Alcohol
Volume 27, Issue 2 , Pages 89-98, June 2002

Synergetic signaling for apoptosis in vitro by ethanol and acetaminophen☆

  • Manuela G. Neuman

      Affiliations

    • In Vitro Toxicology Laboratory, Division of Clinical Pharmacology, Sunnybrook and Women's College Health Sciences Centre, Room E235, 2075 Bayview Ave., Toronto, Ontario, Canada, M4N 3M5
    • Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 1A8
    • Corresponding Author InformationCorresponding author. Tel.: +1-416-480-6100, ext. 3503; fax: +1-416-480-6025.(M.G. Neuman)

Received 31 July 2001; received in revised form 27 January 2002; accepted 1 February 2002.

Abstract 

In vitro, ethanol in combination with acetaminophen induces hepatocyte apoptosis resembling immune-mediated fulminant hepatic failure in human beings. Intracellular pathways originating at the mitochondria are linked to apoptosis. I studied ethanol-induced apoptosis and hepatocytotoxicity after using an in vitro model of normal human primary hepatocytes that were exposed to 5 or 10 mM acetaminophen, 40 or 100 mM ethanol, 40 mM ethanol + 5 mM acetaminophen, or 40 mM ethanol + 10 mM acetaminophen, or nonexposed (control; plain medium). Transmission electron microscopy was performed at different time points after exposure to the various treatments. Apoptosis, as assessed by transmission electron microscopy, was increased in a time-dependent manner after exposure to ethanol + acetaminophen. In the ethanol + acetaminophen model, mitochondrial injury was associated with apoptosis of hepatocytes. Ultrastructural damage and induction of apoptosis were seen in response to N-acetyl-benzoquinone-imine plus ethanol, supporting the suggestion that the damage was due to the active metabolite of acetaminophen. The modulation of mitochondrial damage in vitro may have implications for the development of new therapeutic strategies to prevent apoptosis.

Keywords:  Alcohol, Acetaminophen, In vitro, Cytotoxicity, Ethanol, Normal human primary hepatocytes, Hep G2 cells

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☆ Editor: T.R. Jerrells

PII: S0741-8329(02)00214-8

Alcohol
Volume 27, Issue 2 , Pages 89-98, June 2002

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