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1、Comparison of Inhibition Capability of Scutellarein and Scutellarin Towards Important Liver UDP Glucuronosyltransferase (UGT) isoforms,汇报人：. 2015.03.18,Keywords scutellarin; scutellarein; UGT; enzyme inhibition.,Contents,1. Introduction 2. Experimental section 3. Results and discussion 4. Conclusion
2、,1. Introduction,In the recent years,another important drug metabolizing enzyme UDP-glucuronosyltransferase (UGT) has been demonstrated to exhibit significant contribution towards the metabolism of clinical drugs and herbal components,and more and more attention has been given to this enzymes (Malik
3、 and Black, 2012; Li etal., 2012). UGTs have been demonstrated to be involved in the metabolic elimination of many important endogenous substances, such as bilirubin, bile acid and estradiol (Erichsen et al., 2010).,Guo et al. showed deglycosylation process of liquiritin strongly enhanced the inhibi
4、tory capability towards UGTs (2012). Huang et al. showed strong inhibition of glycyrrhetinic acid towards UGT1A3 and 2B7 (2012). Liu et al. also used in vitro incubation system to find the strong inhibition of deoxyschizandrin and schisantherin A towards UGT1A3 (2012).,Chemicals and reagents. Scutel
5、larin,Scutellarein,4-MU,Tris-HCl, 7-hydroxycoumarin,UDPGA(缓冲盐)， 重组UGTs亚型（UGT1A1，UGT1A6， UGT1A9，UGT2B7），HPLC reagents.,2. Experimental section,Incubation and analysis methods for inhibition evaluation. After 5min pre-incubation at 37, the UDPGA was added in the mixture to initiate the reaction. The i
6、ncubation time was 120min for UGT1A1 and UGT2B7, 30min,or UGT1A6 and UGT1A9, respectively. The reactions were terminated by adding 100 mL acetonitrile with 7-hydroxycoumarin (100mM) as internal standard.The mixture was centrifuged at 20000g for 10min, HPLC analysis.,Data fitting for determination of
7、 inhibition type and parameters (Ki). The reaction velocity was determined using various concentrations of 4-MU and scutellarein. The data were fitted using Dixon plot and LineweaverBurk double reciprocal plot. The second plot with the slopes from the LineweaverBurk plot versus the concentrations of
8、 scutellarein was utilized to calculate the Kivalue.Prediction of in vivo drugdrug interaction magnitude.,Prediction of in vivo drugdrug interaction magnitude. The most common equation for drugdrug interaction prediction was employed to predict the AUC alteration of coadministered drugs caused by co
9、-administration of scutellarein.,3. Results and discussion,图2表明，100mM野黄芩苷对UGT1A1，UGT1A6，UGT1A9，UGT2B7的活性抑制率分别为48.8%、20.2%、36.1%、73.8% 。同浓度野黄芩素对以上4种UGTs的活性抑制率分别为99.2%、89.8%、85.4%、86.4% 。,Figure 3.,Figure 4.,Figure 5.,Figure 6.,野黄芩素对被测试UGTs的抑制作用表现出一定浓度的行为依赖性(A)。 Dxion图(B)和Lineweaver-Burk图(C)反映了抑制动力学类型
10、；野黄芩素对被测试UGTs都有竞争性抑制作用。 由Lineweaver-Burk图及其斜率计算得野黄芩素对被测试UGTs的Ki值分别为0.02、5.0、5.8、35.9(C).,本实验研究了野黄芩苷和野黄芩素对4种UGT的抑制作用。结果表明，野黄芩素比野黄芩苷对被测试UGTs表现出更强的抑制作用，提示野黄芩苷的去糖基化过程可增强其抑制作用，与文献报道相符(Guo etal,2012)。 无论野黄芩素对被测试UGTs的体外抑制是否转化为体内抑制；在体内，野黄芩素的浓度是一个重要影响因素。,（2）Discussion,任何抑制UGT1A1的因素都将导致严重的不良反应（HIV、伊立替康）。故野黄芩素对UGT1A1的强抑制作用方面应给予更多关注。 实验中较高浓度的野黄芩素被利用可能夸大了体内抑制程度，中草药的复杂系统也可能影响这种抑制结果，理解体外参数时上述因素都应考虑。,野黄芩素对UGT1A1,UGT1A6,UGT1A9和UGT2B7潜在抑制作用与野黄芩苷相比较，表明：在野黄芩苷对被测试UGTs的抑制作用中野黄芩苷的去糖基化过程起着重要作用。体内外推结果提示，临床检测野黄芩苷及其苷元野黄芩素和含这两种成分的中草药对人体所致不良反应有重要作用。,4. Conclusion,
