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National Institute of Environmental Health Sciences

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Publication Detail

Title: Enhanced acetaminophen hepatotoxicity in transgenic mice overexpressing BCL-2.

Authors: Adams, M L; Pierce, R H; Vail, M E; White, C C; Tonge, R P; Kavanagh, T J; Fausto, N; Nelson, S D; Bruschi, S A

Published In Mol Pharmacol, (2001 Nov)

Abstract: Mitochondria play an important role in the cell death induced by many drugs, including hepatotoxicity from overdose of the popular analgesic, acetaminophen (APAP). To investigate mitochondrial alterations associated with APAP-induced hepatotoxicity, the subcellular distribution of proapoptotic BAX was determined. Based on the antiapoptotic characteristics of BCL-2, we further hypothesized that if a BAX component was evident then BCL-2 overexpression may be hepatoprotective. Mice, either with a human bcl-2 transgene (-/+) or wild-type mice (WT; -/-), were dosed with 500 or 600 mg/kg (i.p.) APAP or a nonhepatotoxic isomer, N-acetyl-m-aminophenol (AMAP). Immunoblot analyses indicated increased mitochondrial BAX-beta content very early after APAP or AMAP treatment. This was paralleled by disappearance of BAX-alpha from the cytosol of APAP treated animals and, to a lesser extent, with AMAP treatment. Early pathological evidence of APAP-induced zone 3 necrosis was seen in bcl-2 (-/+) mice, which progressed to massive panlobular necrosis with hemorrhage by 24 h. In contrast, WT mice dosed with APAP showed a more typical, and less severe, centrilobular necrosis. AMAP-treated bcl-2 (-/+) mice displayed only early microvesicular steatosis without progression to extensive necrosis. Decreased complex III activity, evident as early as 6 h after treatment, correlated well with plasma enzyme activities at 24 h (AST r(2) = 0.89, ALT r(2) = 0.87) thereby confirming a role for mitochondria in APAP-mediated hepatotoxicity. In conclusion, these data suggest for the first time that BAX may be an early determinant of APAP-mediated hepatotoxicity and that BCL-2 overexpression unexpectedly enhances APAP hepatotoxicity.

PubMed ID: 11641418 Exiting the NIEHS site

MeSH Terms: Acetaminophen/toxicity*; Analgesics, Non-Narcotic/toxicity*; Animals; Electron Transport Complex III/drug effects; Electron Transport Complex III/metabolism; Humans; Immunoblotting; Liver/drug effects*; Liver/pathology; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Proto-Oncogene Proteins c-bcl-2/biosynthesis*; Proto-Oncogene Proteins c-bcl-2/genetics; Proto-Oncogene Proteins c-bcl-2/physiology; Proto-Oncogene Proteins/metabolism; Subcellular Fractions; bcl-2-Associated X Protein

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