Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

P53 Contributes to Differentiating Gene Expression Following Exposure to Acetaminophen and Its Less Hepatotoxic Regioisomer Both In Vitro and In Vivo

ABSTRACT: The goal of the present study was to compare hepatic toxicogenomic signatures across in vitro and in vivo mouse models following exposure to acetaminophen (APAP) or its relatively nontoxic regioisomer 3'-hydroxyacetanilide (AMAP). Two different Affymetrix microarray platforms and one Agilent Oligonucleotide microarray were utilized. APAP and AMAP treatments resulted in significant and large changes in gene expression that were quite disparate, and likely related to their different toxicologic profiles. Ten transcripts, all of which have been implicated in p53 signaling, were identified as differentially regulated at all time-points following APAP and AMAP treatments across multiple microarray platforms. Protein-level quantification of p53 activity aligned with results from the transcriptomic analysis, thus supporting the implicated mechanism of APAP-induced toxicity. Therefore, the results of this study provide good evidence that APAP-induced p53 phosphorylation and an altered p53-driven transcriptional response are fundamental steps in APAP-induced toxicity.

ORGANISM(S): Mus musculus

PROVIDER: GSE56576 | GEO | 2016/03/29

SECONDARY ACCESSION(S): PRJNA244071

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

p53 Contributes to Differentiating Gene Expression Following Exposure to Acetaminophen and Its Less Hepatotoxic Regioisomer Both In Vitro and In Vivo

Project description:The goal of the present study was to compare hepatic toxicogenomic signatures across in vitro and in vivo mouse models following exposure to acetaminophen (APAP) or its relatively nontoxic regioisomer 3'-hydroxyacetanilide (AMAP). Two different Affymetrix microarray platforms and one Agilent Oligonucleotide microarray were utilized. APAP and AMAP treatments resulted in significant and large changes in gene expression that were quite disparate, and likely related to their different toxicologic profiles. Ten transcripts, all of which have been implicated in p53 signaling, were identified as differentially regulated at all time-points following APAP and AMAP treatments across multiple microarray platforms. Protein-level quantification of p53 activity aligned with results from the transcriptomic analysis, thus supporting the implicated mechanism of APAP-induced toxicity. Therefore, the results of this study provide good evidence that APAP-induced p53 phosphorylation and an altered p53-driven transcriptional response are fundamental steps in APAP-induced toxicity. Preliminary study utilizing 9 arrays, 9 experimental groups, 2 h AMAP, 2 h APAP, 2 h control, 6 h AMAP, 6 h APAP, 6 h control, 24 h AMAP, 24 h APAP, 24 h control.

2016-03-29 | E-GEOD-56576 | biostudies-arrayexpress

Reactive Metabolite-induced Protein Glutathionylation Mechanistically Accounts for Acetaminophen Hepatotoxicity

Project description:Although covalent protein binding is established as the pivotal event underpinning acetaminophen (APAP) toxicity, its mechanistic details remain unclear. In this study, we demonstrated that APAP induces widespread protein glutathionylation in a time-, dose- and bioactivation-dependent manner in HepaRG cells. Proteo-metabonomic mapping provided evidence that APAP-induced glutathionylation resulted in functional deficits in energy metabolism, elevations in oxidative stress and cytosolic calcium, as well as mitochondrial dysfunction that correlate strongly with the well-established toxicity features of APAP. We also provide novel evidence that APAP-induced glutathionylation of carnitine O-palmitoyltransferase 1 (CPT1) and voltage-dependent anion-selective channel protein 1 are respectively involved in inhibition of fatty acid β-oxidation and opening of the mitochondrial permeability transition pore. Importantly, we show that the inhibitory effect of CPT1 glutathionylation can be mitigated by PPARα induction, which provides a mechanistic explanation for the prophylactic effect of fibrates, which are PPARα ligands, against APAP toxicity. Finally, we suggest that APAP-induced protein glutathionylation likely occurs secondary to covalent binding, which is a previously unknown mechanism of glutathionylation, demonstrating that this post-translational modification is functionally implicated in drug-induced toxicity.

2018-09-20 | PXD009986 | JPOST Repository

The effects of differential gut microbiota on hepatic gene expression

Project description:Our preliminary data suggest that differential gut microbiota modulates acetaminophen-induced hepatotoxicity (APAP toxicity) in mice model. The goal of our study is to determine whether commensal gut microbiota modulates the hepatic gene expressions potentially responsible for modulating APAP toxicity.

2025-01-10 | GSE125418 | GEO

Inhalation exposure of hexanal in rats (mRNA)

Project description:To further development of insight into the mechanism of toxicity, it is important to employ whole genome microarray expression profiling as a discovery platform to ientify genes with the potential to distinguish hexanal exposure across an exposure range relevant for toxicologic mechanisms. However, few reports have described the effect of hexanal on gene expression profiles using animal model. In this respect, we studied the expression profiles of mRNAs in hexanal-exposed in rats by microarray analysis.

2014-08-06 | GSE60118 | GEO

Differential Regulation of Mitogen-Activated Protein Kinases by Acetaminophen in TAMH cells

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

Differential Regulation of Mitogen-Activated Protein Kinases by Acetaminophen in TAMH cells

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

Shifted Metabolic Bias in Livers of Mice Lacking Hepatocytic Thioredoxin Reductase-1 Protects Against Acetaminophen Toxicity

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

Inhalation exposure of hexanal in rats (miRNA)

Project description:To further development of insight into the mechanism of toxicity, it is important to employ whole genome microarray expression profiling to identify and characterize miRNAs profiles as a discovery platform relevant for toxicologic mechanisms of hexanal. miRNAs have prominent role in cell cycle control, apoptosis, cancer development and proliferation-related processes. However, few reports have described the effect of hexanal on miRNA expression profiles using animal model. In this respect, we studied the expression profiles of miRNAs in hexanal-exposed in rats by miRNA microarray analysis.

2014-08-08 | GSE60203 | GEO

Investigating the effect of inflammatory conditions on acetaminophen-induced liver injury using 3D human multicellular microtissues

Project description:To investigate the molecular mechanisms of the inflammation-mediated exacerbation of increased acetaminophen (APAP) toxicity.

2020-10-04 | GSE104601 | GEO

Proteomic Analysis of Protective Effects of Dl-3-n-Butylphthalide against mpp+-Induced Toxicity via downregulating P53 pathway in N2A Cells

Project description:NBP significantly relived mpp+-induced cell toxicity. In addition, the neuroprotective role of NBP was implicated with P53 signaling pathway in some extent. These findings will reinforce the understanding of the mechanism of NBP in PD and identify new therapeutic targets

2022-10-17 | PXD037468 |

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data