Department of Nephrology, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300, China.
Molecules. 2012 Aug 8;17(8):9469-75. doi: 10.3390/molecules17089469.
Inhibition of UDP-glucuronosyltransferase (UGT) isoforms can result in severe clinical results, including clinical drug-drug interactions (DDI) and metabolic disorders of endogenous substances. The present study aims to investigate the inhibition of demethylzeylasteral (an important active component isolated from Tripterygium wilfordii Hook F.) towards three important UGT isoforms UGT1A6, UGT1A9 and UGT2B7. The results showed that 100 μM of demethylzeylasteral exhibited strong inhibition towards UGT1A6 and UGT2B7, with negligible influence towards UGT1A9. Furthermore, Dixon and Lineweaver-Burk plots showed the inhibition of UGT1A6 and UGT2B7 by demethylzeylasteral was best fit to competitive inhibition, and the inhibition kinetic parameters (Ki) were calculated to be 0.6 μM and 17.3 μM for UGT1A6 and UGT2B7, respectively. This kind of inhibitory effect need much attention when demethylzeylasteral and demethylzeyasteral-containing herbs (e.g., Tripterygium wilfordii Hook F.) were co-administered with the drugs mainly undergoing UGT1A6, UGT2B7-catalyzed metabolism. However, when extrapolating the in vivo clinical results using our present in vitro data, many complex factors might affect final results, including the contribution of UGT1A6 and UGT2B7 to the metabolism of compounds, and the herbal or patients' factors affecting the in vivo concentration of demethylzeylasteral.
抑制 UDP-葡萄糖醛酸基转移酶 (UGT) 同工酶可导致严重的临床后果，包括临床药物-药物相互作用 (DDI) 和内源性物质的代谢紊乱。本研究旨在探讨去甲基泽拉木醛（从雷公藤属植物中分离得到的一种重要活性成分）对三种重要的 UGT 同工酶 UGT1A6、UGT1A9 和 UGT2B7 的抑制作用。结果表明，100μM 的去甲基泽拉木醛对 UGT1A6 和 UGT2B7 表现出强烈的抑制作用，对 UGT1A9 的影响可忽略不计。此外，Dixon 和 Lineweaver-Burk 图表明，去甲基泽拉木醛对 UGT1A6 和 UGT2B7 的抑制作用最符合竞争性抑制，抑制动力学参数（Ki）分别为 0.6μM 和 17.3μM。当去甲基泽拉木醛和含有去甲基泽拉木醛的草药（如雷公藤属植物）与主要经 UGT1A6、UGT2B7 催化代谢的药物同时给药时，需要注意这种抑制作用。然而，当使用我们目前的体外数据推断体内临床结果时，许多复杂因素可能会影响最终结果，包括 UGT1A6 和 UGT2B7 对化合物代谢的贡献，以及草药或患者因素对内源性去甲基泽拉木醛体内浓度的影响。
