title: Activation of Fas death receptor pathway and Bid in hepatocytes is involved in saikosaponin D induction of hepatotoxicity.
abstract: Drug-induced liver injury can lead to acute liver failure. Saikosaponin D (SSD) is a major component isolated from the medicinal herb Bupleurum falcatum, which has been linked to hepatotoxicity. We previously reported that SSD disrupted PDGF-βR pathway leading to mitochondrial apoptosis in human LO2 hepatocytes. The present study was aimed at further exploring the underlying mechanisms in vitro and in vivo. We initially determined the concentration range of SSD at up to 2μM for subsequent apoptosis examinations. SSD significantly upregulated Fas expression, promoted caspase-8 cleavage and activated the pro-apoptotic protein Bid in LO2 cells. Moreover, SSD reduced the abundance of cytochrome c in mitochondria and increased the cleaved-caspase-3 in LO2 cells, but did not apparently affect PI3K/AKT, ERK and STAT3 pathways that are involved in cell fate regulation. Experiments in vivo showed that one-week treatment with SSD at 300 mg/kg significantly elevated the liver/body weight ratio and caused histological injury in mouse liver. Furthermore, SSD treatment induced massive hepatocyte apoptosis, and significantly downregulated Bcl-2 but upregulated Bax in mouse liver. Taken together, these results revealed a specific mechanism of activation of extrinsic apoptosis pathway and Bid by SSD, which was involved in SSD-induced mitochondrial apoptosis in hepatocytes and potential hepatotoxicity.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Pharmacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Jiangjuan
authors.initials: J
authors.lastname: Shao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: nytws@163.com.
authors.forename: Shizhong
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D029972:Bupleurum / Q000737:chemistry* / Q000633:toxicity; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D012503:Saponins / Q000008:administration & dosage / Q000633:toxicity*; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C491901:FAS protein, human; D012503:Saponins; D019014:fas Receptor; D009828:Oleanolic Acid; C505530:CASP8 protein, human; D053181:Caspase 8; C025759:saikosaponin D
keywords: Bid; Extrinsic apoptosis; Fas; Hepatotoxicity; Saikosaponin D