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

Journal Article · Thu Nov 15 00:00:00 EST 2012 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2012.09.021· OSTI ID:22215976

Mohammad, Mohammad K. ^[1]; Avila, Diana ^[1]; Zhang, Jingwen ^[1]; Barve, Shirish ^[1]; Arteel, Gavin ^[2]; McClain, Craig ^[1]; Joshi-Barve, Swati ^[1]

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1. Department of Medicine, University of Louisville (United States)
2. Department of Pharmacology and Toxicology, University of Louisville (United States)

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.

• OSTI ID: 22215976
• Journal Information: Toxicology and Applied Pharmacology, Vol. 265, 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); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

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