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Seneciphylline, a main pyrrolizidine alkaloid in Gynura japonica, induces hepatotoxicity in mice and primary hepatocytes via activating mitochondria-mediated apoptosis
- Source :
- Journal of applied toxicology : JATREFERENCES. 40(11)
- Publication Year :
- 2020
-
Abstract
- 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 as Gynura 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 in G. 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 μM 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-Jun N-terminal kinase (JNK). The Seph-induced apoptosis in hepatocytes could be alleviated by Mdivi-1 (50 μM, a dynamin-related protein 1 inhibitor), as well as SP600125 (25 μM, a specific JNK inhibitor) and ZVAD-fmk (50 μM, 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 as G. japonica.
- Subjects :
- Dynamins
Male
Pyrrolizidine alkaloid
Primary Cell Culture
Apoptosis
Mitochondria, Liver
010501 environmental sciences
Pharmacology
Matrix metalloproteinase
Toxicology
01 natural sciences
03 medical and health sciences
chemistry.chemical_compound
DNM1L
medicine
Animals
Humans
Cells, Cultured
Pyrrolizidine Alkaloids
030304 developmental biology
0105 earth and related environmental sciences
Liver injury
Membrane Potential, Mitochondrial
0303 health sciences
biology
Kinase
Cytochrome c
JNK Mitogen-Activated Protein Kinases
Cytochromes c
medicine.disease
Mice, Inbred C57BL
chemistry
Liver
Pyrrolizidine
biology.protein
Hepatocytes
Chemical and Drug Induced Liver Injury
Drugs, Chinese Herbal
Signal Transduction
Subjects
Details
- ISSN :
- 10991263
- Volume :
- 40
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Journal of applied toxicology : JATREFERENCES
- Accession number :
- edsair.doi.dedup.....6b0db9edca9cb9d6a49d0ebd99ac8ab6