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Related Experiment Videos

Acetaminophen toxicity in fed and fasted mice.

R M Walker, T E Massey, T F McElligott

    Canadian Journal of Physiology and Pharmacology
    |March 1, 1982
    PubMed
    Summary

    Fasting increases acetaminophen toxicity in mice by reducing glutathione stores, impairing metabolite inactivation. N-acetylcysteine (NAC) effectively counteracts this toxicity and hypothermia.

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    Area of Science:

    • Pharmacology
    • Toxicology
    • Biochemistry

    Background:

    • Acetaminophen overdose is a leading cause of acute liver failure.
    • N-acetylcysteine (NAC) is the standard antidote for acetaminophen toxicity.
    • The role of fasting in acetaminophen toxicity is not fully understood.

    Purpose of the Study:

    • To compare acetaminophen toxicity in fed versus fasted mice.
    • To investigate the protective effects of N-acetylcysteine (NAC) in fasted mice.
    • To elucidate the mechanisms underlying enhanced acetaminophen toxicity in fasting.

    Main Methods:

    • Mice were administered acetaminophen (750 mg/kg) and/or NAC (1200 mg/kg) in fed or fasted states.
    • Liver toxicity was assessed via histology and liver enlargement.
    • Microsomal protein, cytochrome P-450, glucuronyl transferase, and aryl hydrocarbon hydroxylase activities were measured.
    • Covalent binding of acetaminophen metabolites and hepatic sulfhydryl concentrations were quantified.

    Main Results:

    • Fasted mice exhibited greater acetaminophen-induced hepatotoxicity, liver enlargement, and covalent binding of metabolites compared to fed mice.
    • Glucuronyl transferase activity was higher in fasted mice, while other measured enzyme activities were similar.
    • Fasting significantly reduced hepatic glutathione (sulfhydryl) stores.
    • NAC administration ameliorated acetaminophen-induced toxicity, reduced metabolite binding, and alleviated hypothermia.

    Conclusions:

    • Enhanced acetaminophen toxicity in fasted mice is attributed to reduced inactivation of reactive metabolites due to depleted hepatic glutathione, not increased metabolite formation.
    • NAC effectively mitigates acetaminophen toxicity and associated hypothermia, even in fasted states.
    • These findings highlight the importance of hepatic glutathione status in acetaminophen metabolism and toxicity.

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