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TOXICOLOGY

Inhibition of Acrolein-Induced Apoptosis by the Antioxidant N-Acetylcysteine

Département des Sciences Biologiques, TOXEN, Université du Québec à Montréal, Montréal, Québec, Canada

Acrolein is a highly electrophilic ,-unsaturated aldehyde to which humans are exposed in many situations. It is an environmental pollutant that is responsible for multiple respiratory diseases and has been implicated in neurodegenerative diseases such as Alzheimer's disease. The hypothesis of the study is that the antioxidant N-acetylcysteine (NAC), a precursor of glutathione, could protect cells against acrolein-induced apoptosis. Exposure of Chinese hamster ovary cells to a noncytotoxic dose of acrolein (4 fmol/cell) depleted intracellular glutathione to 45% of initial levels. NAC, which increased intracellular glutathione levels by 30%, afforded protection against acrolein-induced cytotoxicity (loss of cell proliferation) and apoptosis. NAC protected against apoptosis by diminishing acrolein-induced activation of the mitochondrial death pathway. NAC inhibited acrolein-induced Bad translocation from the cytosol to the mitochondria, as well as Bcl-2 translocation from mitochondria to the cytosol, as evaluated by Western blot analysis. However, NAC had no effect on acrolein-induced Bax translocation to mitochondria and cytochrome c liberation into the cytosol. Meanwhile, NAC inhibited depolarization of mitochondrial membrane potential, as evaluated by rhodamine fluorescence using flow cytometry. NAC also inhibited procaspase-9 processing, activation of enzymatic activity of caspase-9, -7, and -8, and poly(ADP-ribose) polymerase cleavage induced by acrolein. Inhibition of acrolein-induced apoptosis using NAC was confirmed morphologically by diminished condensation of nuclear chromatin, as evaluated by fluorescence microscopy. These findings suggest that NAC could be potentially useful as a protective agent for people exposed to acrolein.

Address correspondence to: Diana A. Averill-Bates, Département des Sciences Biologiques, Université du Québec à Montréal, CP 8888, Succursale Centre Ville, Montréal, QC H3C 3P8, Canada. E-mail: averill.diana{at}uqam.ca

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