Regioselective glucuronidation of flavonols by six human UGT1A isoforms.
Regioselective glucuronidation of flavonols by six human UGT1A isoforms.
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DOI：
10.1007/s11095-011-0418-5
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发表时间：
2011-08
影响因子：
3.7
通讯作者：
Hu, Ming
中科院分区：
文献类型：
--
作者：
Wu, Baojian;Xu, Beibei;Hu, Ming
黄酮醇是一类多酚类化合物，具有抗氧化、抗癌等多种生物活性。然而，体内快速的O-葡萄糖醛酸化反应对将其发展为治疗药物提出了挑战。本论文的目的是研究UGT1A亚型(即UGT1A1、UGT1A3、UGT1A7、UGT1A8、UGT1A9和UGT1A10)对黄酮醇的区域选择性葡萄糖醛酸化反应。研究了含7-羟基的4种黄酮醇在UGT1A1、1A3和1A7~1A10介导下的代谢动力学，测定了动力学参数(Km、Vmax和本征清除量(CLINT=Vmax/Km))。UGT1A1和1A3区域选择性地代谢7-OH，而UGT1A7~1A10优先于葡萄糖醛酸基。UGT1A1和UGT1A9是最有效的结合酶，其≤为1µM，Vmax/Km为3ml/min/mg蛋白，其克林特值高达6ml/min/mg蛋白。此外，4种黄酮醇对UGT1A1介导的葡萄糖醛酸化反应具有较强的自抑制作用，其底物抑制常数(Ks)为≤5.4uM。3-O-和7-O-葡萄糖醛酸化反应的差异化动力学性质表明，催化区域内至少有两种不同的结合模式导致了这两种葡萄糖醛酸异构体的形成。
Flavonols, a class of polyphenols, show a variety of biological activities such as antioxidant and anticancer. However, rapid in vivo O-glucuronidation posed a challenge to develop them as therapeutic agents. The objective of this paper is to determine the regioselective glucuronidation of flavonols by UGT1A isoforms (i.e., UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9 and UGT1A10). The kinetics of UGT1A1-, 1A3- and 1A7~1A10-mediated metabolisms of four flavonols that contain 7-OH group were characterized and kinetic parameters (Km, Vmax and intrinsic clearance (CLint=Vmax/Km)) were determined. UGT1A1 and 1A3 regioselectively metabolized 7-OH, whereas UGT1A7~1A10 preferred to glucuronidate 3-OH group. UGT1A1 and UGT1A9 were the most efficient conjugating enzymes with Km of ≤1 µM and Vmax/Km of >3 ml/min/mg protein, resulting in a CLint value as high as 6 ml/min/mg protein. Additionally, the four flavonols generally strongly self-inhibited the UGT1A1-mediated glucuronidation, with Ks (substrate inhibition constant) of ≤ 5.4 µM. UGT1A isoforms displayed distinct positional preferences between 3-OH and 7-OH in the glucuronidation of flavonols. The differentiated kinetics properties between 3-O- and 7-O- glucuronidation indicated that at least two distinct binding modes within the catalytic domain were responsible for the formation of these two glucuronide isomers.
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DOI：
10.1097/00008571-200211000-00008
发表时间：
2002-11-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Sorich, MJ;Smith, PA;Miners, JO
通讯作者：
Miners, JO
影响因子：
3.9
作者：
Ohno, Shuji;Nakajin, Shizuo
通讯作者：
Nakajin, Shizuo
多变量外显子的适应性演变和药物代谢酶的结构多样性。
影响因子：
3.4
作者：
Li, Can;Wu, Qiang
通讯作者：
Wu, Qiang
影响因子：
2.1
作者：
Barve, Avantika;Chen, Chi;Hebbar, Vidya;Desiderio, Joseph;Saw, Constance Lay-Lay;Kong, Ah-Ng
通讯作者：
Kong, Ah-Ng
影响因子：
5.8
作者：
Miners, JO;Knights, KM;Mackenzie, PI
通讯作者：
Mackenzie, PI