studies

1148A AASLD ABSTRACTS HEPATOLOGY, October, 2015
cytochrome P450 enzymes. At supratherapeutic doses saturation
of the sulfation and glucuronidation pathways lead to an
increase of NAPQI and therefore to APAP-mediated hepatotoxicity
potentially causing acute liver failure (ALF). Previous studies
have already reported gender-related differences in APAP
metabolism with females displaying relative resistance towards
APAP-induced hepatotoxicity. However, the exact molecular
mechanisms involved are not fully understood. Aim of this study
was therefore to evaluate possible gender-related differences
in glucuronidation of APAP in a humanized tgUGT1A mouse
model. Methods: Male and female htgUGT1A WT mice were
intraperitoneally (i.p.) treated with acetaminophen (APAP, 5
mg/kg) or vehicle for three consecutive days. Expression of
UGT1A genes and transcription factors (TF) HNF-4α, PXR and
ESR were analyzed by Taqman-PCR. Results: Assessment of
hepatic UGT1A mRNA expression in APAP-treated animals
revealed a 10-, 36- and 11-fold increase of UGT1A1, UGT1A6
and UGT1A9 in female mice contrasting an only 7-, 9- and
10-fold induction of the aforementioned isoforms in males.
Additionally, female mice exhibited significant increases of
UGT1A1 (3.2-, 7.4-fold) and UGT1A6 (5.6-, 4.8-fold) in both
jejunum and colon, whereas in males upregulation of intestinal
UGT1A genes was only observed in colon (UGT1A1: 6.3-fold;
UGT1A6: 7.2-fold). Interestingly, investigation of TFs in APAPtreated
htgUGT1A WT mice revealed upregulation of ESR and
PXR mRNA in livers of females, which was reduced in male
mice. Moreover, HNF4-a expression was downregulated in
males. Conclusions: Analyses of hepatic as well as intestinal
UGT1A genes relevant for APAP glucuronidation uncovers significant
differences in UGT1A mRNA expression between male
and female mice following treatment with acetaminophen. Particularly
APAP-mediated upregulation of hepatic UGT1A6 was
profoundly reduced in male htgUGT1A WT mice in comparison
to their female counterparts. These data suggest a possible
role of glucuronidation for gender-related distinctions in
susceptibility towards APAP-mediated hepatotoxicity and clinically
observed sex-related differences in acetaminophen pharmacokinetics
and –dynamics. Furthermore, reduced hepatic
expression of the TFs ESR, PXR and HNF4-a represents a possible
molecular mechanism for differential UGT1A regulation
in males
Disclosures:
Christian P. Strassburg - Advisory Committees or Review Panels: Novartis, Roche;
Speaking and Teaching: Novartis, Merz, MSD, Falk Pharma, BMS, Abbvie
The following authors have nothing to disclose: Anja Winkler, Sandra Kalthoff
1928
Drug Induced Liver Injury (DILI) in the East
Sarah E. Low 1 , Kieron B. Lim 1 , Seng Gee Lim 1,2 ; 1 Gastroenterology
& Hepatology, National University Health System, Singapore,
Singapore; 2 Yong Loo Lin School of Medicine, National University
of Singapore, Singapore, Singapore
Background Is Drug Induced Liver Injury (DILI) different in the
East compared with the West? There are only a handful of
population studies worldwide estimating crude incidence rates
of 3-19 of 100,000 inhabitants. Asians have different pharmacogenetic
profiles with different disease patterns, susceptibility
and hence handle drugs differently. There is widespread use
of herbal and alternative medicines (HM), the safety of which
is poorly defined. Aims To review existing literature on prevalence
of DILI in the East compared to the West. We also
seek to examine differences in frequency of causative agents
of DILI in the East and postulate why. Methods A Medline
search with “Drug-Induced Liver Injury[Mesh] OR Hepatotoxicity
AND” was undertaken. Countries included:Singapore,
Malaysia, Indonesia, Thailand, India, Sri Lanka,
Vietnam, China, Korea, Taiwan, Pakistan, Cambodia, Japan,
Hong Kong, Nepal, Mongolia, Laos, Philippines. Results Anti
tuberculosis (TB) drugs (57% of DILI in India) and HM were most
commonly implicated. Of 290 articles, 43.5% were on TB DILI.
Although TB is more prevalent in Asia, Asians appear more
susceptibile to TB DILI, with twice as much prevalence, 6.1%
versus 3.1%, likely due to polymorphisms of drug metabolizing
genes (NAT2, CYP2D1, GSTM1, GSTT1). Despite under
reporting, proportion of DILI from HM ranged from 18%-40%
with incidence of DILI in HM consumers to be 0.7%-1.5%. Hepatotoxicity
from Amoxicillin Clavulanate was rarely reported in
the East. Severity of intrinsic hepatotoxicity of Acetaminophen
is attenuated in the East, with virtually no cases of liver failure
or death reported. Conclusion The profile of DILI appears to
be different in the Asia compared to the West, with primarily
TB DILI and Herbal DILI, and rarely Amoxicillin Clavulanate or
Acetaminophen in contrast to the West
Disclosures:
Kieron B. Lim - Advisory Committees or Review Panels: Gilead, Abbvie, Sirtex;
Consulting: Novartis; Grant/Research Support: Astellas, Bayer
Seng Gee Lim - Advisory Committees or Review Panels: Bristol-Myers Squibb,
Novartis Pharmaceuticals, Merck Sharp and Dohme Pharmaceuticals, Gilead
Pharmaceuticals, Roche Pharmaceuticals; Speaking and Teaching: Bristol-Myers
Squibb, Novartis Pharmaceuticals, Merck Sharp and Dohme Pharmaceuticals,
Gilead Pharmaceuticals
The following authors have nothing to disclose: Sarah E. Low
1929
Application of the Drug-Induced Liver Injury Expert
Working Group Criteria in the Assessment of Hepatotoxicity
With the BRAF Inhibitor Vemurafenib
Marie Lou Gacusan Munson, Liat Schwartz Sagi, Mason Shih,
Edwin Tucker; Genentech, South San Francisco, CA
Background: Vemurafenib (VEM) is the first BRAF inhibitor
approved by the US Food and Drug Administration (FDA) and
the European Medicines Agency (EMA) for patients with metastatic
melanoma. At the time of its approval, based on a safety
database of ~500 patients (EMA. Public Assessment Report
on Vemurafenib. 2011), VEM was known to cause liver laboratory
abnormalities. After 2 y of commercial use, Hy’s law
cases were identified, prompting a comprehensive hepatotoxicity
risk review of VEM. The international Drug-Induced Liver
Injury (DILI) Expert Working Group (EWG) DILI criteria (Aithal
et al. Clinical Pharmacol Ther. 2011;89:806-815), with an
EBM 2B level of evidence, were used to evaluate VEM. The