Acetaminophen induces ER dependent signaling in mouse liver

Research output: Contribution to journalArticle

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Abstract

Role of endoplasmic reticulum (ER) in liver injury by acetaminophen (AAP) was studied in vivo in mice. Sublethal dose of AAP resulted in a decrease in microsomal total glutathione and in the reduced-to-total glutathione ratio; redox state of thiols of ER resident oxidoreductases ERp72, PDI was shifted towards the oxidized form; ER stress-responsive transcription factor ATF6 was activated. Transcriptional activation and elevated expression of GADD153/CHOP, an ER stress-responsive proapoptotic transcription factor, was observed upon AAP addition. Transient activation of the ER-resident caspase-12 was shown followed by an elevation in procaspase-12 level. Caspase-3 and caspase-8 activation could not be detected. AAP treatment resulted in an increased apoptosis of hepatocytes. Buthionine-sulfoximine treatment was unable to mimic the effects by AAP indicating that glutathione depletion itself is insufficient to provoke apoptosis. The results show that intraluminal redox imbalance of the ER and consequential activation of signaling processes and proapoptotic events are involved in hepatocellular damage caused by AAP overdose.

Original languageEnglish
Pages (from-to)273-279
Number of pages7
JournalArchives of Biochemistry and Biophysics
Volume459
Issue number2
DOIs
Publication statusPublished - Mar 15 2007

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Acetaminophen
Endoplasmic Reticulum
Liver
Chemical activation
Endoplasmic Reticulum Stress
Glutathione
Oxidation-Reduction
Activating Transcription Factor 6
Caspase 12
Apoptosis
Buthionine Sulfoximine
Caspase 8
Sulfhydryl Compounds
Caspase 3
Transcriptional Activation
Hepatocytes
Oxidoreductases
Transcription Factors
Wounds and Injuries

Keywords

  • ATF6
  • Caspase-12
  • Endoplasmic reticulum
  • GADD153
  • Glutathione
  • Redox shift

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Acetaminophen induces ER dependent signaling in mouse liver. / Nagy, Gábor; Kardon, T.; Wunderlich, L.; Szarka, A.; Kiss, András; Schaff, Z.; Bánhegyi, G.; Mandl, J.

In: Archives of Biochemistry and Biophysics, Vol. 459, No. 2, 15.03.2007, p. 273-279.

Research output: Contribution to journalArticle

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