BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury

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Abstract

It has been recently shown that acute acetaminophen toxicity results in endoplasmic reticulum redox stress and an increase in cells with apoptotic phenotype in liver. Since activation of effector caspases was absent, the relevance of caspase-independent mechanisms in acetaminophen-induced programmed cell death was investigated. BGP-15, a drug with known protective actions in conditions involving redox imbalance, has been co-administered with a single sublethal dose of acetaminophen. Proapoptotic events and outcome of the injury were investigated. ER redox alterations and early ER-stress-related signaling events induced by acetaminophen, such as ER glutathione depletion, phosphorylation of eIF2α and JNK and induction of the transcription factor GADD153, were not counteracted by co-treatment with BGP-15. However, BGP-15 prevented AIF mitochondria-to-nucleus translocation and mitochondrial depolarization. BGP-15 co-treatment attenuated the rate of acetaminophen-induced cell death as assessed by apoptotic index and enzyme serum release. These results reaffirm that acute acetaminophen toxicity involves oxidative stress-induced caspase-independent cell death. In addition, pharmacological inhibition of AIF translocation may effectively protect against or at least delay acetaminophen-induced programmed cell death.

Original languageEnglish
Pages (from-to)96-103
Number of pages8
JournalToxicology and Applied Pharmacology
Volume243
Issue number1
DOIs
Publication statusPublished - Feb 15 2010

Fingerprint

Cell death
Acetaminophen
Caspases
Liver
Cell Death
Wounds and Injuries
Oxidation-Reduction
Toxicity
Effector Caspases
Phosphorylation
Mitochondria
Endoplasmic Reticulum Stress
Oxidative stress
Depolarization
BGP 15
Glutathione
Oxidative Stress
Transcription Factors
Chemical activation
Pharmacology

Keywords

  • Acetaminophen
  • AIF
  • BGP-15
  • Endoplasmic reticulum
  • Liver
  • Mitochondria
  • Programmed cell death

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

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title = "BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury",
abstract = "It has been recently shown that acute acetaminophen toxicity results in endoplasmic reticulum redox stress and an increase in cells with apoptotic phenotype in liver. Since activation of effector caspases was absent, the relevance of caspase-independent mechanisms in acetaminophen-induced programmed cell death was investigated. BGP-15, a drug with known protective actions in conditions involving redox imbalance, has been co-administered with a single sublethal dose of acetaminophen. Proapoptotic events and outcome of the injury were investigated. ER redox alterations and early ER-stress-related signaling events induced by acetaminophen, such as ER glutathione depletion, phosphorylation of eIF2α and JNK and induction of the transcription factor GADD153, were not counteracted by co-treatment with BGP-15. However, BGP-15 prevented AIF mitochondria-to-nucleus translocation and mitochondrial depolarization. BGP-15 co-treatment attenuated the rate of acetaminophen-induced cell death as assessed by apoptotic index and enzyme serum release. These results reaffirm that acute acetaminophen toxicity involves oxidative stress-induced caspase-independent cell death. In addition, pharmacological inhibition of AIF translocation may effectively protect against or at least delay acetaminophen-induced programmed cell death.",
keywords = "Acetaminophen, AIF, BGP-15, Endoplasmic reticulum, Liver, Mitochondria, Programmed cell death",
author = "G{\'a}bor Nagy and A. Szarka and G. Lotz and Judit D{\'o}czi and L. Wunderlich and Andr{\'a}s Kiss and K. Jemnitz and Z. Veres and G. B{\'a}nhegyi and Z. Schaff and B. S{\"u}megi and J. Mandl",
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T1 - BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury

AU - Nagy, Gábor

AU - Szarka, A.

AU - Lotz, G.

AU - Dóczi, Judit

AU - Wunderlich, L.

AU - Kiss, András

AU - Jemnitz, K.

AU - Veres, Z.

AU - Bánhegyi, G.

AU - Schaff, Z.

AU - Sümegi, B.

AU - Mandl, J.

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N2 - It has been recently shown that acute acetaminophen toxicity results in endoplasmic reticulum redox stress and an increase in cells with apoptotic phenotype in liver. Since activation of effector caspases was absent, the relevance of caspase-independent mechanisms in acetaminophen-induced programmed cell death was investigated. BGP-15, a drug with known protective actions in conditions involving redox imbalance, has been co-administered with a single sublethal dose of acetaminophen. Proapoptotic events and outcome of the injury were investigated. ER redox alterations and early ER-stress-related signaling events induced by acetaminophen, such as ER glutathione depletion, phosphorylation of eIF2α and JNK and induction of the transcription factor GADD153, were not counteracted by co-treatment with BGP-15. However, BGP-15 prevented AIF mitochondria-to-nucleus translocation and mitochondrial depolarization. BGP-15 co-treatment attenuated the rate of acetaminophen-induced cell death as assessed by apoptotic index and enzyme serum release. These results reaffirm that acute acetaminophen toxicity involves oxidative stress-induced caspase-independent cell death. In addition, pharmacological inhibition of AIF translocation may effectively protect against or at least delay acetaminophen-induced programmed cell death.

AB - It has been recently shown that acute acetaminophen toxicity results in endoplasmic reticulum redox stress and an increase in cells with apoptotic phenotype in liver. Since activation of effector caspases was absent, the relevance of caspase-independent mechanisms in acetaminophen-induced programmed cell death was investigated. BGP-15, a drug with known protective actions in conditions involving redox imbalance, has been co-administered with a single sublethal dose of acetaminophen. Proapoptotic events and outcome of the injury were investigated. ER redox alterations and early ER-stress-related signaling events induced by acetaminophen, such as ER glutathione depletion, phosphorylation of eIF2α and JNK and induction of the transcription factor GADD153, were not counteracted by co-treatment with BGP-15. However, BGP-15 prevented AIF mitochondria-to-nucleus translocation and mitochondrial depolarization. BGP-15 co-treatment attenuated the rate of acetaminophen-induced cell death as assessed by apoptotic index and enzyme serum release. These results reaffirm that acute acetaminophen toxicity involves oxidative stress-induced caspase-independent cell death. In addition, pharmacological inhibition of AIF translocation may effectively protect against or at least delay acetaminophen-induced programmed cell death.

KW - Acetaminophen

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KW - Liver

KW - Mitochondria

KW - Programmed cell death

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