Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
Department of Pharmacy, Eye Ear Nose Throat Hospital of Fudan University, Shanghai 200031, China.
Molecules. 2017 Oct 25;22(11):1809. doi: 10.3390/molecules22111809.
Our previous study showed that kurarinone was the main hepatotoxic ingredient of , accumulating in the liver. This study characterized the mechanism of 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.
我们之前的研究表明，苦参酮是苦参的主要肝毒性成分，在肝脏中蓄积。本研究旨在探讨苦参提取物（ESF）肝毒性及其苦参酮肝蓄积的作用机制。ESF 经口给药（大鼠，14 天，1.25 和 2.5 g/kg）可损害肝功能并导致肝脏脂肪堆积。采用高分辨质谱血清代谢组学评价法，实时 PCR 法检测 CPT-1、CPT-2、PPAR-α和 LCAD 基因的表达水平。在 HL-7702 细胞中评估苦参酮对甘油三酯水平的影响。在给予 ESF（2.5 g/kg）的大鼠中分析苦参酮和苦参酮葡萄糖醛酸苷的组织分布。在 OAT2、OATP1B1、OATP2B1 和 OATP1B3 转染的 HEK293 细胞中研究苦参酮和苦参酮葡萄糖醛酸苷的主动摄取。我们的研究结果表明，大鼠口服 ESF 后，苦参酮葡萄糖醛酸苷可被 OATP1B3 主动转运入肝细胞，并水解为苦参酮，通过降低肉碱和抑制 PPAR-α通路，抑制脂肪酸β氧化，最终导致脂质堆积和肝损伤。这些发现有助于理解口服 ESF 后苦参酮的肝毒性。
