Gao Wei-Feng, Li Yi-Xuan, Zhang Wei-Hua, Tao Ran, Yin Ting-Ting, Wang Yi-Jia, Liu Li-Na, Fu Zhi-Wei, Li Sai-Nan, Liu Nai-Rong, Zhang Heng, Liu Guang, Zhao Li-Zhong, Zhang Xi-Peng, Zhang Chun-Ze
a Department of Colorectal Surgery , Tianjin Union Medical Center , Tianjin , China.
b Department of Clinical Science of Integrated TCM and Western Medicine , Tianjin University of Traditional Chinese Medicine , Tianjin , China.
Xenobiotica. 2019 Oct;49(10):1158-1163. doi: 10.1080/00498254.2018.1544383. Epub 2019 Apr 25.
Parthenolide (PTL) and micheliolide (MCL) are sesquiterpene lactones with similar structures, and both of them have been reported to exhibit multiple biochemical and pharmacological activities. This study aims to investigate the inhibition of these two compounds on the activity of UDP-glucuronosyltransferases (UGTs). incubation mixture for recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was utilized to investigate the inhibition potential. Inhibition kinetics (including inhibition type and parameters) were determined, and docking was employed to elucidate the inhibition difference between PTL and MCL on UGT1A1. MCL showed no inhibition toward all the UGT isoforms, and PTL showed strong inhibition toward UGT1A1. The half-maximal inhibitory concentration (IC) of PTL on the activity of UGT1A1 was determined to be 64.4 μM. Inhibition kinetics determination showed that PTL exerted noncompetitive inhibition toward UGT1A1, and the inhibition kinetic constant () was determined to be 12.1 μM. docking method has been employed to show that hydrogen bonds between PTL and the activity cavity of UGT1A1 contributed to the stronger inhibition of PTL on the activity of UGT1A1 than MCL. In conclusion, PTL can more easily induce drug-drug interaction (DDI) with clinical drugs mainly undergoing UGT1A1-catalyzed glucuronidation.
小白菊内酯（PTL）和米氏千里光碱（MCL）是结构相似的倍半萜内酯，据报道二者均具有多种生化和药理活性。本研究旨在探究这两种化合物对尿苷二磷酸葡萄糖醛酸转移酶（UGTs）活性的抑制作用。利用重组UGTs催化4-甲基伞形酮（4-MU）葡萄糖醛酸化代谢的孵育混合物来研究抑制潜力。测定抑制动力学（包括抑制类型和参数），并采用对接方法阐明PTL和MCL对UGT1A1的抑制差异。MCL对所有UGT同工型均无抑制作用，而PTL对UGT1A1表现出强烈抑制作用。PTL对UGT1A1活性的半数最大抑制浓度（IC）测定为64.4μM。抑制动力学测定表明PTL对UGT1A1发挥非竞争性抑制作用，抑制动力学常数（）测定为12.1μM。对接方法已用于表明PTL与UGT1A1活性腔之间的氢键导致PTL对UGT1A1活性的抑制作用比MCL更强。总之，PTL更容易与主要经UGT1A1催化葡萄糖醛酸化的临床药物发生药物相互作用（DDI）。
