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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 order to explore the mechanism of the metabolic interaction between Coptis and other drugs, the interaction between six Coptis alkaloids and uridine diphosphate glucuronosyltransferase (UGTs) and UGT1A1 was investigated. The microsomal in vitro culture model was constructed by using mouse liver microsomes and liver microsomes induced by alkaloid in vivo. The activities of UGTs were detected by 4-NP (4-NP) UGT1A1 activity was detected as a substrate, and substrate or metabolite content was determined by UV and HPLC. As a result, berberine, epiberberine, berberine, and jatrorrhizine all significantly inhibited the activity of UGTs in rats in vitro, with the strongest inhibitory effect on berberine; and that for jugular base UGT1A1 (IC50 ≈227μmol·L-1), while coptisine and palmatine showed significant activation. In vitro experiments in mice, berberine, berberine, jatrorrhizine and palmatine on UGTs were significantly inhibited; and six kinds of alkaloids UGT1A1 showed significant activation. In mice induction experiment, only berberine on UGTs, jatrorrhizine on UGT1A1 activity showed a significant role in the increase, the role of other alkaloids is not obvious. In summary, Coptis alkaloids in the role of UGT showed obvious species and in vitro differences, while changes in the structure of alkaloids UGT activity will have a greater impact, this effect may be Coptis and other drugs One of the causes of metabolic interactions.