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Title: Implication of caspases and subcellular compartments in tert-butylhydroperoxide induced apoptosis

Abstract

Oxidative stress has been implicated in many physiopathologies including neurodegenerative diseases, cancer, cardiovascular and respiratory diseases, and in mechanisms of action of environmental toxicants. tert-butylhydroperoxide (t-BHP) is an organic lipid hydroperoxide analogue, which is commonly used as a pro-oxidant for evaluating mechanisms involving oxidative stress in cells and tissues. This study investigates mechanisms of apoptosis induced by oxidative stress in hepatocytes, in particular, the involvement of caspases and subcellular compartments. Freshly isolated hepatocytes were exposed to 0.4 mM t-BHP during 1 h. A general caspase inhibitor, Boc-D-FMK, reduced t-BHP-induced apoptosis (chromatin condensation), confirming the involvement of caspases in apoptosis. A caspase-9 inhibitor, Z-LEHD-FMK, also reduced t-BHP-induced apoptosis, suggesting that caspase-9 plays a critical role in this process. Procaspase-9 underwent cleavage in mitochondria and translocation to the nucleus, where increased caspase-9 activity was detected. The caspase-9 substrates, caspase-3 and caspase-7, were not activated. Caspase-7 was translocated from the cytosol to the endoplasmic reticulum (ER), where it underwent processing; however, enzymatic activity of caspase-7 was inhibited by t-BHP. t-BHP caused cleavage of procaspase-12 at the ER and its subsequent translocation to the nucleus, where increased caspase-12 activity was found. t-BHP caused translocation of calpain from the cytosol to the ER. Calpain inhibitionmore » reduced chromatin condensation and caspase-12 activity in the nucleus, suggesting that calpain is involved in caspase-12 activation and apoptosis. This study demonstrates that caspase-9 and caspase-12 are activated in t-BHP-induced apoptosis in hepatocytes. We highlight the importance of subcellular compartments such as mitochondria, ER and nuclei in the apoptotic process.« less

Authors:
 [1];  [1];  [2];  [1]
  1. Departement de Chimie, TOXEN, Universite du Quebec a Montreal, Montreal (Canada)
  2. Departement de Pharmacologie, Universite de Montreal, Montreal (Canada)
Publication Date:
OSTI Identifier:
21140841
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 229; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2008.01.010; PII: S0041-008X(08)00020-3; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADP; APOPTOSIS; CATTLE; CHROMATIN; CLEAVAGE; ELECTROMECHANICS; ENDOPLASMIC RETICULUM; LIPIDS; LIVER CELLS; MITOCHONDRIA; NEOPLASMS; NERVOUS SYSTEM DISEASES; OXIDATION; PERMEABILITY; POLYMERASES; RIBOSE; TRANSLOCATION

Citation Formats

Haidara, Khadidja, Departement de Pharmacologie, Universite de Montreal, Montreal, Marion, Michel, Gascon-Barre, Marielle, Denizeau, Francine, and Averill-Bates, Diana A. Implication of caspases and subcellular compartments in tert-butylhydroperoxide induced apoptosis. United States: N. p., 2008. Web. doi:10.1016/j.taap.2008.01.010.
Haidara, Khadidja, Departement de Pharmacologie, Universite de Montreal, Montreal, Marion, Michel, Gascon-Barre, Marielle, Denizeau, Francine, & Averill-Bates, Diana A. Implication of caspases and subcellular compartments in tert-butylhydroperoxide induced apoptosis. United States. https://doi.org/10.1016/j.taap.2008.01.010
Haidara, Khadidja, Departement de Pharmacologie, Universite de Montreal, Montreal, Marion, Michel, Gascon-Barre, Marielle, Denizeau, Francine, and Averill-Bates, Diana A. 2008. "Implication of caspases and subcellular compartments in tert-butylhydroperoxide induced apoptosis". United States. https://doi.org/10.1016/j.taap.2008.01.010.
@article{osti_21140841,
title = {Implication of caspases and subcellular compartments in tert-butylhydroperoxide induced apoptosis},
author = {Haidara, Khadidja and Departement de Pharmacologie, Universite de Montreal, Montreal and Marion, Michel and Gascon-Barre, Marielle and Denizeau, Francine and Averill-Bates, Diana A.},
abstractNote = {Oxidative stress has been implicated in many physiopathologies including neurodegenerative diseases, cancer, cardiovascular and respiratory diseases, and in mechanisms of action of environmental toxicants. tert-butylhydroperoxide (t-BHP) is an organic lipid hydroperoxide analogue, which is commonly used as a pro-oxidant for evaluating mechanisms involving oxidative stress in cells and tissues. This study investigates mechanisms of apoptosis induced by oxidative stress in hepatocytes, in particular, the involvement of caspases and subcellular compartments. Freshly isolated hepatocytes were exposed to 0.4 mM t-BHP during 1 h. A general caspase inhibitor, Boc-D-FMK, reduced t-BHP-induced apoptosis (chromatin condensation), confirming the involvement of caspases in apoptosis. A caspase-9 inhibitor, Z-LEHD-FMK, also reduced t-BHP-induced apoptosis, suggesting that caspase-9 plays a critical role in this process. Procaspase-9 underwent cleavage in mitochondria and translocation to the nucleus, where increased caspase-9 activity was detected. The caspase-9 substrates, caspase-3 and caspase-7, were not activated. Caspase-7 was translocated from the cytosol to the endoplasmic reticulum (ER), where it underwent processing; however, enzymatic activity of caspase-7 was inhibited by t-BHP. t-BHP caused cleavage of procaspase-12 at the ER and its subsequent translocation to the nucleus, where increased caspase-12 activity was found. t-BHP caused translocation of calpain from the cytosol to the ER. Calpain inhibition reduced chromatin condensation and caspase-12 activity in the nucleus, suggesting that calpain is involved in caspase-12 activation and apoptosis. This study demonstrates that caspase-9 and caspase-12 are activated in t-BHP-induced apoptosis in hepatocytes. We highlight the importance of subcellular compartments such as mitochondria, ER and nuclei in the apoptotic process.},
doi = {10.1016/j.taap.2008.01.010},
url = {https://www.osti.gov/biblio/21140841}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1,
volume = 229,
place = {United States},
year = {Thu May 15 00:00:00 EDT 2008},
month = {Thu May 15 00:00:00 EDT 2008}
}