Structure-inhibition relationship of ginsenosides towards UDP-glucuronosyltransferases (UGTs)
Structure-inhibition relationship of ginsenosides towards UDP-glucuronosyltransferases (UGTs)
复制标题
人参皂苷对 UDP-葡萄糖醛酸基转移酶 (UGT) 的结构抑制关系
DOI：
10.1016/j.taap.2012.12.019
复制
发表时间：
2013-03-01
影响因子：
3.8
通讯作者：
Sun, Hong-Zhi
中科院分区：
文献类型：
--
作者：
Fang, Zhong-Ze;Cao, Yun-Feng;Sun, Hong-Zhi
人参的广泛应用为其与许多临床药物的相互作用提供了高风险。人参皂苷对药物代谢酶（DMEs）的抑制作用被认为是引起药物相互作用（HDI）的重要原因。与人参皂苷对细胞色素P450 （CYP）的抑制作用的深入研究相比，人参皂苷对重要的II期酶udp -葡萄糖醛酸转移酶（UGTs）的抑制作用尚不清楚。本研究旨在通过体外方法评估人参皂苷对肝脏和肠道中重要UGT异构体的抑制作用。采用重组UGT异构体催化4-甲基伞形酮（4-MU）糖醛酸化反应作为体外探针反应。结果表明，人参皂苷对UGT异构体的抑制存在结构依赖性。为了明确这种抑制诱导体内药物相互作用的可能性，以人参皂苷Rg(3)为例，测定其抑制动力学类型和参数（IQ）。Rg(3)竞争性抑制UGT1A7、2B7和2b15催化的4-MU糖醛酸化反应，对ugt1a8催化的4-MU糖醛酸化反应具有非竞争性抑制作用。对UGT1A7、1A8、2B7和2B15的抑制参数（K-i值）分别为22.6、7.9、1.9和2.0 mu M。以肌肉注射60 mg Rg(3)后人体最大血药浓度（400 ng/ml (0.5 μ M)）为例，推断经UGT1A7、1A8、2B7和2B15完全催化代谢的共给药组血药浓度-时间曲线下面积（AUC）分别增加22%、63%、26.3%和25%。这些结果表明，人参皂苷对UGT异构体的抑制作用可能是人参与药物相互作用的重要原因。(C) 2013爱思唯尔公司版权所有。
The wide utilization of ginseng provides the high risk of herb-drug interaction (HDI) with many clinical drugs. The inhibition of ginsenosides towards drug-metabolizing enzymes (DMEs) has been regarded as an important reason for herb-drug interaction (HDI). Compared with the deep studies on the ginsenosides' inhibition towards cytochrome P450 (CYP), the inhibition of ginsenosides towards the important phase II enzymes UDP-glucuronosyltransferases (UGTs) remains to be unclear. The present study aims to evaluate the inhibition behavior of ginsenosides towards important UGT isoforms located in the liver and intestine using in vitro methods. The recombinant UGT isoform-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction was employed as in vitro probe reaction. The results showed that structure-dependent inhibition existed for the inhibition of ginsenosides towards UGT isoforms. To clarify the possibility of in vivo herb-drug interaction induced by this kind of inhibition, the ginsenoside Rg(3) was selected as an example, and the inhibition kinetic type and parameters (IQ were determined. Rg(3) competitively inhibited UGT1A7, 2B7 and 2B15-catalyzed 4-MU glucuronidation reaction, and exerted noncompetitive inhibition towards UGT1A8-catalyzed 4-MU glucuronidation. The inhibition parameters (K-i values) were calculated to be 22.6, 7.9, 1.9, and 2.0 mu M for UGT1A7, 1A8, 2B7 and 2B15. Using human maximum plasma concentration of Rg(3) (400 ng/ml (0.5 mu M)) after intramuscular injection of 60 mg Rg(3), the area under the plasma concentration-time curve (AUC) was extrapolated to increase by 22%, 63%, 26.3%, and 25% for the co-administered drugs completely undergoing the metabolism catalyzed by UGT1A7, 1A8, 2B7 and 2B15, respectively. All these results indicated that the ginsenosides' inhibition towards UGT isoforms might be an important reason for ginseng-drug interaction. (C) 2013 Elsevier Inc. All rights reserved.