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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...

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Autores principales: Wang, Shuting, Bao, Jie, Li, Jie, Li, Wanfang, Tian, Mengyin, Qiu, Caixia, Pang, Fei, Li, Xin, Yang, Jianbo, Hu, Yuchi, Wang, Sujuan, Jin, Hongtao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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