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

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 o...

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Autores principales: Zhang, Yong-Sheng, Tu, Yan-Yang, Gao, Xing-Chun, Yuan, Jun, Li, Gang, Wang, Liang, Deng, Jian-Ping, Wang, Qi, Ma, Ru-Meng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6268241/
https://www.ncbi.nlm.nih.gov/pubmed/22669039
http://dx.doi.org/10.3390/molecules17066832
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author Zhang, Yong-Sheng
Tu, Yan-Yang
Gao, Xing-Chun
Yuan, Jun
Li, Gang
Wang, Liang
Deng, Jian-Ping
Wang, Qi
Ma, Ru-Meng
author_facet Zhang, Yong-Sheng
Tu, Yan-Yang
Gao, Xing-Chun
Yuan, Jun
Li, Gang
Wang, Liang
Deng, Jian-Ping
Wang, Qi
Ma, Ru-Meng
author_sort Zhang, Yong-Sheng
collection PubMed
description 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.
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spelling pubmed-62682412018-12-12 Strong Inhibition of Celastrol Towards UDP-Glucuronosyl Transferase (UGT) 1A6 and 2B7 Indicating Potential Risk of UGT-Based Herb-Drug Interaction Zhang, Yong-Sheng Tu, Yan-Yang Gao, Xing-Chun Yuan, Jun Li, Gang Wang, Liang Deng, Jian-Ping Wang, Qi Ma, Ru-Meng Molecules Article 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. MDPI 2012-06-05 /pmc/articles/PMC6268241/ /pubmed/22669039 http://dx.doi.org/10.3390/molecules17066832 Text en © 2012 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Zhang, Yong-Sheng
Tu, Yan-Yang
Gao, Xing-Chun
Yuan, Jun
Li, Gang
Wang, Liang
Deng, Jian-Ping
Wang, Qi
Ma, Ru-Meng
Strong Inhibition of Celastrol Towards UDP-Glucuronosyl Transferase (UGT) 1A6 and 2B7 Indicating Potential Risk of UGT-Based Herb-Drug Interaction
title Strong Inhibition of Celastrol Towards UDP-Glucuronosyl Transferase (UGT) 1A6 and 2B7 Indicating Potential Risk of UGT-Based Herb-Drug Interaction
title_full Strong Inhibition of Celastrol Towards UDP-Glucuronosyl Transferase (UGT) 1A6 and 2B7 Indicating Potential Risk of UGT-Based Herb-Drug Interaction
title_fullStr Strong Inhibition of Celastrol Towards UDP-Glucuronosyl Transferase (UGT) 1A6 and 2B7 Indicating Potential Risk of UGT-Based Herb-Drug Interaction
title_full_unstemmed Strong Inhibition of Celastrol Towards UDP-Glucuronosyl Transferase (UGT) 1A6 and 2B7 Indicating Potential Risk of UGT-Based Herb-Drug Interaction
title_short Strong Inhibition of Celastrol Towards UDP-Glucuronosyl Transferase (UGT) 1A6 and 2B7 Indicating Potential Risk of UGT-Based Herb-Drug Interaction
title_sort strong inhibition of celastrol towards udp-glucuronosyl transferase (ugt) 1a6 and 2b7 indicating potential risk of ugt-based herb-drug interaction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6268241/
https://www.ncbi.nlm.nih.gov/pubmed/22669039
http://dx.doi.org/10.3390/molecules17066832
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