studies

1144A AASLD ABSTRACTS HEPATOLOGY, October, 2015
for the treatment or prevention of drug-induced fulminant liver
failure.
Disclosures:
Etsuro Hatano - Speaking and Teaching: Bayer
Masa Asagiri - Grant/Research Support: Astellas Pharma Inc.
The following authors have nothing to disclose: Kenji Takemoto, Keiko Iwaisako,
Masatoshi Takeiri, Naruto Noma, Saori Ohmae, Kan Toriguchi, Kazutaka
Tanabe, Keigo Machida, Kojiro Taura, Shinji Uemoto
1919
Statins prevent liver tumor promoting effect of dioxin-like
environmental toxins in different biological models
Alvarez Laura; Facultad de medicina UBA, Argentina, Argentina
Hepatocellular carcinoma (HCC) is the third leading cause of
cancer death worldwide. Hormonal imbalance plays a key role
in the development of neoplasms. There is an open relationship
between HCC and environmental toxins. Hexachlorobenzene
(HCB) is an environmental pollutant, associated with a broad
spectrum of harmful effects on human health as alterations in
thyroid metabolism, neurotoxicity, developmental and carcinogenic
effects in human and experimental animals. Statins
reduce the incidence of various tumors. Their anti-tumor activity
has been related to their pro-apoptotic and anti-angiogenic
effect and the prevention of metastasis. However, the exact
mechanism mediating the in vivo anti-tumor effect of statins has
not been yet fully clarified. The objective of this study was to
determine: key molecules involved in HCB promotion of liver
preneoplastic foci in an initiation-promotion model in rats [diethylnitrosamine
(DEN) (100 mg / kg bw) and HCB (100 mg / kg
bw)]. 1- We evaluated in rat liver: a) Proliferating cell nuclear
antigen levels (PCNA) in focal and non-focal areas, (Western
blot); b) thyroid hormones (TH) concentration, c) deiodinase
types I (DI) and III (DIII) mRNA levels; c) 3-Hydroxy-3-methylglutaryl-coenzyme
A reductase (HMGCoAR) (RIA and RT-PCR),
d) Thioredoxin 1 levels (TRX1) and d) serum cholesterol. 2-In
Hep-G2 cells, we analyzed the ability of atorvastatin (AT) and
simvastatin (SM) to reverse the effect of HCB on key molecules
involved in the proliferative effect of HCB. Hep-G2 cells were
treated with HCB (5 uM), in the presence and absence of AT
(10, 20 and 30 mM) and SM (5, 10, 20 uM). We analyzed
protein levels of: a) PCNA, b) pERK1/2, c) cyclin D1 (CD1); b)
TRX1; d) TGF-β1 and HMGCoAR mRNA expression (RT-PCR).
Results: In vivo: HCB increased (60% p≤0,001) PCNA positive
cells in focal areas (DEN + HCB) vs. DEN. HMGCoAR
increased 31% (p≤0,01); T 4
increased 38% (p≤0.01) and T 3
decreased 37% (p≤0,01). DIII increased 30% (p≤0.01) and
DI declined 41% (p≤0.01). TRX1 increased 29% (p≤0.01) in
(DEN + HCB) (p≤0,01). Cholesterol increased 28% (p ≤ 0.05).
In vitro, the proliferative effect of HCB decreased with AT or
SM. HMGCoAR decreased 29% and 38% with AT (20 and
30 mM), and 20% and 31% with SM (10 to 20 mM) respectively.
TRX 1 and TGF-β1 protein levels decreased with AT (30
mM) and SM (20 mM, 34%), p ≤ 0.05. Conclusion: AT and
SM reduced HCB-induced cell proliferation in Hep-G2 cells.
HMGCoAR, TGF-β1, TRX1 and HT, may be potential target
molecules for statins mechanism of action on HCC caused by
environmental toxins.
Disclosures:
The following authors have nothing to disclose: Alvarez Laura
1920
Drug-Induced Liver Injury Associated With Vemurafenib
Treatment
Marie Lou Gacusan Munson, Liat Schwartz Sagi, Roland Morley,
Wassim Aldairy, Mason Shih, Edwin Tucker; Genentech, South
San Francisco, CA
Background: Vemurafenib (VEM) is the first-in-class selective
oncogenic BRAF V600 kinase inhibitor approved for adults
with unresectable or metastatic melanoma. In preclinical and
clinical development programs, VEM has been identified to
cause liver laboratory abnormalities. The general incidence
of drug-induced liver injury (DILI) is reported to be 1:10,000
to 1:100,000 (all severity grades) and is usually identified in
the postmarketing setting after considerable patient (pt) exposure.
We describe the incidence, characteristics, risk factors,
specific clinical signature, and clinical course of hepatotoxicity
with VEM. Methods: The Genentech company safety database
was searched for medically confirmed, serious cases of hepatic
adverse events. The definition of DILI was based on the clinical
chemistry criteria threshold recommended by the International
DILI Expert Working Group (EWG) (Aithal et al. Clinical Pharmacol
Ther. 2011;89:806-815). The WHO Global Introspection
method was used in the assessment of causality. Clinical
pattern of liver injury was categorized using the R value; severity
grading was based on the EWG DILI severity index. Results:
63 cases of DILI attributed to VEM were identified: 46 from clinical
trials and 17 from spontaneous reports. Median age was
58 years (range, 28-83); 17 pts were elderly (≥65 years old).
27 pts were male and 36 were female. The R value was provided
for 43 pts; the pattern of injury was cholestatic/mixed in
28 pts and hepatocellular in 15. Median latency was 43 days
(range, 1-265) and was similar between cholestatic/mixed
and hepatocellular patterns. The distribution of clinical pattern
of injury was similar for elderly and younger pts. DILI severity
was assessed in 40 pts and was mild, moderate, and severe in
11, 27, and 2 pts, respectively. No cases had fatal outcomes,
and no cases required liver transplantation. VEM treatment
interruption was necessary in 46 of 63 pts; dose modifications
according to guidance in the product label were necessary in
25 of those 46. The event did not recur in 20 of the 25 pts.
In 5 cases, treatment interruption/dose modification required
permanent discontinuation. Conclusion: The crude reporting
rate of DILI for VEM is 5.13 per 1000 pt-years (95% CI, 3.8-
6.4) based on estimated 12,262 pt-years’ exposure. A median
latency of 43 days with a tendency toward a cholestatic/mixed
pattern was observed, and 2 cases were assessed as severe.
Risk factors and populations at risk were not identified. The prescribed
dose modification in the label was helpful in managing
cases. To our knowledge, this is the first publication describing
DILI with a BRAF inhibitor.
Disclosures:
Marie Lou Gacusan Munson - Employment: Genentech
Liat Schwartz Sagi - Employment: Genentech-Roche
Roland Morley - Employment: Roche Genentech; Stock Shareholder: Bristol Myers
Squibb
The following authors have nothing to disclose: Wassim Aldairy, Mason Shih,
Edwin Tucker