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Title: Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress

Abstract

Acrolein is a common environmental, food and water pollutant and a major component of cigarette smoke. Also, it is produced endogenously via lipid peroxidation and cellular metabolism of certain amino acids and drugs. Acrolein is cytotoxic to many cell types including hepatocytes; however the mechanisms are not fully understood. We examined the molecular mechanisms underlying acrolein hepatotoxicity in primary human hepatocytes and hepatoma cells. Acrolein, at pathophysiological concentrations, caused a dose-dependent loss of viability of hepatocytes. The death was apoptotic at moderate and necrotic at high concentrations of acrolein. Acrolein exposure rapidly and dramatically decreased intracellular glutathione and overall antioxidant capacity, and activated the stress-signaling MAP-kinases JNK, p42/44 and p38. Our data demonstrate for the first time in human hepatocytes, that acrolein triggered endoplasmic reticulum (ER) stress and activated eIF2α, ATF-3 and -4, and Gadd153/CHOP, resulting in cell death. Notably, the protective/adaptive component of ER stress was not activated, and acrolein failed to up-regulate the protective ER-chaperones, GRP78 and GRP94. Additionally, exposure to acrolein disrupted mitochondrial integrity/function, and led to the release of pro-apoptotic proteins and ATP depletion. Acrolein-induced cell death was attenuated by N-acetyl cysteine, phenyl-butyric acid, and caspase and JNK inhibitors. Our data demonstrate that exposure to acroleinmore » induces a variety of stress responses in hepatocytes, including GSH depletion, oxidative stress, mitochondrial dysfunction and ER stress (without ER-protective responses) which together contribute to acrolein toxicity. Our study defines basic mechanisms underlying liver injury caused by reactive aldehyde pollutants such as acrolein. -- Highlights: ► Human primary hepatocytes and cultured cell lines are used. ► Multiple cell death signaling pathways are activated by acrolein. ► Novel finding of acrolein-induced ER stress ► Acrolein fails to activate ER stress-induced protective responses. ► Combinatorial therapies may be needed for preventing acrolein hepatotoxicity.« less

Authors:
 [1];  [2];  [1];  [2];  [2];  [1];  [2];  [1];  [2];  [2];  [3];  [2];  [1];  [2];  [2];  [2];  [1];  [2];  [2]
  1. Department of Medicine, University of Louisville (United States)
  2. (United States)
  3. Department of Pharmacology and Toxicology, University of Louisville (United States)
Publication Date:
OSTI Identifier:
22215976
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 265; Journal Issue: 1; Other Information: Copyright (c) 2012 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; ACROLEIN; APOPTOSIS; ATP; BUTYRIC ACID; CYSTEINE; DNA DAMAGES; ENDOPLASMIC RETICULUM; ENZYME IMMUNOASSAY; GLUCOSE; GLUTATHIONE; HEPATOMAS; INOSITOL; LEUCINE; LIVER; LIVER CELLS; MITOCHONDRIA; OXIDATION; PERMEABILITY; PHOSPHOTRANSFERASES; POLYMERASE CHAIN REACTION; THERAPY; TOBACCO SMOKES; TOXICITY; TRANSCRIPTION FACTORS

