Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi

Colin J. Henderson, C. Roland Wolf, Neil Kitteringham, Helen Powell, Diana Otto, B. Kevin Park

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    175 Citations (Scopus)

    Abstract

    Overdose of acetaminophen, a widely used analgesic drug, can result in severe hepatotoxicity and is often fatal. This toxic reaction is associated with metabolic activation by the P450 system to form a quinoneimine metabolite. N-acetyl-p-benzoquinoneimine (NAPQI), which covalently binds to proteins and other macromolecules to cause cellular damage. At low doses, NAPQI is efficiently detoxified, principally by conjugation with glutathione, a reaction catalyzed in part by the glutathione S-transferases (GST), such as CST Pi. To assess the role of GST in acetaminophen hepatotoxicity, we examined acetaminophen metabolism and liver damage in mice nulled for GstP (GstP1/P2((-/-))). Contrary to our expectations, instead of being more sensitive, GstP null mice were highly resistant to the hepatotoxic effects of this compound. No significant differences between wild-type (GstP1/P2((+/+))) mice and GstP1/ P2((-/-)) nulls in either the rate or route of metabolism, particularly to glutathione conjugates, or in the levels of covalent binding of acetaminophen-reactive metabolites to cellular protein were observed. However, although a similar rapid depletion of hepatic reduced glutathione (GSH) was found in both GstP1/P2((+/+)) and GstP1/P2((-/-)) mice, GSH levels only recovered in the GstP1/P2((-/-)) mice. These data demonstrate that GstP does not contribute in vivo to the formation of glutathione conjugates of acetaminophen but plays a novel and unexpected role in the toxicity of this compound. This study identifies new ways in which GST can modulate cellular sensitivity to toxic effects and suggests that the level of CST Pi may be an important and contributing factor in the sensitivity of patients with acetaminophen-induced hepatotoxicity.
    Original languageEnglish
    Pages (from-to)12741-12745
    Number of pages5
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume97
    Issue number23
    DOIs
    Publication statusPublished - 7 Nov 2000

    Cite this

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    title = "Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi",
    abstract = "Overdose of acetaminophen, a widely used analgesic drug, can result in severe hepatotoxicity and is often fatal. This toxic reaction is associated with metabolic activation by the P450 system to form a quinoneimine metabolite. N-acetyl-p-benzoquinoneimine (NAPQI), which covalently binds to proteins and other macromolecules to cause cellular damage. At low doses, NAPQI is efficiently detoxified, principally by conjugation with glutathione, a reaction catalyzed in part by the glutathione S-transferases (GST), such as CST Pi. To assess the role of GST in acetaminophen hepatotoxicity, we examined acetaminophen metabolism and liver damage in mice nulled for GstP (GstP1/P2((-/-))). Contrary to our expectations, instead of being more sensitive, GstP null mice were highly resistant to the hepatotoxic effects of this compound. No significant differences between wild-type (GstP1/P2((+/+))) mice and GstP1/ P2((-/-)) nulls in either the rate or route of metabolism, particularly to glutathione conjugates, or in the levels of covalent binding of acetaminophen-reactive metabolites to cellular protein were observed. However, although a similar rapid depletion of hepatic reduced glutathione (GSH) was found in both GstP1/P2((+/+)) and GstP1/P2((-/-)) mice, GSH levels only recovered in the GstP1/P2((-/-)) mice. These data demonstrate that GstP does not contribute in vivo to the formation of glutathione conjugates of acetaminophen but plays a novel and unexpected role in the toxicity of this compound. This study identifies new ways in which GST can modulate cellular sensitivity to toxic effects and suggests that the level of CST Pi may be an important and contributing factor in the sensitivity of patients with acetaminophen-induced hepatotoxicity.",
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    Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi. / Henderson, Colin J. ; Wolf, C. Roland ; Kitteringham, Neil ; Powell, Helen ; Otto, Diana ; Park, B. Kevin .

