PMID- 19623661
OWN - NLM
STAT- MEDLINE
DCOM- 20091211
LR  - 20171116
IS  - 1097-4644 (Electronic)
IS  - 0730-2312 (Linking)
VI  - 108
IP  - 2
DP  - 2009 Oct 1
TI  - Protective mechanisms of N-acetyl-cysteine against pyrrolizidine alkaloid 
      clivorine-induced hepatotoxicity.
PG  - 424-32
LID - 10.1002/jcb.22269 [doi]
AB  - Pyrrolizidine alkaloid (PA) clivorine, isolated from traditional Chinese 
      medicinal plant Ligularia hodgsonii Hook, has been shown to induce apoptosis in 
      hepatocytes via mitochondrial-mediated apoptotic pathway in our previous 
      research. The present study was designed to observe the protection of 
      N-acetyl-cysteine (NAC) on clivorine-induced hepatocytes apoptosis. Our results 
      showed that 5 mM NAC significantly reversed clivorine-induced cytotoxicity via 
      MTT and Trypan Blue staining assay. DNA apoptotic fragmentation analysis and 
      Western-blot results showed that NAC decreased clivorine-induced apoptotic DNA 
      ladder and caspase-3 activation. Further results showed that NAC inhibited 
      clivorine-induced Bcl-xL decrease, mitochondrial cytochrome c release and 
      caspase-9 activation. Intracellular glutathione (GSH) is an important ubiquitous 
      redox-active reducing sulfhydryl (--SH) tripeptide, and our results showed that 
      clivorine (50 microM) decreased cellular GSH amounts and the ratio of GSH/GSSG in 
      the time-dependent manner, while 5 mM NAC obviously reversed this depletion. 
      Further results showed that GSH synthesis inhibitor BSO augmented 
      clivorine-induced cytotoxicity, while exogenous GSH reversed its cytotoxicity on 
      hepatocytes. Clivorine (50 microM) significantly induced cellular reactive oxygen 
      species (ROS) generation. Further results showed that 50 microM Clivorine 
      decreased glutathione peroxidase (GPx) activity and increased glutathione S 
      transferase (GST) activity, which are both GSH-related antioxidant enzymes. 
      Thioredoxin-1 (Trx) is also a ubiquitous redox-active reducing (--SH) protein, 
      and clivorine (50 microM) decreased cellular expression of Trx in a 
      time-dependent manner, while 5 mM NAC reversed this decrease. Taken together, our 
      results demonstrate that the protection of NAC is major via maintaining cellular 
      reduced environment and thus prevents clivorine-induced mitochondrial-mediated 
      hepatocytes apoptosis.
CI  - (c) 2009 Wiley-Liss, Inc.
FAU - Ji, Lili
AU  - Ji L
AD  - Key Laboratory of Standardization of Chinese Medicines of Ministry of Education, 
      Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese 
      Medicine, Shanghai 201203, PR China.
FAU - Liu, Tianyu
AU  - Liu T
FAU - Chen, Ying
AU  - Chen Y
FAU - Wang, Zhengtao
AU  - Wang Z
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0 (BCL2L1 protein, human)
RN  - 0 (Cytotoxins)
RN  - 0 (Pyrrolizidine Alkaloids)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (bcl-X Protein)
RN  - 52500-60-4 (Thioredoxins)
RN  - 9007-43-6 (Cytochromes c)
RN  - EC 1.11.1.9 (Glutathione Peroxidase)
RN  - EC 2.5.1.18 (Glutathione Transferase)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 9)
RN  - EC 6.3.2.3 (Glutathione Synthase)
RN  - GAN16C9B8O (Glutathione)
RN  - P180OM3SJM (clivorine)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - Acetylcysteine/metabolism/*pharmacology
MH  - Apoptosis/drug effects
MH  - Caspase 3/metabolism
MH  - Caspase 9/metabolism
MH  - Cell Line
MH  - Cell Survival/drug effects
MH  - Chemical and Drug Induced Liver Injury/*prevention & control
MH  - Cytochromes c/metabolism
MH  - Cytotoxins/isolation & purification/*toxicity
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation/drug effects
MH  - Glutathione/metabolism
MH  - Glutathione Peroxidase/metabolism
MH  - Glutathione Synthase/antagonists & inhibitors
MH  - Glutathione Transferase/metabolism
MH  - Hepatocytes/*drug effects
MH  - Humans
MH  - Pyrrolizidine Alkaloids/isolation & purification/*toxicity
MH  - Reactive Oxygen Species/metabolism
MH  - Thioredoxins/metabolism
MH  - bcl-X Protein/metabolism
EDAT- 2009/07/23 09:00
MHDA- 2009/12/16 06:00
CRDT- 2009/07/23 09:00
PHST- 2009/07/23 09:00 [entrez]
PHST- 2009/07/23 09:00 [pubmed]
PHST- 2009/12/16 06:00 [medline]
AID - 10.1002/jcb.22269 [doi]
PST - ppublish
SO  - J Cell Biochem. 2009 Oct 1;108(2):424-32. doi: 10.1002/jcb.22269.