Shifted Metabolic Bias in Livers of Mice Lacking Hepatocytic Thioredoxin Reductase-1 Protects Against Acetaminophen Toxicity
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE37874 | GEO | 2013/06/08
SECONDARY ACCESSION(S): PRJNA164703
REPOSITORIES: GEO
Similar Datasets
Project description:Genetic disruption of thioredoxin reductase 1 protects against acetaminophen (APAP) toxicity. To determine the role of the thioredoxin system on xenobiotic metabolism we challeneged wildtype and txnrd1liver-null mice with acetaminophen. Adult male wildtype and txnrd1 liver-null mice (C57BL6/J) were treated with either saline (PBS) or 100mg/kg APAP. Liver RNA was harvested eight hours after challenge and processed for microarray analysis. Comparison of 2 treatment conditions in 2 genotypes, biological replicates in triplicate.
2013-06-08 | E-GEOD-37874 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series:; GSE5593: Acetaminophen (APAP) Rat Blood Training Gene Expression Data Set; GSE5594: Acetaminophen (APAP) Rat Blood Test Gene Expression Data Set; GSE5595: Acetaminophen (APAP) Rat Liver Test Gene Expression Data Set; The Supplementary files (appended below) contain the mapping for the decoding of blinded samples. Experiment Overall Design: Refer to individual Series
2008-06-14 | E-GEOD-5652 | biostudies-arrayexpress
Project description:Overdose of acetaminophen (APAP) is the major cause of acute liver failure in the Western world with very limited treatment options. Previous studies from our groups and others have shown that timely activation of liver regeneration is a critical determinant of transplant-free survival of APAP-induced acute liver failure (ALF) patients. We used affy microarrays to explore the mechanisms of transcriptional expression in YAP-KO mice after 300mg/kg APAP overdose.
2021-10-04 | GSE183119 | GEO
Project description:To investigate the molecular mechanisms of the inflammation-mediated exacerbation of increased acetaminophen (APAP) toxicity.
2020-10-04 | GSE104601 | GEO
Project description:Acetaminophen (APAP) is the most widely used analgesic in the United States. Its acute overdose causes liver damage by inducing localized centrilobular cell death. Because of widespread use, APAP toxicity has become the most frequent cause of acute liver failure. Many factors have been associated with the susceptibility of APAP-induced liver injuries, however, few of them have been confirmed and used in the clinical setting. We tried to identify the subset of factors that could affect susceptibility to APAP-induced liver injury by an integrative genetic, transcriptional and 2-D-NMR-based metabolomic analysis across a panel of inbred mouse strains.
2009-08-14 | GSE17649 | GEO
Project description:Acetaminophen (APAP), a widely used analgesic and antipyretic that is considered to be relatively safe at recommended doses, is the leading cause of drug-induced liver failure in the United States. 3M-bM-^@M-^Y-Hydroxyacetanilide (AMAP), a regioisomer of acetaminophen is useful as a comparative tool for studying APAP-induced toxicity since it is non-toxic relative to APAP. TGF-alpha transgenic mouse hepatocytes were treated with both isomers to investigate mitogen-activated protein kinase cascades in order to differentiate their toxicological outcomes. Mitogen-activated protein kinase (MAPK) cascade expression and activation were measured using microarray and Bioplex technologies, respectively. APAP treatment led to c-Jun N-terminal kinase (JNK) activation, whereas AMAP treatment led to the activation of extracellular-signal-regulated protein kinase (ERK). The microarray data suggested APAP treatment may upregulate gene expression at multiple levels of the JNK cascade including a JNK-related scaffold protein. Expression data was related to phosphoprotein levels using the Bioplex system. APAP treatment led to a significant activation of JNK compared to its regioisomer. In contrast, microarray analysis of AMAP showed a slight upregulation of ERK gene activity. Furthermore, Bioplex data showed AMAP treatment led to significant ERK phosphorylation compared to APAP. Cell viability assays confirmed that APAP-induced activation of JNK was related to higher rates of cell death, whereas activation of ERK by AMAP may be cytoprotective. 27 arrays, 9 experimental groups, 2hr AMAP, 2hr APAP, 2hr Control, 6hr AMAP, 6hr APAP, 6hr Control, 24hr AMAP, 24hr APAP, 24hr Control.
2010-07-06 | E-GEOD-18614 | biostudies-arrayexpress
Project description:Sluka2016 - Acetaminophen metabolism
Liver metabolism of Acetaminophen: Acetaminophen (APAP) is
metabolized in the liver in both Phase I and Phase II reactions.
Phase II reactions convert APAP to APAP-glucuronide and
APAP-sulfate. Phase I reactions involve Cytochrome P450 mediated
(mostly Cyp450-2E1 and -1A2) conversion of APAP to
N-acetyle-p-quinoneimine (NAPQI), which goes on to react with
cellular nucleophiles such as glutathione (GSH). At high doses of
APAP significant GSH depletion in hepatocyte occurs resulting in
cell necrosis and and in extreme cases death.
This model is described in the article:
A Liver-Centric Multiscale
Modeling Framework for Xenobiotics.
