Acetaminophen Induces a Caspase‐Dependent and Bcl‐xLSensitive Apoptosis in Human Hepatoma Cells and Lymphocytes

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Abstract
Acetaminophen is a widely used analgesic and antipyretic drug that exhibits toxicity at high doses to the liver and kidneys. This toxicity has been attributed to cytochrome P‐450‐generated metabolites which covalently modify target proteins. Recently, acetaminophen, in its unmetabolized form, has been shown to affect a variety of cells and tissues, for instance, testicular and lymphoid tissues and lymphocyte cell lines. The effects on cell viability of acetaminophen at a concentration comparable to that achieved in plasma during acetaminophen toxicity have now been examined with a hepatoma cell line SK‐Hep1, primary human peripheral blood lymphocytes and human Jurkat T cells. Acetaminophen reduced cell viability in a time‐dependent manner. Staining of cells with annexin‐V also revealed that acetaminophen induced, after 8 hr of treatment, a loss of the asymmetry of membrane phospholipids, which is an early event associated with apoptosis. Acetaminophen triggered the release of cytochrome c from mitochondria into the cytosol, activation of caspase‐3, 8, and 9, cleavage of poly(ADP‐ribose) polymerase, and degradation of lamin B1and DNA. Whereas cleavage of DNA into internucleosomal fragments was apparent in acetaminophen treated SK‐Hep1 and primary lymphocytes, DNA was only degraded to 50‐kb fragments in treated Jurkat cells. Overexpression of the antiapoptotic protein Bcl‐xLprevented these various apoptotic events induced by acetaminophen in Jurkat cells. Caspase‐8 activation was a postmictochondrial event and occurred in a Fas‐independent manner. These results demonstrate that acetaminophen induces caspases‐dependent apoptosis with mitochondria as a primary target. These results also reiterate the potential role of apoptosis in acetaminophen hepatic and extrahepatic toxicity.

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