Sodium 4-phenylbutyric acid prevents murine acetaminophen hepatotoxicity by minimizing endoplasmic reticulum stress.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Hiromi
H
Kusama
Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. kazukon@juntendo.ac.jp.
Kazuyoshi
K
Kon
Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Kenichi
K
Ikejima
Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Kumiko
K
Arai
Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Tomonori
T
Aoyama
Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Akira
A
Uchiyama
Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Shunhei
S
Yamashina
Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Sumio
S
Watanabe
D000082:Acetaminophen / Q000506:poisoning*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D062787:Drug Overdose / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects; D010654:Phenylbutyrates / Q000494:pharmacology / Q000627:therapeutic use*; D000637:Transaminases / Q000097:blood; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D010654:Phenylbutyrates; D051028:bcl-2-Associated X Protein; D000082:Acetaminophen; C075773:4-phenylbutyric acid; D000637:Transaminases
4-phenylbutylic acid; Acetaminophen; Activating transcription factor; Endoplasmic reticulum stress; Oxidative stress