daphnane diterpene esters with anti-proliferative activities against human lung cancer cells from Daphne genkwa[J].Chem Pharm Bull,2010,58:234.
[5] ZHAN Z J,FAN C Q,DING J,et al.Novel diterpenoids with potent inhibitory activity against endothelium cell HMEC and cytotoxic activities from a well-known TCM plant Daphne genkwa[J].Bioorg Med Chem,2005,13:645.
[6] ZHANG S X,LI X N,ZHANG F H,et al.Preparation of yuanhuacine and relative daphne diterpene esters from Daphne genkwa and structure-activity relationship of potent inhibitory activity against DNA topoisomerase I[J].Bioorg Med Chem,2006,14:3888.
[7] ZHENG W F,GAO X W,CHEN C F,et al.Total flavonoids of Daphne genkwa root significantly inhibit the growth and metastasis of Lewis lung carcinoma in C57BL6 mice[J].Int Immunopharmacol,2007,7:117.
[8] 郭嫦娥,苗培培,陈红影,等.芫花醇提物对不同种属体系UGTs及UGT1A1活性的影响[J].中国中医药信息杂志,2017,24(4):83.
[9] KING C D,RIOS G R,GREEN M D,et al.UDP-glucuronosyltransferase[J].Curr Drug Metab,2000,1:143
[10] RUEFER C E,GERHAUSER C,FRANK N,et al.In vitro phase Ⅱ metabolism of xanthohumol by human UDP-glucuronosyltrasferases and sulfotransferases[J].Mol Nutr Food Res,2005,49:851.
[11] WANG Q,WANG Y D,LI Y,et al.Identification and characterization of the structure-activity relationships involved in UGT1A1 inhibition by anthraquinone and dianthrone constituents of Polygonum multiflorum [J].Sci Rep,2017,7:17592.DOI:10.1038/s41598-017-18231-y.
[12] 汪祺,戴忠,张玉杰,等.何首乌中二蒽酮类成分肝毒性研究[J].药物分析杂志,2018,38(2):268.
[13] 汪祺,戴忠,张玉杰,等.基于二相代谢酶介导胆红素代谢考察不同体系UGT1A1酶动力学参数[J].中国药学杂志,2015,50(19):56.
[14] 汪祺,戴忠,张玉杰,等.基于UGT1A1酶介导的胆红素代谢考察大黄素在肝微粒体体系中的肝毒性[J].中国中药杂志,2016,41(23):4424.
[15] 汪祺,王亚丹,文海若,等.基于UGT1A1酶抑制探讨何首乌中顺(反)式二苯乙烯苷体外肝微粒体中潜在毒性作用[J].中国现代中药,2019,21(3):291-295.
[16] WANG Q,DAI Z,WEN B,et al.Estimating the differences of UGT1A1 activity in recombinant UGT1A1 enzyme,human liver microsomes and rat liver microsomes incubation systems in vitro[J].J Biol Pharm Bull,2015,38(12):1910.