Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats.
Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats.
复制标题
DOI：
10.3390/molecules22111809
复制
发表时间：
2017-10-25
期刊：
影响因子：
--
通讯作者：
Ma Y
中科院分区：
文献类型：
--
作者：
Jiang P;Zhang X;Huang Y;Cheng N;Ma Y
我们前期的研究表明苦参酮是苦参的主要肝毒性成分，在肝脏中积累。本研究表征了苦参提取物（ESF）的肝毒性和苦参酮在肝脏积累的机制。口服ESF（大鼠1.25和2.5g/kg，连续14天）后会损害肝功能并引起肝脏脂肪堆积。进行基于高分辨率质谱的血清代谢组学评估，并采用实时PCR测定CPT-1、CPT-2、PPAR-α和LCAD基因的表达水平。在 HL-7702 细胞中评估了苦参酮对甘油三酯水平的影响。在接受 ESF（2.5 g/kg）的大鼠中分析了苦参酮和苦参酮葡萄糖苷酸的组织分布。在 OAT2、OATP1B1、OATP2B1 和 OATP1B3 转染的 HEK293 细胞中研究了苦参酮和苦参酮葡萄糖苷酸的主动摄取。结果表明，大鼠口服ESF后，苦参酮葡萄糖醛酸苷通过OATP1B3主动转运至肝细胞并水解为苦参酮，苦参酮通过还原左旋肉碱和抑制PPAR-α途径抑制脂肪酸β-氧化，最终导致脂质积累和肝损伤。这些发现有助于了解口服 ESF 后苦参酮的肝毒性。
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.
登录
查看更多内容
影响因子：
3.4
作者：
Jung KA;Min HJ;Yoo SS;Kim HJ;Choi SN;Ha CY;Kim HJ;Kim TH;Jung WT;Lee OJ;Lee JS;Shim SG
通讯作者：
Shim SG
DOI：
10.1152/ajpgi.00301.2011
发表时间：
2012-01-01
影响因子：
4.5
作者：
Kakisaka, Keisuke;Cazanave, Sophie C.;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
3.9
作者：
Jiang, Wen;Xu, Beibei;Hu, Ming
通讯作者：
Hu, Ming
影响因子：
4.3
作者：
Huang, Yin;Tian, Yuan;Zhang, Zunjian
通讯作者：
Zhang, Zunjian
影响因子：
4.2
作者：
Abdelmegeed, Mohamed A.;Yoo, Seong-Ho;Song, Byoung-Joon
通讯作者：
Song, Byoung-Joon