Cargando…
Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats
Our previous study showed that kurarinone was the main hepatotoxic ingredient of Sophora flavescens, accumulating in the liver. This study characterized the mechanism of Sophora flavescens extract (ESF) hepatotoxicity and hepatic accumulation of kurarinone. ESF impaired hepatic function and caused f...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150336/ https://www.ncbi.nlm.nih.gov/pubmed/29068394 http://dx.doi.org/10.3390/molecules22111809 |
_version_ | 1783356970706665472 |
---|---|
author | Jiang, Peng Zhang, Xiuwen Huang, Yutong Cheng, Nengneng Ma, Yueming |
author_facet | Jiang, Peng Zhang, Xiuwen Huang, Yutong Cheng, Nengneng Ma, Yueming |
author_sort | Jiang, Peng |
collection | PubMed |
description | Our previous study showed that kurarinone was the main hepatotoxic ingredient of Sophora flavescens, accumulating in the liver. This study characterized the mechanism of Sophora flavescens extract (ESF) hepatotoxicity and hepatic accumulation of kurarinone. ESF impaired hepatic function and caused fat accumulation in the liver after oral administration (1.25 and 2.5 g/kg for 14 days in rats). Serum metabolomics evaluation based on high-resolution mass spectrometry was conducted and real-time PCR was used to determine the expression levels of CPT-1, CPT-2, PPAR-α, and LCAD genes. Effects of kurarinone on triglyceride levels were evaluated in HL-7702 cells. Tissue distribution of kurarinone and kurarinone glucuronides was analyzed in rats receiving ESF (2.5 g/kg). Active uptake of kurarinone and kurarinone glucuronides was studied in OAT2-, OATP1B1-, OATP2B1-, and OATP1B3-transfected HEK293 cells. Our results revealed that after oral administration of ESF in rats, kurarinone glucuronides were actively transported into hepatocytes by OATP1B3 and hydrolyzed into kurarinone, which inhibited fatty acid β-oxidation through the reduction of l-carnitine and the inhibition of PPAR-α pathway, ultimately leading to lipid accumulation and liver injury. These findings contribute to understanding hepatotoxicity of kurarinone after oral administration of ESF. |
format | Online Article Text |
id | pubmed-6150336 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-61503362018-11-13 Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats Jiang, Peng Zhang, Xiuwen Huang, Yutong Cheng, Nengneng Ma, Yueming Molecules Article Our previous study showed that kurarinone was the main hepatotoxic ingredient of Sophora flavescens, accumulating in the liver. This study characterized the mechanism of Sophora flavescens extract (ESF) hepatotoxicity and hepatic accumulation of kurarinone. ESF impaired hepatic function and caused fat accumulation in the liver after oral administration (1.25 and 2.5 g/kg for 14 days in rats). Serum metabolomics evaluation based on high-resolution mass spectrometry was conducted and real-time PCR was used to determine the expression levels of CPT-1, CPT-2, PPAR-α, and LCAD genes. Effects of kurarinone on triglyceride levels were evaluated in HL-7702 cells. Tissue distribution of kurarinone and kurarinone glucuronides was analyzed in rats receiving ESF (2.5 g/kg). Active uptake of kurarinone and kurarinone glucuronides was studied in OAT2-, OATP1B1-, OATP2B1-, and OATP1B3-transfected HEK293 cells. Our results revealed that after oral administration of ESF in rats, kurarinone glucuronides were actively transported into hepatocytes by OATP1B3 and hydrolyzed into kurarinone, which inhibited fatty acid β-oxidation through the reduction of l-carnitine and the inhibition of PPAR-α pathway, ultimately leading to lipid accumulation and liver injury. These findings contribute to understanding hepatotoxicity of kurarinone after oral administration of ESF. MDPI 2017-10-25 /pmc/articles/PMC6150336/ /pubmed/29068394 http://dx.doi.org/10.3390/molecules22111809 Text en © 2017 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Jiang, Peng Zhang, Xiuwen Huang, Yutong Cheng, Nengneng Ma, Yueming Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats |
title | Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats |
title_full | Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats |
title_fullStr | Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats |
title_full_unstemmed | Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats |
title_short | Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats |
title_sort | hepatotoxicity induced by sophora flavescens and hepatic accumulation of kurarinone, a major hepatotoxic constituent of sophora flavescens in rats |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150336/ https://www.ncbi.nlm.nih.gov/pubmed/29068394 http://dx.doi.org/10.3390/molecules22111809 |
work_keys_str_mv | AT jiangpeng hepatotoxicityinducedbysophoraflavescensandhepaticaccumulationofkurarinoneamajorhepatotoxicconstituentofsophoraflavescensinrats AT zhangxiuwen hepatotoxicityinducedbysophoraflavescensandhepaticaccumulationofkurarinoneamajorhepatotoxicconstituentofsophoraflavescensinrats AT huangyutong hepatotoxicityinducedbysophoraflavescensandhepaticaccumulationofkurarinoneamajorhepatotoxicconstituentofsophoraflavescensinrats AT chengnengneng hepatotoxicityinducedbysophoraflavescensandhepaticaccumulationofkurarinoneamajorhepatotoxicconstituentofsophoraflavescensinrats AT mayueming hepatotoxicityinducedbysophoraflavescensandhepaticaccumulationofkurarinoneamajorhepatotoxicconstituentofsophoraflavescensinrats |