Uridine Diphosphate Glucuronosyltransferase Isoform-Dependent Regiospecificity of Glucuronidation of Flavonoids
Uridine Diphosphate Glucuronosyltransferase Isoform-Dependent Regiospecificity of Glucuronidation of Flavonoids
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DOI：
10.1021/jf1041454
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发表时间：
2011-07-13
影响因子：
6.1
通讯作者：
Hu, Ming
中科院分区：
文献类型：
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作者：
Singh, Rashim;Wu, Baojian;Hu, Ming
本研究的目的是确定负责黄酮和黄酮醇糖醛酸化的重要尿苷二磷酸葡萄糖醛酸转移酶（UGT）异构体的区域特异性。我们系统地研究了在10 μ M的底物浓度下，8种重组人UGT异构体对13种黄酮类化合物（7种黄酮类化合物和6种黄酮醇，其羟基位于黄酮类化合物结构的C-3、C-4′、C-5和/或C-7位置）的糖醛酸化作用，这些异构体主要负责黄酮类化合物的代谢，分别是UGT 1A1、1A3、1A6、1A7、1A8、1A9、1A10和2B7。在10 μ M底物浓度下，不同的UGT异构体产生不同的区域特异性糖醛酸化模式。UGT 1A1同样地使3-O（葡萄糖醛酸在C-3羟基上取代）、7-O和4'-O糖醛酸化，而UGT 1A8和1A9最好只使3-O和7-O位置糖醛酸化。UGT 1A1通常对任何位置的葡萄糖醛酸化都没有区域特异性，而UGT 1A8和UGT 1A9对3-O或7-O位置表现出明显、中等或弱的区域特异性，这取决于化合物的结构。UGT 1A3对7-O位点表现出显性区域特异性，而UGT 1A7对3-O位点表现出显性区域特异性。我们还发现，黄酮和黄酮醇中3-O和7-O位置的葡萄糖醛酸化速率受到不同位置添加多个羟基以及底物浓度（2.5、10和35 μ M）的影响。综上所述，黄酮醇的葡萄糖醛酸化具有区域特异性的异构体和浓度依赖性，而黄酮主要在7-O位置被大多数UGT异构体葡萄糖醛酸化。我们还得出结论，UGTs 1A3和1A7分别仅在7-O和3-O位点上表现出显性区域特异性。UGT 1A8和1A9对3-O位置的糖醛酸化表现出中等或弱的偏好，而其他UGT异构体对任何特定位置的糖醛酸化都没有偏好。
The objective of this study was to determine the regiospecificity of the important uridine diphosphate glucuronosyltransferase (UGT) isoforms responsible for the glucuronidation of flavones and flavonols. We systematically studied the glucuronidation of 13 flavonoids (7 flavones and 6 flavonols, with hydroxyl groups at C-3, C-4', C-5, and/or C-7 positions in flavonoid structure) at a substrate concentration of 10 mu M by 8 recombinant human UGT isoforms mainly responsible for the metabolism of flavonoids, UGTs 1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, and 2B7. At 10 mu M substrate concentration, different UGT isoforms gave different regiospecific glucuronidation patterns. UGT 1A1 equally glucuronidated 3-O (glucuronic acid substituted at C-3 hydroxyl group), 7-O, and 4'-O, whereas UGTs 1A8 and 1A9 preferably glucuronidated only 3-O and 7-O positions. UGT 1A1 usually showed no regiospecificity for glucuronidating any position, whereas UGT 1A8 and UGT 1A9 showed dominant, moderate, or weak regiospecificity for 3-O or 7-O position, depending on the structure of the compound. UGT 1A3 showed dominant regiospecificity for the 7-O position, whereas UGT 1A7 showed dominant regiospecificity for the 3-O position. We also showed that the glucuronidation rates of 3-O and 7-O positions in flavones and flavonols were affected by the addition of multiple hydroxyl groups at different positions as well as by the substrate concentrations (2.5, 10, and 35 mu M). In conclusion, regiospecific glucuronidation of flavonols was isoform- and concentration-dependent, whereas flavones were dominantly glucuronidated at the 7-O position by most UGT isoforms. We also concluded that UGTs 1A3 and 1A7 showed dominant regiospecificity for only the 7-O and 3-O positions, respectively. UGTs 1A8 and 1A9 showed moderate or weak preference on glucuronidating position 3-O over the 7-O position, whereas other UGT isoforms did not prefer glucuronidating any particular positions.