苗培培;赵园园;苗青;郭嫦娥;陈红影;陈宁;张玉杰;马双成;
MIAO Pei-pei;ZHAO Yuan-yuan;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 Chinese Traditional Medicine and Ethnic Medicine,National Institutes for Food and Drug Control;

• 1:北京中医药大学中药学院
• 2:中国食品药品检定研究院中药民族药检定所

摘要(Abstract)：

考察羟基芫花素对尿苷二磷酸葡萄糖醛酸转移酶(UGTs)及UGT1A1活性的影响,为预测其与其他药物的代谢性相互作用提供理论借鉴。该实验采用体外肝微粒体孵育模型,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。结果表明,在大鼠、小鼠和人肝微粒体(HLM)孵育体系,羟基芫花素能显著抑制UGTs活性;对UGT1A1,在小鼠肝微粒体(MLM)孵育体系中,羟基芫花素几乎无抑制作用(IC50=190μmol·L-1);在大鼠肝微粒体(RLM)和重组酶(r UGT1A1)孵育体系中,羟基芫花素表现为中等强度的抑制作用(IC50=10.93,20.07μmol·L-1),抑制类型分别为竞争性抑制和线性混合型抑制;在HLM孵育体系中,羟基芫花素表现为弱抑制作用(IC50=76.31μmol·L-1),抑制类型为竞争性抑制;其抑制强弱顺序为RLM>r UGT1A1>HLM>MLM。综上,羟基芫花素对不同肝微粒体孵育体系中UGTs及UGT1A1活性均可产生抑制作用且存在种属差异性,提示羟基芫花素可能存在基于UGT1A1酶的药物相互作用。该研究可为合理开发利用羟基芫花素提供实验依据,并为研究药物在临床上的联合用药提供理论借鉴。
To predit the mechanism of metabolic drug-drug interactions of hydroxygenkwanin with other drugs,we investigated the inhibition inhibitory effect of hydroxygenkwanin on UGTs and UGT1A1 activities of different liver microsomes. In the present study,4-nitrophenol( 4-NP) and β-estradiol were elected as substrates to determine activities of UGTs and UGT1A1 by UV and HPLC,respectively. The results showed that,hydroxygenkwanin significantly inhibited UGTs activity in rat,mouse and human liver microsomes.UGT1A1 activity was inhibited by hydroxygenkwanin to varying degrees,with IC50 about 190,10. 93,20. 07,76. 31 μmol· L- 1in mouse liver microsome( MLM),rat liver microsome( RLM) and recombinant UGT1A1,and human liver microsome( HLM),respectively. The inhibition types were competitive inhibition( RLM, HLM) and linear mixed-typed linear inhibition( recombinant UGT1A1). The order for the inhibitory intensity was RLM > r UGT1A1 > HLM > MLM. In conclusion,hydroxygenkwanin has an inhibitory effect on UGTs and UGT1A1 activities of different liver microsomes,with differences in species,indicating its potential drug interactions based on UGT1A1 enzyme. This study aims to provide a reliable experimental basis for its further research and development of hydroxygenkwanin,and provide theoretical reference for the clinic drug combination research.

关键词(KeyWords)： 羟基芫花素;UGTs;UGT1A1;相互作用;肝微粒体;体外
hydroxygenkwanin;UGTs;UGT1A1;interaction;liver microsomes;in vitro

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-XS085;2015-JYB-XS083;2015-JYBXS055)

作者(Authors): 苗培培;赵园园;苗青;郭嫦娥;陈红影;陈宁;张玉杰;马双成;
MIAO Pei-pei;ZHAO Yuan-yuan;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 Chinese Traditional Medicine and Ethnic Medicine,National Institutes for Food and Drug Control;

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