Schisandrin B elicits a glutathione antioxidant response and protects against apoptosis via the redox-sensitive ERK/Nrf2 pathway in AML12 hepatocytes.
Abstract This study examined the effects of (-)schisandrin B [(-)Sch B] on MAPK and Nrf2 activation and the subsequent induction of glutathione antioxidant response and cytoprotection against apoptosis in AML12 hepatocytes. Pharmacological tools, such as cytochrome P-450 (CYP) inhibitor, antioxidant, MAPK inhibitors and Nrf2 RNAi, were used to delineate the signalling pathway. (-)Sch B caused a time-dependent activation of MAPK in AML12 cells, particularly the ERK1/2. The MAPK activation was followed by an enhancement in Nrf2 nuclear translocation and the eliciting of a glutathione antioxidant response. Reactive oxygen species arising from a CYP-catalysed reaction with (-)Sch B seemed to be causally related to the activation of MAPK and Nrf2. ERK inhibition by U0126 or Nrf2 suppression by Nrf2 RNAi transfection almost completely abrogated the cytoprotection against menadione-induced apoptosis in (-)Sch B-pre-treated cells. (-)Sch B pre-treatment potentiated the menadione-induced ERK activation, whereas both p38 and JNK activations were suppressed. Under the condition of ERK inhibition, Sch B treatment did not protect against carbon tetrachloride-hepatotoxicity in an in vivo mouse model. In conclusion, (-)Sch B triggers a redox-sensitive ERK/Nrf2 signalling, which then elicits a cellular glutathione antioxidant response and protects against oxidant-induced apoptosis in AML12 cells.
Section of Biochemistry and Cell Biology, Division of Life Science, The Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong SAR, PR China.
Pou Kuan
PK
Leong
Po Yee
PY
Chiu
Na
N
Chen
Hoiyan
H
Leung
Kam Ming
KM
Ko
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D002251:Carbon Tetrachloride / Q000633:toxicity; D002460:Cell Line; D034242:Cyclooctanes / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism*; D022781:Hepatocytes / Q000201:enzymology; D017705:Lignans / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D011083:Polycyclic Compounds / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D024483:Vitamin K 3 / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D002070:Butadienes; D034242:Cyclooctanes; D004791:Enzyme Inhibitors; D017705:Lignans; D051267:NF-E2-Related Factor 2; D009570:Nitriles; D011083:Polycyclic Compounds; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C113580:U 0126; C015499:schizandrin B; D024483:Vitamin K 3; D002251:Carbon Tetrachloride; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D005978:Glutathione