Seneciphylline, a main pyrrolizidine alkaloid inGynura japonica, induces hepatotoxicity in mice and primary hepatocytes via activating mitochondria-mediated apoptosis

被引：19

作者：

Wang, Weiqian ^{[1
,2
,3
]}

Yang, Xiao ^{[1
,2
]}

Chen, Yan ^{[1
,2
]}

Ye, Xuanling ^{[1
,2
]}

Jiang, Kaiyuan ^{[1
,2
]}

Xiong, Aizhen ^{[1
,2
]}

Yang, Li ^{[1
,2
,3
]}

Wang, Zhengtao ^{[1
,2
]}

机构：

[1] Shanghai Univ Tradit Chinese Med, Inst Chinese Mat Med, MOE Key Lab Standardizat Chinese Med, Shanghai 201203, Peoples R China

[2] Shanghai Univ Tradit Chinese Med, Inst Chinese Mat Med, SATCM Key Lab New Resources & Qual Evaluat Chines, Shanghai 201203, Peoples R China

[3] Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai, Peoples R China

来源：

JOURNAL OF APPLIED TOXICOLOGY | 2020年 / 40卷 / 11期

关键词：

dynamin-related protein 1; Gynura japonica; hepatic sinusoidal obstruction syndrome; mitochondria-mediated apoptosis; pyrrolizidine alkaloids; seneciphylline; HEPATIC VENOOCCLUSIVE DISEASE; PROTEIN-KINASE; CELL-DEATH; LIVER; DRP1; MEDICINE; DIVISION; INHIBITION; DYNAMICS; FISSION;

D O I：

10.1002/jat.4004

中图分类号：

R99 [毒物学（毒理学）];

学科分类号：

100405 ;

摘要：

Herbal drug-induced liver injury has been reported worldwide and gained global attention. Thousands of hepatic sinusoidal obstruction syndrome (HSOS) cases have been reported after consumption of herbal medicines and preparations containing pyrrolizidine alkaloids (PAs), which are natural phytotoxins globally distributed. And herbal medicines, such asGynura japonica, are the current leading cause of PA-induced HSOS. The present study aimed to reveal the mechanism underlying the hepatotoxicity of seneciphylline (Seph), a main PA inG. japonica. Results showed that Seph induced severe liver injury through apoptosis in mice (70 mg/kg Seph, orally) and primary mouse and human hepatocytes (5-50 mu M Seph). Further research uncovered that Seph induced apoptosis by disrupting mitochondrial homeostasis, inducing mitochondrial depolarization, mitochondrial membrane potential (MMP) loss, and cytochrome c (Cyt c) release and activating c-JunN-terminal kinase (JNK). The Seph-induced apoptosis in hepatocytes could be alleviated by Mdivi-1 (50 mu M, a dynamin-related protein 1 inhibitor), as well as SP600125 (25 mu M, a specific JNK inhibitor) and ZVAD-fmk (50 mu M, a general caspase inhibitor). Moreover, the Seph-induced MMP loss in hepatocytes was also rescued by Mdivi-1. In conclusion, Seph induced liver toxicity via activating mitochondrial-mediated apoptosis in mice and primary hepatocytes. Our results provide further information on Seph detoxification and herbal medicines containing Seph such asG. japonica.

引用

页码：1534 / 1544

页数：11