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The roles of serine hydrolases and serum albumin in alisol B 23-acetate hydrolysis in humans
Introduction: Alisol B 23-acetate (AB23A), a major bioactive constituent in the Chinese herb Zexie (Rhizoma Alismatis), has been found with multiple pharmacological activities. AB23A can be readily hydrolyzed to alisol B in mammals, but the hydrolytic pathways of AB23A in humans and the key enzymes...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10117764/ https://www.ncbi.nlm.nih.gov/pubmed/37089921 http://dx.doi.org/10.3389/fphar.2023.1160665 |
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author | Zhang, Tiantian Zhang, Feng Zhang, Yani Li, Hongxin Zhu, Guanghao Weng, Taotao Huang, Cheng Wang, Ping He, Yuqi Hu, Jing Ge, Guangbo |
author_facet | Zhang, Tiantian Zhang, Feng Zhang, Yani Li, Hongxin Zhu, Guanghao Weng, Taotao Huang, Cheng Wang, Ping He, Yuqi Hu, Jing Ge, Guangbo |
author_sort | Zhang, Tiantian |
collection | PubMed |
description | Introduction: Alisol B 23-acetate (AB23A), a major bioactive constituent in the Chinese herb Zexie (Rhizoma Alismatis), has been found with multiple pharmacological activities. AB23A can be readily hydrolyzed to alisol B in mammals, but the hydrolytic pathways of AB23A in humans and the key enzymes responsible for AB23A hydrolysis are still unrevealed. This study aims to reveal the metabolic organs and the crucial enzymes responsible for AB23A hydrolysis in human biological systems, as well as to decipher the impact of AB23A hydrolysis on its biological effects. Methods: The hydrolytic pathways of AB23A in human plasma and tissue preparations were carefully investigated by using Q-Exactive quadrupole-Orbitrap mass spectrometer and LC-UV, while the key enzymes responsible for AB23A hydrolysis were studied via performing a set of assays including reaction phenotyping assays, chemical inhibition assays, and enzyme kinetics analyses. Finally, the agonist effects of both AB23A and its hydrolytic metabolite(s) on FXR were tested at the cellular level. Results: AB23A could be readily hydrolyzed to form alisol B in human plasma, intestinal and hepatic preparations, while human butyrylcholinesterase (hBchE) and human carboxylesterases played key roles in AB23A hydrolysis in human plasma and tissue preparations, respectively. It was also found that human serum albumin (hSA) could catalyze AB23A hydrolysis, while multiple lysine residues of hSA were covalently modified by AB23A, suggesting that hSA catalyzed AB23A hydrolysis via its pseudo-esterase activity. Biological tests revealed that both AB23A and alisol B exhibited similar FXR agonist effects, indicating AB23A hydrolysis did not affect its FXR agonist effect. Discussion: This study deciphers the hydrolytic pathways of AB23A in human biological systems, which is very helpful for deep understanding of the metabolic rates of AB23A in humans, and useful for developing novel prodrugs of alisol B with desirable pharmacokinetic behaviors. |
format | Online Article Text |
id | pubmed-10117764 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-101177642023-04-21 The roles of serine hydrolases and serum albumin in alisol B 23-acetate hydrolysis in humans Zhang, Tiantian Zhang, Feng Zhang, Yani Li, Hongxin Zhu, Guanghao Weng, Taotao Huang, Cheng Wang, Ping He, Yuqi Hu, Jing Ge, Guangbo Front Pharmacol Pharmacology Introduction: Alisol B 23-acetate (AB23A), a major bioactive constituent in the Chinese herb Zexie (Rhizoma Alismatis), has been found with multiple pharmacological activities. AB23A can be readily hydrolyzed to alisol B in mammals, but the hydrolytic pathways of AB23A in humans and the key enzymes responsible for AB23A hydrolysis are still unrevealed. This study aims to reveal the metabolic organs and the crucial enzymes responsible for AB23A hydrolysis in human biological systems, as well as to decipher the impact of AB23A hydrolysis on its biological effects. Methods: The hydrolytic pathways of AB23A in human plasma and tissue preparations were carefully investigated by using Q-Exactive quadrupole-Orbitrap mass spectrometer and LC-UV, while the key enzymes responsible for AB23A hydrolysis were studied via performing a set of assays including reaction phenotyping assays, chemical inhibition assays, and enzyme kinetics analyses. Finally, the agonist effects of both AB23A and its hydrolytic metabolite(s) on FXR were tested at the cellular level. Results: AB23A could be readily hydrolyzed to form alisol B in human plasma, intestinal and hepatic preparations, while human butyrylcholinesterase (hBchE) and human carboxylesterases played key roles in AB23A hydrolysis in human plasma and tissue preparations, respectively. It was also found that human serum albumin (hSA) could catalyze AB23A hydrolysis, while multiple lysine residues of hSA were covalently modified by AB23A, suggesting that hSA catalyzed AB23A hydrolysis via its pseudo-esterase activity. Biological tests revealed that both AB23A and alisol B exhibited similar FXR agonist effects, indicating AB23A hydrolysis did not affect its FXR agonist effect. Discussion: This study deciphers the hydrolytic pathways of AB23A in human biological systems, which is very helpful for deep understanding of the metabolic rates of AB23A in humans, and useful for developing novel prodrugs of alisol B with desirable pharmacokinetic behaviors. Frontiers Media S.A. 2023-04-06 /pmc/articles/PMC10117764/ /pubmed/37089921 http://dx.doi.org/10.3389/fphar.2023.1160665 Text en Copyright © 2023 Zhang, Zhang, Zhang, Li, Zhu, Weng, Huang, Wang, He, Hu and Ge. 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 Zhang, Tiantian Zhang, Feng Zhang, Yani Li, Hongxin Zhu, Guanghao Weng, Taotao Huang, Cheng Wang, Ping He, Yuqi Hu, Jing Ge, Guangbo The roles of serine hydrolases and serum albumin in alisol B 23-acetate hydrolysis in humans |
title | The roles of serine hydrolases and serum albumin in alisol B 23-acetate hydrolysis in humans |
title_full | The roles of serine hydrolases and serum albumin in alisol B 23-acetate hydrolysis in humans |
title_fullStr | The roles of serine hydrolases and serum albumin in alisol B 23-acetate hydrolysis in humans |
title_full_unstemmed | The roles of serine hydrolases and serum albumin in alisol B 23-acetate hydrolysis in humans |
title_short | The roles of serine hydrolases and serum albumin in alisol B 23-acetate hydrolysis in humans |
title_sort | roles of serine hydrolases and serum albumin in alisol b 23-acetate hydrolysis in humans |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10117764/ https://www.ncbi.nlm.nih.gov/pubmed/37089921 http://dx.doi.org/10.3389/fphar.2023.1160665 |
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