PMID- 22342442
OWN - NLM
STAT- MEDLINE
DCOM- 20120907
LR  - 20161125
IS  - 1879-3177 (Electronic)
IS  - 0887-2333 (Linking)
VI  - 26
IP  - 4
DP  - 2012 Jun
TI  - A new approach on valproic acid induced hepatotoxicity: involvement of lysosomal 
      membrane leakiness and cellular proteolysis.
PG  - 545-51
LID - 10.1016/j.tiv.2012.01.020 [doi]
AB  - Although valproic acid (VPA) a proven anticonvulsant agent thought to have 
      relatively few side-effects VPA has been referred as the third most common 
      xenobiotic suspected of causing death due to liver injury. In this study the 
      cellular pathways involved in VPA hepatotoxicity were investigated in isolated 
      rat hepatocytes. Accelerated cytotoxicity mechanism screening (ACMS) techniques 
      using fluorescent probes including, ortho-phthalaldehyde, rhodamine 123 and 
      acridine orange were applied for measurement of ROS formation, glutathione 
      depletion, mitochondrial membrane potential and Lysosomal membrane damage, 
      respectively. Our results showed that cytotoxic action of VPA is mediated by 
      lysosomal membrane leakiness along with reactive oxygen species (ROS) formation 
      and decline of mitochondrial membrane potential before cell lysis ensued. 
      Incubation of hepatocytes with VPA also caused rapid hepatocyte glutathione (GSH) 
      depletion which is another marker of cellular oxidative stress. Most of the VPA 
      induced GSH depletion could be attributed to the expulsion of GSSG. Our results 
      also showed that CYP2EI is involved in the mechanism of VPA cytotoxicity. We 
      finally concluded that VPA hepatotoxicity is a result of metabolic activation by 
      CYP2E1 and ROS formation, leading to lysosomal labialization, 
      mitochondrial/lysosomal toxic cross-talk and finally general cellular proteolysis 
      in the rat hepatocytes.
CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
FAU - Pourahmad, Jalal
AU  - Pourahmad J
AD  - Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran 
      14155-6153, Iran. j.pourahmadjaktaji@utoronto.ca
FAU - Eskandari, Mohammad Reza
AU  - Eskandari MR
FAU - Kaghazi, Amineh
AU  - Kaghazi A
FAU - Shaki, Fatemeh
AU  - Shaki F
FAU - Shahraki, Jafar
AU  - Shahraki J
FAU - Fard, Javad Khalili
AU  - Fard JK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120208
PL  - England
TA  - Toxicol In Vitro
JT  - Toxicology in vitro : an international journal published in association with 
      BIBRA
JID - 8712158
RN  - 0 (Anticonvulsants)
RN  - 0 (Antioxidants)
RN  - 0 (Cytochrome P-450 CYP2E1 Inhibitors)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Reactive Oxygen Species)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - EC 1.14.13.- (Cytochrome P-450 CYP2E1)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Anticonvulsants/*toxicity
MH  - Antioxidants/pharmacology
MH  - Cells, Cultured
MH  - Chemical and Drug Induced Liver Injury/*metabolism
MH  - Cytochrome P-450 CYP2E1/metabolism
MH  - Cytochrome P-450 CYP2E1 Inhibitors
MH  - Enzyme Inhibitors/pharmacology
MH  - Glutathione/metabolism
MH  - Hepatocytes/drug effects/physiology
MH  - Lysosomes/drug effects/*metabolism/pathology
MH  - Male
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Proteolysis/drug effects
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reactive Oxygen Species/metabolism
MH  - Valproic Acid/*toxicity
EDAT- 2012/02/22 06:00
MHDA- 2012/09/08 06:00
CRDT- 2012/02/21 06:00
PHST- 2011/04/25 00:00 [received]
PHST- 2011/12/04 00:00 [revised]
PHST- 2012/01/23 00:00 [accepted]
PHST- 2012/02/21 06:00 [entrez]
PHST- 2012/02/22 06:00 [pubmed]
PHST- 2012/09/08 06:00 [medline]
AID - S0887-2333(12)00038-0 [pii]
AID - 10.1016/j.tiv.2012.01.020 [doi]
PST - ppublish
SO  - Toxicol In Vitro. 2012 Jun;26(4):545-51. doi: 10.1016/j.tiv.2012.01.020. Epub 
      2012 Feb 8.