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首页> 外文期刊>Molecules >Evaluation and Comparison of the Inhibition Effect of Astragaloside IV and Aglycone Cycloastragenol on Various UDP-Glucuronosyltransferase (UGT) Isoforms
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Evaluation and Comparison of the Inhibition Effect of Astragaloside IV and Aglycone Cycloastragenol on Various UDP-Glucuronosyltransferase (UGT) Isoforms

机译：黄芪甲苷IV和糖苷环己三醇对多种UDP-葡萄糖醛酸转移酶（UGT）同工型抑制作用的评价和比较

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摘要

As one of the main active ingredients from Radix Astragali (RA), orally dosed astragaloside IV (AST) is easily transformed to sapogenin-cycloastragenol (CAG) by deglycosylation in the gastrointestinal tract. Because the potential adverse effects of AST and CAG remain unclear, the present study in this article was carried out to investigate the inhibition effects of AST and CAG on UDP-glucuronosyltransferases (UGTs) to explore potential clinical toxicity. An in vitro UGTs incubation mixture was employed to study the inhibition of AST and CAG towards UGT isoforms. Concentrations of 100 mu M for each compound were used to initially screen the inhibitory efficiency. Deglycosylation of AST to CAG could strongly increase the inhibitory effects towards almost all of the tested UGT isoforms, with an IC50 of 0.84 mu M and 11.28 mu M for UGT1A8 and UGT2B7, respectively. Ulteriorly, the inhibition type and kinetics of CAG towards UGT1A8 and UGT2B7 were evaluated depending on the initial screening results. Data fitting using Dixon and Lineweaver-Burk plots demonstrated that CAG competitively inhibited UGT1A8 and noncompetitively inhibited UGT2B7. From the second plot drawn with the slopes from the Lineweaver-Burk plot versus the concentrations of CAG, the inhibition constant (Ki) was calculated to be 0.034 mu M and 20.98 mu M for the inhibition of UGT1A8 and UGT2B7, respectively. Based on the [I]/Ki standard ([I]/Ki < 0.1, low possibility; 1 > [I]/Ki > 0.1, medium possibility; [I]/Ki > 1, high possibility), it was successfully predicted here that an in vivo herb-drug interaction between AST/CAG and drugs mainly undergoing UGT1A8-or UGT2B7-catalyzed metabolism might occur when the plasma concentration of CAG is above 0.034 mu M and 20.98 mu M, respectively.
机译：作为来自黄芪（RA）的主要活性成分之一，口服给药的黄芪甲苷IV（AST）可以通过胃肠道中的去糖基化轻松转化为皂甙元-环黄芪醇（CAG）。由于尚不清楚AST和CAG的潜在不良反应，因此本文进行了本研究，以研究AST和CAG对UDP-葡萄糖醛酸转移酶（UGT）的抑制作用，以探讨潜在的临床毒性。使用体外UGTs温育混合物来研究AST和CAG对UGT同工型的抑制。每种化合物的浓度为100μM，最初用于筛选抑制效果。 AST脱糖基化为CAG可以显着提高对几乎所有测试的UGT亚型的抑制作用，UGT1A8和UGT2B7的IC50分别为0.84μM和11.28μM。后来，根据初始筛选结果评估了CAG对UGT1A8和UGT2B7的抑制类型和动力学。使用Dixon和Lineweaver-Burk图进行的数据拟合表明，CAG竞争性抑制UGT1A8，而非竞争性抑制UGT2B7。从用Lineweaver-Burk图的斜率对CAG浓度绘制的第二幅图得出，抑制UGT1A8和UGT2B7的抑制常数（Ki）分别为0.034μM和20.98μM。基于[I] / Ki标准（[I] / Ki <0.1，低可能性; 1> [I] / Ki> 0.1，中可能性; [I] / Ki> 1，高可能性）在此，当CAG的血浆浓度分别超过0.034μM和20.98μM时，AST / CAG与主要经历UGT1A8或UGT2B7催化代谢的药物之间可能发生体内药-药相互作用。

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