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Dysregulated hepatic UDP-glucuronosyltransferases and flavonoids glucuronidation in experimental colitis

Affiliation
Institute of Molecular Rhythm and Metabolism ,School of Pharmaceutical Sciences ,Guangzhou University of Chinese Medicine ,Guangzhou ,China
Zeng, Wanying;
Affiliation
Department of Rheumatology and Immunology ,Union Hospital ,Tongji Medical College ,Huazhong University of Science and Technology ,Wuhan ,China
Liu, Xiaojing;
Affiliation
Institute of Molecular Rhythm and Metabolism ,School of Pharmaceutical Sciences ,Guangzhou University of Chinese Medicine ,Guangzhou ,China
Wu, Yangyang;
Affiliation
Institute of Molecular Rhythm and Metabolism ,School of Pharmaceutical Sciences ,Guangzhou University of Chinese Medicine ,Guangzhou ,China
Cai, Yuting;
Affiliation
Institute of Molecular Rhythm and Metabolism ,School of Pharmaceutical Sciences ,Guangzhou University of Chinese Medicine ,Guangzhou ,China
Li, Zhennan;
Affiliation
Institute of Molecular Rhythm and Metabolism ,School of Pharmaceutical Sciences ,Guangzhou University of Chinese Medicine ,Guangzhou ,China
Ye, Fei;
Affiliation
Institute of Molecular Rhythm and Metabolism ,School of Pharmaceutical Sciences ,Guangzhou University of Chinese Medicine ,Guangzhou ,China
Sun, Yuanhong;
Affiliation
Infectious Diseases Institute ,Guangzhou Eighth People’s Hospital ,Guangzhou ,China
Li, Feng;
Affiliation
Institution of Laboratory Animal ,Jinan University ,Guangzhou ,China
Xing, Huijie;
Affiliation
Institute of Molecular Rhythm and Metabolism ,School of Pharmaceutical Sciences ,Guangzhou University of Chinese Medicine ,Guangzhou ,China
Wang, Shuai

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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License Holder: Copyright © 2022 Zeng, Liu, Wu, Cai, Li, Ye, Sun, Li, Xing and Wang.

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