Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Laboratory of Drug Metabolism & Pharmacokinetics, Science Park, Luo Gang District, Guangzhou, China.
J Enzyme Inhib Med Chem. 2011 Jun;26(3):386-93. doi: 10.3109/14756366.2010.518965. Epub 2010 Oct 13.
Human uridine-5'-diphosphoglucuronosyltransferases (UGTs) are the major phase II metabolizing enzymes. In the present study, five human UGTs (UGT1A1, 1A4, 1A6, 2B7, and 2B10) were individually expressed and used to examine the inhibition IC(50) values of 20 selective substrates and inhibitors of major cytochromes P450 (CYPs). The inhibition kinetics of UGT1A1 was also analyzed. The results showed that some compounds like α-naphthoflavone, paclitaxel, midazolam, cyclosporine A, and ketoconazole displayed strong inhibitions on UGT activities with their IC(50) values in a range of 4.1-26 µM. Especially, the IC(50) values were 4.1 ± 0.8 µM for ketoconazole in inhibiting UGT1A1-mediated β-estradiol-3-glucuronidation, and 4.9 ± 0.3 µM for paclitaxel towards UGT1A4-mediated midazolam-N-glucuronidation. Additionally, the IC(50) values of bupropion, tolbutamide, and testosterone in inhibiting UGT-mediated metabolisms were similar with the K(m) values of respective CYPs. Some kinetic behaviours of UGTs were following Michaelis-Menten kinetics, while some were not.
人尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）是主要的 II 相代谢酶。在本研究中，单独表达了 5 个人 UGT（UGT1A1、1A4、1A6、2B7 和 2B10），并用于检测 20 种主要细胞色素 P450（CYPs）的选择性底物和抑制剂的抑制 IC（50）值。还分析了 UGT1A1 的抑制动力学。结果表明，一些化合物，如α-萘黄酮、紫杉醇、咪达唑仑、环孢素 A 和酮康唑，对 UGT 活性表现出强烈的抑制作用，其 IC（50）值在 4.1-26µM 范围内。特别是酮康唑对 UGT1A1 介导的雌二醇-3-葡糖苷酸化的抑制 IC（50）值为 4.1±0.8µM，紫杉醇对 UGT1A4 介导的咪达唑仑-N-葡糖苷酸化的抑制 IC（50）值为 4.9±0.3µM。此外，丁丙诺啡、甲苯磺丁脲和睾酮抑制 UGT 代谢的 IC（50）值与各自 CYP 的 K（m）值相似。一些 UGT 的动力学行为遵循米氏动力学，而另一些则不遵循。
