studies

326A AASLD ABSTRACTS HEPATOLOGY, October, 2015
[95%CI 12.51-288.9] (p=6.7x10 -10 )). Associations were also
found between the risk allele and DILI from fenofibrate (n=7,
OR 58.7[95%CI 12.31-279.8](p=3.2x10-7)) and ticlopidine
(n=5, OR 163.1[95%CI 16.2-1642.0] (p=0.00002)). Suggestive
signals were found also for sertraline (n=5), enalapril
(n=4), methyldopa (n=4) and erythromycin (n=10). We confirmed
by sequence-based typing 99% of the predictions for 34
of 46 samples whose DILI was due to those seven drugs. HLA
typing of a limited set of additional cases (n=13) showed 4
further HLA-A*33 positive cases relating to terbinafine and sertraline.
Conclusions: The novel genome-wide significant association
of HLA-A*33:01 with all cause DILI coupled with its
strong association with liver injury from terbinafine and other
unrelated compounds confirms an important role for adaptive
immunity in DILI pathogenesis and widens the range of drugs
associated with idiosyncratic DILI for which HLA is a risk factor.
Disclosures:
Dominique G. Larrey - Advisory Committees or Review Panels: BAYER, SANOFI,
PFIZER, SERVIER-BIG, AEGERION, MMV, BIAL-QUINTILES, TEVA, ORION, NEG-
MA-LERADS, ASTELLAS, ASTRAZENECA, DNDI, GSK, J AND J; Board Membership:
BMS, GILEAD, ABBVIE, BMS, GILEAD, ITREAS, MMS; Grant/Research
Support: GILEAD, MSD, BMS, ABBVIE, TIBOTEC/JANSSEN, BMS
Mariam Molokhia - Grant/Research Support: SAEC
Fernando Bessone - Advisory Committees or Review Panels: Schering Plough,
Gilead, Glaxo, MSD, Janssen; Speaking and Teaching: Bristol Myers Squibb,
Janssen, Bayer, Gilead, Abbvie
Naga P. Chalasani - Consulting: Abbvie, Lilly, Celgene, Tobira, NuSirt, Takeda,
Merck/Anthem, Salix; Grant/Research Support: Intercept, Gilead, Galectin
Robert J. Fontana - Consulting: GlaxoSmithKline, CLDF; Grant/Research Support:
Gilead, vertex, BMS, Jansen, Gilead
The following authors have nothing to disclose: Guruprasad P. Aithal, Paola
Nicoletti, Einar Bjornsson, M. I. Lucena, Raul J. Andrade, Jane Grove, C. Stephens,
Par Hallberg, Anke H. Maitland-van der Zee, Jennifer H. Martin, Ingolf
Cascorbi, John F. Dillon, Tarja Laitinen, Gerd A. Kullak-Ublick, Luisa Ibanez,
Munir Pirmohamed, Shengying Qin, Ashley Sawle, Nelia Hernández, Andrew
Stolz, Jose Serrano, Huiman X. Barnhart, Paul Watkins, Thomas J. Urban, Ann
K. Daly
226
Sodium 4-phenylbutyric acid protects against mice from
acetaminophen-induced liver injury through attenuation
of endoplasmic reticulum stress.
Hiromi Kusama, Kazuyoshi Kon, Kenichi Ikejima, Akira Uchiyama,
Kumiko Arai, Shunhei Yamashina, Sumio Watanabe; Gastroenterology,
Juntendo University School of Medicine, Tokyo, Japan
Background: Acetaminophen (AAP) overdose consequently
elicits massive necrosis of hepatocytes, resulting in acute liver
failure. Recent lines of reports have suggested that endoplasmic
reticulum (ER) stress is contributed to AAP hepatotoxicity; however,
therapeutic targeting toward ER stress has not been well
evaluated. Therefore, here we investigate the effect of 4-phenylbutyric
acid (PBA), a chemical chaperone, on AAP-induced
liver injury in mice. Methods: Male, 8 week-old C57Bl/6 mice
were exposed to AAP (450 mg/kg BW, i.p.), and serially sacrificed
up to 12 h later. Some mice were repeatedly injected
with PBA (120 mg/kg BW, i.p.) every 3 h starting at 0.5 h
after AAP challenge, since PBA demonstrates relatively rapid
decay in vivo. Liver pathology was evaluated by H-E staining,
and serum aminotransferases levels were determined.
Oxidative stress was assessed by immunohistological staining
for 4-hydroxynonenal (HNE). Total glutathione (GSH) content
in the liver was measured colorimetrically. Apoptotic cell
death was visualized by TdT-mediated dUTP nick end labeling
(TUNEL). Phosphorylation of c-jun N—terminal kinase (p-JNK/
JNK) and cleavage of activating transcription factor (ATF) 6
were detected by Western blotting. Results: A single injection
of AAP caused massive necrosis of hepatocytes predominantly
in pericentral area in 12 h as expected; however, subsequent
repeated injections of PBA dramatically ameliorated these
pathological changes in the liver. Indeed, the ALT levels were
elevated to 11200 ± 455 IU/L at 6 h after AAP, whereas the
values only reached 4510 ± 434 IU/L in mice treated with
repeated PBA (p