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

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Received: 27 April 2012; in revised form: 25 May 2012 / Accepted: 25 May 2012 / Published: 5 June 2012
(This article belongs to the Section Metabolites)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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
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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.

AMA 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(6):6832-6839.

Chicago/Turabian Style

Zhang, Yong-Sheng; Tu, Yan-Yang; Gao, Xing-Chun; Yuan, Jun; Li, Gang; Wang, Liang; Deng, Jian-Ping; Wang, Qi; Ma, Ru-Meng. 2012. "Strong Inhibition of Celastrol Towards UDP-Glucuronosyl Transferase (UGT) 1A6 and 2B7 Indicating Potential Risk of UGT-Based Herb-Drug Interaction." Molecules 17, no. 6: 6832-6839.

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