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Fraxinellone Induces Hepatotoxicity in Zebrafish through Oxidative Stress and the Transporters Pathway
Fraxinellone (FRA), a major active component from Cortex Dictamni, produces hepatotoxicity via the metabolization of furan rings by CYP450. However, the mechanism underlying the hepatotoxicity of FRA remains unclear. Therefore, zebrafish larvae at 72 h post fertilization were used to evaluate the me...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103149/ https://www.ncbi.nlm.nih.gov/pubmed/35566003 http://dx.doi.org/10.3390/molecules27092647 |
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author | Wang, Shuting Bao, Jie Li, Jie Li, Wanfang Tian, Mengyin Qiu, Caixia Pang, Fei Li, Xin Yang, Jianbo Hu, Yuchi Wang, Sujuan Jin, Hongtao |
author_facet | Wang, Shuting Bao, Jie Li, Jie Li, Wanfang Tian, Mengyin Qiu, Caixia Pang, Fei Li, Xin Yang, Jianbo Hu, Yuchi Wang, Sujuan Jin, Hongtao |
author_sort | Wang, Shuting |
collection | PubMed |
description | Fraxinellone (FRA), a major active component from Cortex Dictamni, produces hepatotoxicity via the metabolization of furan rings by CYP450. However, the mechanism underlying the hepatotoxicity of FRA remains unclear. Therefore, zebrafish larvae at 72 h post fertilization were used to evaluate the metabolic hepatotoxicity of FRA and to explore the underlying molecular mechanisms. The results showed that FRA (10–30 μM) induced liver injury and obvious alterations in the metabolomics of zebrafish larvae. FRA induces apoptosis by increasing the level of ROS and activating the JNK/P53 pathway. In addition, FRA can induce cholestasis by down-regulating bile acid transporters P-gp, Bsep, and Ntcp. The addition of the CYP3A inhibitor ketoconazole (1 μM) significantly reduced the hepatotoxicity of FRA (30 μM), which indicated that FRA induced hepatotoxicity through CYP3A metabolism. Targeted metabolomics analysis indicates the changes in amino acid levels can be combined with molecular biology to clarify the mechanism of hepatotoxicity induced by FRA, and amino acid metabolism monitoring may provide a new method for the prevention and treatment of DILI from FRA. |
format | Online Article Text |
id | pubmed-9103149 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-91031492022-05-14 Fraxinellone Induces Hepatotoxicity in Zebrafish through Oxidative Stress and the Transporters Pathway Wang, Shuting Bao, Jie Li, Jie Li, Wanfang Tian, Mengyin Qiu, Caixia Pang, Fei Li, Xin Yang, Jianbo Hu, Yuchi Wang, Sujuan Jin, Hongtao Molecules Article Fraxinellone (FRA), a major active component from Cortex Dictamni, produces hepatotoxicity via the metabolization of furan rings by CYP450. However, the mechanism underlying the hepatotoxicity of FRA remains unclear. Therefore, zebrafish larvae at 72 h post fertilization were used to evaluate the metabolic hepatotoxicity of FRA and to explore the underlying molecular mechanisms. The results showed that FRA (10–30 μM) induced liver injury and obvious alterations in the metabolomics of zebrafish larvae. FRA induces apoptosis by increasing the level of ROS and activating the JNK/P53 pathway. In addition, FRA can induce cholestasis by down-regulating bile acid transporters P-gp, Bsep, and Ntcp. The addition of the CYP3A inhibitor ketoconazole (1 μM) significantly reduced the hepatotoxicity of FRA (30 μM), which indicated that FRA induced hepatotoxicity through CYP3A metabolism. Targeted metabolomics analysis indicates the changes in amino acid levels can be combined with molecular biology to clarify the mechanism of hepatotoxicity induced by FRA, and amino acid metabolism monitoring may provide a new method for the prevention and treatment of DILI from FRA. MDPI 2022-04-20 /pmc/articles/PMC9103149/ /pubmed/35566003 http://dx.doi.org/10.3390/molecules27092647 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Wang, Shuting Bao, Jie Li, Jie Li, Wanfang Tian, Mengyin Qiu, Caixia Pang, Fei Li, Xin Yang, Jianbo Hu, Yuchi Wang, Sujuan Jin, Hongtao Fraxinellone Induces Hepatotoxicity in Zebrafish through Oxidative Stress and the Transporters Pathway |
title | Fraxinellone Induces Hepatotoxicity in Zebrafish through Oxidative Stress and the Transporters Pathway |
title_full | Fraxinellone Induces Hepatotoxicity in Zebrafish through Oxidative Stress and the Transporters Pathway |
title_fullStr | Fraxinellone Induces Hepatotoxicity in Zebrafish through Oxidative Stress and the Transporters Pathway |
title_full_unstemmed | Fraxinellone Induces Hepatotoxicity in Zebrafish through Oxidative Stress and the Transporters Pathway |
title_short | Fraxinellone Induces Hepatotoxicity in Zebrafish through Oxidative Stress and the Transporters Pathway |
title_sort | fraxinellone induces hepatotoxicity in zebrafish through oxidative stress and the transporters pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103149/ https://www.ncbi.nlm.nih.gov/pubmed/35566003 http://dx.doi.org/10.3390/molecules27092647 |
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