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目的考察芫花主要黄酮成分芫花素和芹菜素对尿苷二磷酸葡萄糖醛酸转移酶(UGTs)及UGT1A1活性的影响。方法采用体外肝微粒体孵育模型,以4-硝基酚(4-nitrophenol,4-NP)为底物检测UGTs活性,胆红素为底物检测UGT1A1活性;利用UV及UPLC-MS/MS测定底物或代谢产物的含量。结果对UGTs,在大鼠肝微粒体、小鼠肝微粒体以及人肝微粒体孵育体系中,芫花素和芹菜素均能不同程度地抑制UTGs活性;抑制强弱顺序:在大鼠肝微粒体温孵体系中,芫花素>芹菜素;在小鼠肝微粒体以及人肝微粒体温孵体系中,芹菜素>芫花素。对UGT1A1,在人肝微粒体孵育体系中,芫花素和芹菜素均表现为中等强度的竞争性抑制作用,抑制强弱顺序:芹菜素(IC50=12.40μmol·L-1)>芫花素(IC50=23.21μmol·L-1)。结论芫花素和芹菜素对不同肝微粒体孵育体系中UGTs及UGT1A1均可产生显著抑制作用且存在种属差异。芫花素及芹菜素可能存在基于UGT酶的药物相互作用。
Objective To investigate the effects of Daphne genkwa and apigenin, the main flavonoids of Daphne genkwa, on uridine diphosphate glucuronosyltransferase (UGTs) and UGT1A1 activity. Methods The in vitro liver microsomal incubation model was established. The activities of UGTs were detected by using 4-nitrophenol (4-NP) as substrate and UGT1A1 activity by using bilirubin as substrate. UV and UPLC-MS / MS Substance or metabolite content. Results For gentamycin and apigenin, UGTs inhibited the activity of UTGs in rat liver microsomes, mouse liver microsomes and human liver microsomes. The order of inhibition was as follows: Body temperature incubation system, genkwanin> apigenin; in mouse liver microsomes and human liver microsomal incubation system, apigenin> genkwanin. For UGT1A1, in the human liver microsomal incubation system, both of the genkwanin and the apigenin exhibited moderate-intensity competitive inhibition with the order of inhibition: apigenin (IC50 = 12.40 μmol·L -1)> genkwanin (IC50 = 23.21μmol·L-1). Conclusions Daphne and Apigenin can significantly inhibit the expression of UGTs and UGT1A1 in different liver microsomes and there are some species differences. There may be UGT enzyme-based drug interactions between genkwanin and apigenin.