Next Article in Journal
Water Assisted Growth of C60 Rods and Tubes by Liquid–Liquid Interfacial Precipitation Method
Previous Article in Journal
Binding of Bezafibrate to Human Serum Albumin: Insight into the Non-Covalent Interaction of an Emerging Contaminant with Biomacromolecules
Molecules 2012, 17(6), 6832-6839; doi:10.3390/molecules17066832
Article

Strong Inhibition of Celastrol Towards UDP-Glucuronosyl Transferase (UGT) 1A6 and 2B7 Indicating Potential Risk of UGT-Based Herb-Drug Interaction

†,* , , , , , , ,  and
Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, Shaanxi, China These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 27 April 2012 / Revised: 25 May 2012 / Accepted: 25 May 2012 / Published: 5 June 2012
(This article belongs to the Section Natural Products)
Download PDF [204 KB, uploaded 18 June 2014]

Abstract

Celastrol, a quinone methide triterpene isolated from Tripterygium wilfordii Hook F., has various biochemical and pharmacological activities, and is now being developed as a promising anti-tumor agent. Inhibitory activity of compounds towards UDP-glucuronosyltransferase (UGT) is an important cause of clinical drug-drug interactions and herb-drug interactions. The aim of the present study is to investigate the inhibition of celastrol towards two important UDP-glucuronosyltransferase (UGT) isoforms UGT1A6 and UGT2B7. Recombinant UGT isoforms and non-specific substrate 4-methylumbelliferone (4-MU) were used. The results showed that celastrol strongly inhibited the UGT1A6 and 2B7-mediated 4-MU glucuronidation reaction, with 0.9 ± 0.1% and 1.8 ± 0.2% residual 4-MU glucuronidation activity at 100 μM of celastrol, respectively. Furthermore, inhibition kinetic study (Dixon plot and Lineweaver-Burk plot) demonstrated that celastrol noncompetitively inhibited the UGT1A1-mediated 4-MU glucuronidation, and competitively inhibited UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameters (Ki) were calculated to be 0.49 μM and 0.045 μM for UGT1A6 and UGT2B7, respectively. At the therapeutic concentration of celastrol for anti-tumor utilization, the possibility of celastrol-drug interaction and celastrol-containing herbs-drug interaction were strongly indicated. However, given the complicated nature of herbs, these results should be viewed with more caution.
Keywords: celastrol; UDP-glucuronosyltransferase (UGT); herb-drug interaction celastrol; UDP-glucuronosyltransferase (UGT); herb-drug interaction
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
SciFeed

Share & Cite This Article

Further Mendeley | CiteULike
Export to BibTeX |
EndNote |
RIS
MDPI and ACS Style

Zhang, Y.-S.; Tu, Y.-Y.; Gao, X.-C.; Yuan, J.; Li, G.; Wang, L.; Deng, J.-P.; Wang, Q.; Ma, R.-M. Strong Inhibition of Celastrol Towards UDP-Glucuronosyl Transferase (UGT) 1A6 and 2B7 Indicating Potential Risk of UGT-Based Herb-Drug Interaction. Molecules 2012, 17, 6832-6839.

View more citation formats

Related Articles

Article Metrics

For more information on the journal, click here

Comments

[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert