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Sodium 4-phenylbutyric acid prevents murine acetaminophen hepatotoxicity by minimizing endoplasmic reticulum stress.
- Source :
-
Journal of Gastroenterology . May2017, Vol. 52 Issue 5, p611-622. 12p. - Publication Year :
- 2017
-
Abstract
- <bold>Background: </bold>Acetaminophen (APAP) overdose induces severe oxidative stress followed by hepatocyte apoptosis/necrosis. Previous studies have indicated that endoplasmic reticulum (ER) stress is involved in the cell death process. Therefore, we investigated the effect of the chemical chaperone 4-phenyl butyric acid (PBA) on APAP-induced liver injury in mice.<bold>Methods: </bold>Eight-week-old male C57Bl6/J mice were given a single intraperitoneal (i.p.) injection of APAP (450 mg/kg body weight), following which some were repeatedly injected with PBA (120 mg/kg body weight, i.p.) every 3 h starting at 0.5 h after the APAP challenge. All mice were then serially euthanized up to 12 h later.<bold>Results: </bold>PBA treatment dramatically ameliorated the massive hepatocyte apoptosis/necrosis that was observed 6 h after APAP administration. PBA also significantly prevented the APAP-induced increases in cleaved activating transcription factor 6 and phosphorylation of c-Jun N-terminal protein kinase and significantly blunted the increases in mRNA levels for binding immunoglobulin protein, spliced X-box binding protein-1, and C/EBP homologous protein. Moreover, PBA significantly prevented APAP-induced Bax translocation to the mitochondria, and the expression of heme oxygenase-1 mRNA and 4-hydroxynonenal. By contrast, PBA did not affect hepatic glutathione depletion following APAP administration, reflecting APAP metabolism.<bold>Conclusions: </bold>PBA prevents APAP-induced liver injury even when an APAP challenge precedes its administration. The underlying mechanism of action most likely involves the prevention of ER stress-induced apoptosis/necrosis in the hepatocytes during APAP intoxication. [ABSTRACT FROM AUTHOR]
- Subjects :
- *ACETAMINOPHEN
*APOPTOSIS
*NECROSIS
*ENDOPLASMIC reticulum
*MESSENGER RNA
*PROTEIN metabolism
*AMINOTRANSFERASES
*ANIMAL experimentation
*BIOLOGICAL models
*DRUG design
*DRUG overdose
*CLINICAL drug trials
*LIVER
*MICE
*MITOCHONDRIA
*OXIDATIVE stress
*CARBOCYCLIC acids
*DISEASE complications
*PREVENTION
*THERAPEUTICS
Subjects
Details
- Language :
- English
- ISSN :
- 09441174
- Volume :
- 52
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Journal of Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 122572648
- Full Text :
- https://doi.org/10.1007/s00535-016-1256-3