Establishment of rat liver microsome-hydrogel system for in vitro phase II metabolism and its application to study pharmacological effects of UGT substrates
Establishment of rat liver microsome-hydrogel system for in vitro phase II metabolism and its application to study pharmacological effects of UGT substrates
复制标题
体外II期代谢大鼠肝微粒体-水凝胶体系的建立及其在UGT底物药理作用研究中的应用
DOI：
--
复制
发表时间：
2019
影响因子：
2.1
通讯作者：
Weimin Cai
中科院分区：
文献类型：
--
作者：
Zhe Zhang;Guo Ma;Caifu Xue;Hong Sun;Ziteng Wang;Xiaoqiang Xiang;Weimin Cai
UDP-葡萄糖醛酸转移酶（UGT）底物的有效性评价研究往往忽略了活性代谢产物的存在。然而，本研究旨在建立体外II相代谢系统，以预测其代谢后的药理作用。大鼠肝微粒体。将包封在F1270-Acr-Bis（FAB）水凝胶中的RLM置于孵育系统中。黄芩素(BA)作为模型药物，通过定量代谢产物黄芩苷（BG）来研究代谢活性。采用MTT法测定传统细胞培养系统（TCCS）和II相代谢细胞培养系统（MHCCS-II）中加入微粒体水凝胶后的细胞活力。最后，应用MHCCS-II模型预测了Oroxylin A（OA）和Wogonin（W）的代谢效应。与TCCS组相比，MHCCS-II中BA对HepG 2和MCF-7细胞的存活率降低（P < 0.05），而对PC 12细胞的存活率升高（P < 0.01）。对HepG 2细胞，OA和W代谢后有明显的抑瘤作用，IC_（50）分别为32.7 ± 2.9mM和76.1 ± 5.1mM。（P < 0.01）。总之，MHCCS-II可用于研究UGT底物的药代动力学和药效学。
Studies on the efficacy evaluation of UDP-glucuronosyltransferases (UGTs) substrates often ignore the.existence of active metabolites. However, the present study aims to establish an in-vitro Phase II.metabolism system to predict their pharmacological effects after metabolism. Rat liver microsomes.(RLMs) encapsulated in a F1270-Acr-Bis (FAB) hydrogel were placed in the incubation system. Baicalein.(BA) was chosen as a model drug and the metabolic activity was investigated by quantitating the.metabolite Baicalin (BG). The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT).assay was used to measure the cell viability in Traditional cell culture system (TCCS) and Microsomehydrogel.added to cell culture system for Phase II metabolism (MHCCS-II). Finally, MHCCS-II was.applied to predict the metabolic effects of Oroxylin A (OA) and Wogonin (W). Compared to TCCS group,.for HepG2 and MCF-7 cells, BA in MHCCS-II led to lower survival ratios of cells (P < 0.05), while for.PC12 cells it led to higher survival ratios of cells (P < 0.01). For HepG2 cells, OA and W showed obviously.enhanced tumor inhibition after metabolism with the IC50 of 32.7 ± 2.9 mM and 76.1 ± 5.1 mM, respectively.(P < 0.01). In conclusion, the MHCCS-II could be a useful tool for studying the pharmacokinetics.and pharmacodynamics of UGTs substrates.