中国中药杂志

2016, v.41(02) 309-313

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6种黄连生物碱对鼠肝微粒体UGTs及UGT1A1活性影响的体内外研究
In vitro and In vivo effects of six Coptidis alkaloids on liver microsomes UGTs and UGT1A1 activities in rats and mice

赵园园;苗培培;苗青;郭嫦娥;陈红影;陈宁;张玉杰;马双成;
ZHAO Yuan-yuan;MIAO Pei-pei;MIAO Qing;GUO Chang-e;CHEN Hong-ying;CHEN Ning;ZHANG Yu-jie;MA Shuang-cheng;School of Chinese Materia Medica,Beijing University of Chinese Medicine;Institute for Control of Traditional Chinese Medicine and Ethnic Medicine,National Institutes for Food and Drug Control;

摘要(Abstract):

为探讨黄连与其他药物代谢性相互作用的机制,对6种黄连生物碱与尿苷二磷酸葡萄糖醛酸转移酶(UGTs)及UGT1A1的相互作用进行了考察。采用大小鼠肝微粒体,以及生物碱小鼠体内诱导后的肝微粒体,构建微粒体体外孵育模型,以4-硝基酚(4-NP)为底物检测UGTs活性,β-雌二醇为底物检测UGT1A1活性,利用UV和HPLC测定底物或代谢物含量。结果,在大鼠体外实验中,小檗碱、表小檗碱、黄连碱及药根碱均能显著抑制UGTs活性,其中表小檗碱抑制作用最强;对UGT1A1,药根碱表现为弱的抑制作用(IC50≈227μmol·L-1),而黄连碱和巴马汀则呈显著的激活作用。小鼠体外实验中,小檗碱、黄连碱、药根碱和巴马汀对UGTs均呈显著的抑制作用;而6种生物碱对UGT1A1均表现为显著的激活作用。小鼠体内诱导实验中,只有小檗碱对UGTs,药根碱对UGT1A1活性呈现显著升高作用,其他生物碱的作用不明显。综上,黄连生物碱在对UGT的作用上显示出明显的种属和体内外的差异,同时生物碱结构的变化对UGT活性也会产生较大的影响,这种影响可能是黄连与其他药物发生代谢性相互作用的原因之一。
In the present study,the effects of six Coptidis alkaloids(berberine,epiberberine,coptisine,jatrorrhizine,palmatine and magnoflorine) on liver microsomes UGTs and UGT1A1 activities in rats and mice were investigated in vitro and in vivo to study the mechanism of metabolic drug-drug interactions of Coptidis Rhizoma with other drugs. In vitro rat and mice liver microsomal incubation systems combined with UDPGA were applied,as well as mice liver microsomes after administration of six Coptidis alkaloids. 4-Nitrophenol and β-estradiol were selected as substrates to determine activities of UGTs and UGT1A1 by UV and HPLC,respectively. According to the in vitro rat study,berberine,epiberberine,coptisine and jatrorrhizine significantly inhibited rat liver microsome UGTs activity,particularly epiberberine showed the strongest inhibition. UGT1A1 activity was lowly inhibited by jatrorrhizine,with IC50 at about227 μmol·L- 1,whereas coptisine and magnoflorine significantly activated UGT1A1. According to the in vitro mice study,berberine,coptisine,jatrorrhizine and palmatine significantly inhibited mice liver microsome UGTs activity,and the six alkaloids all significantly activated UGT1A1. According to the in vivo mice study,UGTs activity was significantly activated only in berberine group,while UGT1A1 activity was significantly activated only in jatrorrhizine group. In conclusion,the effects of Coptidis alkaloids on UGT activity showed significant differences in species and between in vitro and in vivo. Meanwhile,the changes in structures of Coptidis alkaloids also have a big impact on UGT activity,which may be one of the causes for the drug-drug interactions between Coptidis Rhizoma and other drugs.

关键词(KeyWords): 6种黄连生物碱;UGTs;UGT1A1;相互作用;鼠肝微粒体;体外;体内
six Coptidis alkaloids;UGTs;UGT1A1;interaction;rat and mice liver microsomes;in vitro;in vivo

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目(81274177;81073140);; 北京中医药大学自主选题项目(2015-JYB-XS083;2015-JYB-XS085;2015-JYB-XS055)

作者(Authors): 赵园园;苗培培;苗青;郭嫦娥;陈红影;陈宁;张玉杰;马双成;
ZHAO Yuan-yuan;MIAO Pei-pei;MIAO Qing;GUO Chang-e;CHEN Hong-ying;CHEN Ning;ZHANG Yu-jie;MA Shuang-cheng;School of Chinese Materia Medica,Beijing University of Chinese Medicine;Institute for Control of Traditional Chinese Medicine and Ethnic Medicine,National Institutes for Food and Drug Control;

参考文献(References):

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