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Dysregulated hepatic UDP-glucuronosyltransferases and flavonoids glucuronidation in experimental colitis

Glucuronidation catalyzed by UDP-glucuronosyltransferases (UGTs) is one of the most important phase II mechanisms, facilitating drug clearance via conjugation of glucuronic acid with polar groups of xenobiotics. Accumulating evidence suggests that IBDs impact drug disposition, but whether and how IB...

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Autores principales: Zeng, Wanying, Liu, Xiaojing, Wu, Yangyang, Cai, Yuting, Li, Zhennan, Ye, Fei, Sun, Yuanhong, Li, Feng, Xing, Huijie, Wang, Shuai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9672319/
https://www.ncbi.nlm.nih.gov/pubmed/36408246
http://dx.doi.org/10.3389/fphar.2022.1053610
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author Zeng, Wanying
Liu, Xiaojing
Wu, Yangyang
Cai, Yuting
Li, Zhennan
Ye, Fei
Sun, Yuanhong
Li, Feng
Xing, Huijie
Wang, Shuai
author_facet Zeng, Wanying
Liu, Xiaojing
Wu, Yangyang
Cai, Yuting
Li, Zhennan
Ye, Fei
Sun, Yuanhong
Li, Feng
Xing, Huijie
Wang, Shuai
author_sort Zeng, Wanying
collection PubMed
description Glucuronidation catalyzed by UDP-glucuronosyltransferases (UGTs) is one of the most important phase II mechanisms, facilitating drug clearance via conjugation of glucuronic acid with polar groups of xenobiotics. Accumulating evidence suggests that IBDs impact drug disposition, but whether and how IBDs regulate UGTs and drug glucuronidation remains undefined. In this study, we aim to investigate the expression of UGTs and drug glucuronidation in experimental colitis. Given that glucuronidation occurs primarily in the liver, we analyzed the mRNA changes in hepatic UGTs with a DSS-induced mouse colitis model. Twelve UGTs were downregulated in the liver of colitis mice including UGT1A1 and UGT1A9 (two representative UGTs). Colitis in mice downregulated UGT1A1 and UGT1A9 in the liver but not in small intestine, colon, and kidney. We also established that the downregulation of UGTs was attributed to the disease itself rather than the DSS compound. Moreover, colitis-reduced UGT1A1 and UGT1A9 lead to dampened baicalein and puerarin glucuronidation. PXR was the only UGT regulator significantly downregulated in colitis mice, suggesting dysregulation of PXR is associated with the downregulation of UGT1A1 and UGT1A9, thereby potentially resulting in dysfunction of baicalein and puerarin glucuronidation. Collectively, we establish that UGTs and glucuronidation are dysregulated in colitis, and this effect may cause variation in drug responsiveness in IBDs.
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spelling pubmed-96723192022-11-19 Dysregulated hepatic UDP-glucuronosyltransferases and flavonoids glucuronidation in experimental colitis Zeng, Wanying Liu, Xiaojing Wu, Yangyang Cai, Yuting Li, Zhennan Ye, Fei Sun, Yuanhong Li, Feng Xing, Huijie Wang, Shuai Front Pharmacol Pharmacology Glucuronidation catalyzed by UDP-glucuronosyltransferases (UGTs) is one of the most important phase II mechanisms, facilitating drug clearance via conjugation of glucuronic acid with polar groups of xenobiotics. Accumulating evidence suggests that IBDs impact drug disposition, but whether and how IBDs regulate UGTs and drug glucuronidation remains undefined. In this study, we aim to investigate the expression of UGTs and drug glucuronidation in experimental colitis. Given that glucuronidation occurs primarily in the liver, we analyzed the mRNA changes in hepatic UGTs with a DSS-induced mouse colitis model. Twelve UGTs were downregulated in the liver of colitis mice including UGT1A1 and UGT1A9 (two representative UGTs). Colitis in mice downregulated UGT1A1 and UGT1A9 in the liver but not in small intestine, colon, and kidney. We also established that the downregulation of UGTs was attributed to the disease itself rather than the DSS compound. Moreover, colitis-reduced UGT1A1 and UGT1A9 lead to dampened baicalein and puerarin glucuronidation. PXR was the only UGT regulator significantly downregulated in colitis mice, suggesting dysregulation of PXR is associated with the downregulation of UGT1A1 and UGT1A9, thereby potentially resulting in dysfunction of baicalein and puerarin glucuronidation. Collectively, we establish that UGTs and glucuronidation are dysregulated in colitis, and this effect may cause variation in drug responsiveness in IBDs. Frontiers Media S.A. 2022-11-04 /pmc/articles/PMC9672319/ /pubmed/36408246 http://dx.doi.org/10.3389/fphar.2022.1053610 Text en Copyright © 2022 Zeng, Liu, Wu, Cai, Li, Ye, Sun, Li, Xing and Wang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zeng, Wanying
Liu, Xiaojing
Wu, Yangyang
Cai, Yuting
Li, Zhennan
Ye, Fei
Sun, Yuanhong
Li, Feng
Xing, Huijie
Wang, Shuai
Dysregulated hepatic UDP-glucuronosyltransferases and flavonoids glucuronidation in experimental colitis
title Dysregulated hepatic UDP-glucuronosyltransferases and flavonoids glucuronidation in experimental colitis
title_full Dysregulated hepatic UDP-glucuronosyltransferases and flavonoids glucuronidation in experimental colitis
title_fullStr Dysregulated hepatic UDP-glucuronosyltransferases and flavonoids glucuronidation in experimental colitis
title_full_unstemmed Dysregulated hepatic UDP-glucuronosyltransferases and flavonoids glucuronidation in experimental colitis
title_short Dysregulated hepatic UDP-glucuronosyltransferases and flavonoids glucuronidation in experimental colitis
title_sort dysregulated hepatic udp-glucuronosyltransferases and flavonoids glucuronidation in experimental colitis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9672319/
https://www.ncbi.nlm.nih.gov/pubmed/36408246
http://dx.doi.org/10.3389/fphar.2022.1053610
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