PMID- 22538170
OWN - NLM
STAT- MEDLINE
DCOM- 20120716
LR  - 20151119
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 261
IP  - 3
DP  - 2012 Jun 15
TI  - Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary 
      hepatocytes.
PG  - 280-91
LID - 10.1016/j.taap.2012.04.010 [doi]
AB  - Dasatinib, a multitargeted inhibitor of BCR-ABL and SRC kinases, exhibits 
      antitumor activity and extends the survival of patients with chronic myeloid 
      leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia 
      (ALL). However, some patients suffer from hepatotoxicity, which occurs through an 
      unknown mechanism. In the present study, we found that Dasatinib could induce 
      hepatotoxicity both in vitro and in vivo. Dasatinib reduced the cell viability of 
      rat primary hepatocytes, induced the release of alanine aminotransferase (ALT) 
      and lactate dehydrogenase (LDH) in vitro, and triggered the ballooning 
      degeneration of hepatocytes in Sprague-Dawley rats in vivo. Apoptotic markers 
      (chromatin condensation, cleaved caspase-3 and cleaved PARP) were detected to 
      indicate that the injury induced by Dasatinib in hepatocytes in vitro was 
      mediated by apoptosis. This result was further validated in vivo using terminal 
      deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Here 
      we found that Dasatinib dramatically increased the level of reactive oxygen 
      species (ROS) in hepatocytes, reduced the intracellular glutathione (GSH) 
      content, attenuated the activity of superoxide dismutase (SOD), generated 
      malondialdehyde (MDA), a product of lipid peroxidation, decreased the 
      mitochondrial membrane potential, and activated nuclear factor erythroid 
      2-related factor 2 (Nrf2) and mitogen-activated protein kinases (MAPK) related to 
      oxidative stress and survival. These results confirm that oxidative stress plays 
      a pivotal role in Dasatinib-mediated hepatotoxicity. N-acetylcysteine (NAC), a 
      typical antioxidant, can scavenge free radicals, attenuate oxidative stress, and 
      protect hepatocytes against Dasatinib-induced injury. Thus, relieving oxidative 
      stress is a viable strategy for reducing Dasatinib-induced hepatotoxicity.
CI  - Crown Copyright (c) 2012. Published by Elsevier Inc. All rights reserved.
FAU - Xue, Tao
AU  - Xue T
AD  - Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, 
      Zhejiang University, Hangzhou 310058, China.
FAU - Luo, Peihua
AU  - Luo P
FAU - Zhu, Hong
AU  - Zhu H
FAU - Zhao, Yuqin
AU  - Zhao Y
FAU - Wu, Honghai
AU  - Wu H
FAU - Gai, Renhua
AU  - Gai R
FAU - Wu, Youping
AU  - Wu Y
FAU - Yang, Bo
AU  - Yang B
FAU - Yang, Xiaochun
AU  - Yang X
FAU - He, Qiaojun
AU  - He Q
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120417
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Antioxidants)
RN  - 0 (Fluorescent Dyes)
RN  - 0 (Indoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Thiazoles)
RN  - 47165-04-8 (DAPI)
RN  - 9007-49-2 (DNA)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 2.6.1.2 (Alanine Transaminase)
RN  - RBZ1571X5H (Dasatinib)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - Acetylcysteine/pharmacology
MH  - Alanine Transaminase/blood
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - Apoptosis/*drug effects
MH  - Blotting, Western
MH  - Cell Separation
MH  - DNA/chemistry
MH  - Dasatinib
MH  - Electrophoresis, Gel, Pulsed-Field
MH  - Fluorescent Dyes
MH  - Hepatocytes/*drug effects
MH  - In Situ Nick-End Labeling
MH  - Indoles
MH  - L-Lactate Dehydrogenase/blood
MH  - Male
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mitochondria, Liver/drug effects
MH  - Mitochondrial Swelling/drug effects
MH  - Oxidative Stress/*drug effects
MH  - Protein Kinase Inhibitors/*toxicity
MH  - Pyrimidines/*toxicity
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reactive Oxygen Species/metabolism
MH  - Thiazoles/*toxicity
EDAT- 2012/04/28 06:00
MHDA- 2012/07/17 06:00
CRDT- 2012/04/28 06:00
PHST- 2011/11/15 00:00 [received]
PHST- 2012/04/06 00:00 [revised]
PHST- 2012/04/07 00:00 [accepted]
PHST- 2012/04/28 06:00 [entrez]
PHST- 2012/04/28 06:00 [pubmed]
PHST- 2012/07/17 06:00 [medline]
AID - S0041-008X(12)00146-9 [pii]
AID - 10.1016/j.taap.2012.04.010 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2012 Jun 15;261(3):280-91. doi: 
      10.1016/j.taap.2012.04.010. Epub 2012 Apr 17.