Citation Formats

Mohammad, Mohammad K., Alcohol Research Center, University of Louisville, Avila, Diana, Department of Pharmacology and Toxicology, University of Louisville, Alcohol Research Center, University of Louisville, Zhang, Jingwen, Alcohol Research Center, University of Louisville, Barve, Shirish, Department of Pharmacology and Toxicology, University of Louisville, Alcohol Research Center, University of Louisville, Arteel, Gavin, Alcohol Research Center, University of Louisville, McClain, Craig, Department of Pharmacology and Toxicology, University of Louisville, Alcohol Research Center, University of Louisville, Robley Rex VAMC, Louisville, KY, Joshi-Barve, Swati, E-mail: s0josh01@louisville.edu, Department of Pharmacology and Toxicology, University of Louisville, and Alcohol Research Center, University of Louisville. Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.09.021.
Mohammad, Mohammad K., Alcohol Research Center, University of Louisville, Avila, Diana, Department of Pharmacology and Toxicology, University of Louisville, Alcohol Research Center, University of Louisville, Zhang, Jingwen, Alcohol Research Center, University of Louisville, Barve, Shirish, Department of Pharmacology and Toxicology, University of Louisville, Alcohol Research Center, University of Louisville, Arteel, Gavin, Alcohol Research Center, University of Louisville, McClain, Craig, Department of Pharmacology and Toxicology, University of Louisville, Alcohol Research Center, University of Louisville, Robley Rex VAMC, Louisville, KY, Joshi-Barve, Swati, E-mail: s0josh01@louisville.edu, Department of Pharmacology and Toxicology, University of Louisville, & Alcohol Research Center, University of Louisville. Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress. United States. doi:10.1016/J.TAAP.2012.09.021.
Mohammad, Mohammad K., Alcohol Research Center, University of Louisville, Avila, Diana, Department of Pharmacology and Toxicology, University of Louisville, Alcohol Research Center, University of Louisville, Zhang, Jingwen, Alcohol Research Center, University of Louisville, Barve, Shirish, Department of Pharmacology and Toxicology, University of Louisville, Alcohol Research Center, University of Louisville, Arteel, Gavin, Alcohol Research Center, University of Louisville, McClain, Craig, Department of Pharmacology and Toxicology, University of Louisville, Alcohol Research Center, University of Louisville, Robley Rex VAMC, Louisville, KY, Joshi-Barve, Swati, E-mail: s0josh01@louisville.edu, Department of Pharmacology and Toxicology, University of Louisville, and Alcohol Research Center, University of Louisville. Thu . "Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress". United States. doi:10.1016/J.TAAP.2012.09.021.
@article{osti_22215976,
title = {Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress},
author = {Mohammad, Mohammad K. and Alcohol Research Center, University of Louisville and Avila, Diana and Department of Pharmacology and Toxicology, University of Louisville and Alcohol Research Center, University of Louisville and Zhang, Jingwen and Alcohol Research Center, University of Louisville and Barve, Shirish and Department of Pharmacology and Toxicology, University of Louisville and Alcohol Research Center, University of Louisville and Arteel, Gavin and Alcohol Research Center, University of Louisville and McClain, Craig and Department of Pharmacology and Toxicology, University of Louisville and Alcohol Research Center, University of Louisville and Robley Rex VAMC, Louisville, KY and Joshi-Barve, Swati, E-mail: s0josh01@louisville.edu and Department of Pharmacology and Toxicology, University of Louisville and Alcohol Research Center, University of Louisville},
abstractNote = {Acrolein is a common environmental, food and water pollutant and a major component of cigarette smoke. Also, it is produced endogenously via lipid peroxidation and cellular metabolism of certain amino acids and drugs. Acrolein is cytotoxic to many cell types including hepatocytes; however the mechanisms are not fully understood. We examined the molecular mechanisms underlying acrolein hepatotoxicity in primary human hepatocytes and hepatoma cells. Acrolein, at pathophysiological concentrations, caused a dose-dependent loss of viability of hepatocytes. The death was apoptotic at moderate and necrotic at high concentrations of acrolein. Acrolein exposure rapidly and dramatically decreased intracellular glutathione and overall antioxidant capacity, and activated the stress-signaling MAP-kinases JNK, p42/44 and p38. Our data demonstrate for the first time in human hepatocytes, that acrolein triggered endoplasmic reticulum (ER) stress and activated eIF2α, ATF-3 and -4, and Gadd153/CHOP, resulting in cell death. Notably, the protective/adaptive component of ER stress was not activated, and acrolein failed to up-regulate the protective ER-chaperones, GRP78 and GRP94. Additionally, exposure to acrolein disrupted mitochondrial integrity/function, and led to the release of pro-apoptotic proteins and ATP depletion. Acrolein-induced cell death was attenuated by N-acetyl cysteine, phenyl-butyric acid, and caspase and JNK inhibitors. Our data demonstrate that exposure to acrolein induces a variety of stress responses in hepatocytes, including GSH depletion, oxidative stress, mitochondrial dysfunction and ER stress (without ER-protective responses) which together contribute to acrolein toxicity. Our study defines basic mechanisms underlying liver injury caused by reactive aldehyde pollutants such as acrolein. -- Highlights: ► Human primary hepatocytes and cultured cell lines are used. ► Multiple cell death signaling pathways are activated by acrolein. ► Novel finding of acrolein-induced ER stress ► Acrolein fails to activate ER stress-induced protective responses. ► Combinatorial therapies may be needed for preventing acrolein hepatotoxicity.},
doi = {10.1016/J.TAAP.2012.09.021},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1,
volume = 265,
place = {United States},
year = {2012},
month = {11}
}