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Phytother Res. 2016 Nov;30(11):1872-1878. doi: 10.1002/ptr.5697. Epub 2016 Aug 18.

The Inhibition of UDP-Glucuronosyltransferase (UGT) Isoforms by Praeruptorin A and B.

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The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China.
Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Ti-Yuan-Bei, Hexi District, Tianjin, 300060, China.
Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and the First Affiliated Hospital of Liaoning Medical University, Dalian, China.
Tianjin Union Medical Center, 190 Jieyuan Road, Hongqiao District, Tianjin, 300121, China.
Department of Radiology, The 464th Hospital of PLA, No.600 Hongqi South Rd, Nankai District, Tianjin, 300381, China.
Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.


Praeruptorin A (PA) and B (PB) are two important compounds isolated from Bai-hua Qian-hu and have been reported to exert multiple biochemical and pharmacological activities. The present study aims to determine the inhibition of PA and PB on the activity of important phase II drug-metabolizing enzymes uridine 5'-diphospho-glucuronosyltransferase (UGTs) isoforms. In vitro UGT incubation system was used to determine the inhibition potential of PA and PB on the activity of various UGT isoforms. In silico docking was performed to explain the inhibition difference between PA and PB towards the activity of UGT1A6. Inhibition behaviour was determined, and in vitro-in vivo extrapolation was performed by using the combination of in vitro inhibition kinetic parameter (Ki ) and in vivo exposure level of PA. Praeruptorin A (100 μM) exhibited the strongest inhibition on the activity of UGT1A6 and UGT2B7, with 97.8% and 90.1% activity inhibited by 100 μM of PA, respectively. In silico docking study indicates the significant contribution of hydrogen bond interaction towards the stronger inhibition of PA than PB towards UGT1A6. Praeruptorin A noncompetitively inhibited the activity of UGT1A6 and competitively inhibited the activity of UGT2B7. The inhibition kinetic parameter (Ki ) of PA towards UGT1A6 and UGT2B7 was calculated to be 1.2 and 3.3 μM, respectively. The [I]/Ki value was calculated to be 15.8 and 5.8 for the inhibition of PA on UGT1A6 and UGT2B7, indicating high inhibition potential of PA towards these two UGT isoforms in vivo. Therefore, closely monitoring the interaction between PA and drugs mainly undergoing UGT1A6 or UGT2B7-catalyzed metabolism is very necessary.


Praeruptorin A; Praeruptorin B; UDP-glucuronosyltransferases (UGTs); drug-drug interaction (DDI)

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