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 23, 07.11.2000, p. 12741-12745.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi

    AU - Henderson, Colin J.

    AU - Wolf, C. Roland

    AU - Kitteringham, Neil

    AU - Powell, Helen

    AU - Otto, Diana

    AU - Park, B. Kevin

    PY - 2000/11/7

    Y1 - 2000/11/7

    N2 - Overdose of acetaminophen, a widely used analgesic drug, can result in severe hepatotoxicity and is often fatal. This toxic reaction is associated with metabolic activation by the P450 system to form a quinoneimine metabolite. N-acetyl-p-benzoquinoneimine (NAPQI), which covalently binds to proteins and other macromolecules to cause cellular damage. At low doses, NAPQI is efficiently detoxified, principally by conjugation with glutathione, a reaction catalyzed in part by the glutathione S-transferases (GST), such as CST Pi. To assess the role of GST in acetaminophen hepatotoxicity, we examined acetaminophen metabolism and liver damage in mice nulled for GstP (GstP1/P2((-/-))). Contrary to our expectations, instead of being more sensitive, GstP null mice were highly resistant to the hepatotoxic effects of this compound. No significant differences between wild-type (GstP1/P2((+/+))) mice and GstP1/ P2((-/-)) nulls in either the rate or route of metabolism, particularly to glutathione conjugates, or in the levels of covalent binding of acetaminophen-reactive metabolites to cellular protein were observed. However, although a similar rapid depletion of hepatic reduced glutathione (GSH) was found in both GstP1/P2((+/+)) and GstP1/P2((-/-)) mice, GSH levels only recovered in the GstP1/P2((-/-)) mice. These data demonstrate that GstP does not contribute in vivo to the formation of glutathione conjugates of acetaminophen but plays a novel and unexpected role in the toxicity of this compound. This study identifies new ways in which GST can modulate cellular sensitivity to toxic effects and suggests that the level of CST Pi may be an important and contributing factor in the sensitivity of patients with acetaminophen-induced hepatotoxicity.

    AB - Overdose of acetaminophen, a widely used analgesic drug, can result in severe hepatotoxicity and is often fatal. This toxic reaction is associated with metabolic activation by the P450 system to form a quinoneimine metabolite. N-acetyl-p-benzoquinoneimine (NAPQI), which covalently binds to proteins and other macromolecules to cause cellular damage. At low doses, NAPQI is efficiently detoxified, principally by conjugation with glutathione, a reaction catalyzed in part by the glutathione S-transferases (GST), such as CST Pi. To assess the role of GST in acetaminophen hepatotoxicity, we examined acetaminophen metabolism and liver damage in mice nulled for GstP (GstP1/P2((-/-))). Contrary to our expectations, instead of being more sensitive, GstP null mice were highly resistant to the hepatotoxic effects of this compound. No significant differences between wild-type (GstP1/P2((+/+))) mice and GstP1/ P2((-/-)) nulls in either the rate or route of metabolism, particularly to glutathione conjugates, or in the levels of covalent binding of acetaminophen-reactive metabolites to cellular protein were observed. However, although a similar rapid depletion of hepatic reduced glutathione (GSH) was found in both GstP1/P2((+/+)) and GstP1/P2((-/-)) mice, GSH levels only recovered in the GstP1/P2((-/-)) mice. These data demonstrate that GstP does not contribute in vivo to the formation of glutathione conjugates of acetaminophen but plays a novel and unexpected role in the toxicity of this compound. This study identifies new ways in which GST can modulate cellular sensitivity to toxic effects and suggests that the level of CST Pi may be an important and contributing factor in the sensitivity of patients with acetaminophen-induced hepatotoxicity.

    U2 - 10.1073/pnas.220176997

    DO - 10.1073/pnas.220176997

    M3 - Article

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    SP - 12741

    EP - 12745

    JO - Proceedings of the National Academy of Sciences

    JF - Proceedings of the National Academy of Sciences

    SN - 0027-8424

    IS - 23

    ER -