Sluka JP, Fu X, Swat M, Belmonte JM,
Cosmanescu A, Clendenon SG, Wambaugh JF, Glazier JA.
PLoS ONE 2016; 11(9): e0162428
Abstract:
We describe a multi-scale, liver-centric in silico modeling
framework for acetaminophen pharmacology and metabolism. We
focus on a computational model to characterize whole body
uptake and clearance, liver transport and phase I and phase II
metabolism. We do this by incorporating sub-models that span
three scales; Physiologically Based Pharmacokinetic (PBPK)
modeling of acetaminophen uptake and distribution at the whole
body level, cell and blood flow modeling at the tissue/organ
level and metabolism at the sub-cellular level. We have used
standard modeling modalities at each of the three scales. In
particular, we have used the Systems Biology Markup Language
(SBML) to create both the whole-body and sub-cellular scales.
Our modeling approach allows us to run the individual
sub-models separately and allows us to easily exchange models
at a particular scale without the need to extensively rework
the sub-models at other scales. In addition, the use of SBML
greatly facilitates the inclusion of biological annotations
directly in the model code. The model was calibrated using
human in vivo data for acetaminophen and its sulfate and
glucuronate metabolites. We then carried out extensive
parameter sensitivity studies including the pairwise
interaction of parameters. We also simulated population
variation of exposure and sensitivity to acetaminophen. Our
modeling framework can be extended to the prediction of liver
toxicity following acetaminophen overdose, or used as a general
purpose pharmacokinetic model for xenobiotics.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000624.
To cite BioModels Database, please use:
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To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2022-02-09 | BIOMD0000000624 | BioModels
Project description:Transcriptomic study of a thioredoxin reductase knock-out mutant.<br> <br> Biological question :<br> Thioredoxins are small redox proteins implicated in crucial pathways of cell life. They are reduced by a conserved flavoprotein named NADPH-dependent thioredoxin reductase (NTR). In order to give an insight into the functions of the NTR/thioredoxin pathway in Arabidopsis, we have used a reverse genetic approch. Both NTR genes (NTRA and NTRB) have been inactivated in the double ntra ntrb mutant. T-DNA lines have been provided by the SALK library. Surprisingly, this mutant shows a limited phenotype suggested that some additional redox pathways are involved in compensating the inactivation of the NTR/thioredoxin pathway. In order to isolate compensatory genes that would be transcriptionally induced in the ntra ntrb mutant, we have performed this CATMA project.<br> <br> Seeds of the wild-type Col-0 ecotype and of the ntra ntrb homozygote double mutant were sowed in soil. Three replicates of lines were made (Col-0 1, 2 and 3 ntra ntrb 1, 2 and 3) : plants were put at different places of the greenhouse and grown at different times. Germination was synchronized by 4 days at 4C and plants were grown during 17 days, until they reached a 6 rosette leaves stage. Entire plants (30 plants per sample) were harvested, frozen in liquid nitrogen and stored at -80C until extraction.<br> <br>
2005-09-15 | E-MEXP-365 | biostudies-arrayexpress
Project description:Acetaminophen (APAP), a widely used analgesic and antipyretic that is considered to be relatively safe at recommended doses, is the leading cause of drug-induced liver failure in the United States. 3’-Hydroxyacetanilide (AMAP), a regioisomer of acetaminophen is useful as a comparative tool for studying APAP-induced toxicity since it is non-toxic relative to APAP. TGF-alpha transgenic mouse hepatocytes were treated with both isomers to investigate mitogen-activated protein kinase cascades in order to differentiate their toxicological outcomes. Mitogen-activated protein kinase (MAPK) cascade expression and activation were measured using microarray and Bioplex technologies, respectively. APAP treatment led to c-Jun N-terminal kinase (JNK) activation, whereas AMAP treatment led to the activation of extracellular-signal-regulated protein kinase (ERK). The microarray data suggested APAP treatment may upregulate gene expression at multiple levels of the JNK cascade including a JNK-related scaffold protein. Expression data was related to phosphoprotein levels using the Bioplex system. APAP treatment led to a significant activation of JNK compared to its regioisomer. In contrast, microarray analysis of AMAP showed a slight upregulation of ERK gene activity. Furthermore, Bioplex data showed AMAP treatment led to significant ERK phosphorylation compared to APAP. Cell viability assays confirmed that APAP-induced activation of JNK was related to higher rates of cell death, whereas activation of ERK by AMAP may be cytoprotective.
2010-07-07 | GSE18614 | GEO
Project description:We examined the effect of acetaminophen (APAP) on the transcriptional response induced by interferon-β (IFN-β). Transcript levels from total RNA isolated rom murine livers were determined using G4121B whole genome arrays. Keywords: Pharmakinetics, drug treatment 6-8 week male CD-1 mice were administered vehicle alone, APAP, IFN-β or IFN-β + APAP (n=5 per treatment per time point 40 animals total) and were euthanized at 1.5 or 4 hours post-treatment. Agilent 22k whole genome arrays were used to measure changes in mRNA transcripts in the liver mRNA. Stratatagene Universal Mouse RNA was used as a reference.
2010-10-18 | E-GEOD-18949 | biostudies-arrayexpress