Hepatic responses of mice and rats to equivalent acetaminophen (APAP) insult [mouse]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205201 | GEO | 2023/06/20
REPOSITORIES: GEO
Similar Datasets
Project description:The well-known difference in sensitivity of mice and rats to acetaminophen (APAP) liver injury has been related to differences in the fraction that is bioactivated to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). Physiologically-based pharmacokinetic modelling was used to identify doses of APAP (300 and 1000 mg/kg in mice and rats, respectively) yielding similar hepatic burdens of NAPQI, to enable the comparison of temporal liver tissue responses under conditions of equivalent chemical insult.
2023-06-20 | GSE205202 | GEO
Project description:The well-known difference in sensitivity of mice and rats to acetaminophen (APAP) liver injury has been related to differences in the fraction that is bioactivated to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). Physiologically-based pharmacokinetic modelling was used to identify doses of APAP (300 and 1000 mg/kg in mice and rats, respectively) yielding similar hepatic burdens of NAPQI, to enable the comparison of temporal liver tissue responses under conditions of equivalent chemical insult.
2023-08-31 | PXD034438 | Pride
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:This SuperSeries is composed of the SubSeries listed below.
2023-06-20 | GSE205203 | GEO
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:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
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:Hepatic RNA specimens from mice (C57BL/6) of the 4 groups (vehicle-treated at 24h/48h, n=6; acetaminophen (APAP)-treated (300mg/kg) at 24h/48h, n=7) were pooled at equal shares. Thereafter, pooled RNA underwent analysis by 3'mRNA sequencing (MACE, GenXPro, Frankurt, Germany).
2021-12-31 | GSE169071 | GEO
Project description:Gene expression training data set from rat blood samples exposed to either 150, 1500 or 2500 mg/kg of APAP for 6, 12 or 24 hours. Experiment Overall Design: Male F344/N rats, 10-12 weeks old, were exposed to 0 (vehicle only), 150, 1500 or 2500 mg/kg APAP in 0.5% ethyl cellulose by oral gavage in two doses to increase absorption. The animals were sacrificed after 6, 12 or 24 hours. Equal amounts of RNA from the blood from each of four vehicle-only treated animals at the 6 and 12 hour time point and from each of six vehicle-only treated animals at the 24 hour time point, were pooled for control gene expression. The pooled controls were compared with individual treated animals at each dose and time period. The samples were hybridized in duplicate for each individual rat for a total of 8 (exception due to insufficient RNA quality: 150 mg/kg APAP and 1500 mg/kg APAP at 12 hour time point only 3 animals) microarray chips per dose and time period. Experiment Overall Design: Experiments were performed according to the guidelines established in the NIH Guide for the Care and Use of Laboratory Animals and an approved Animal Study Protocol was on file prior to initiation of the study.
2008-06-14 | E-GEOD-5593 | biostudies-arrayexpress
Project description:Acetaminophen is the primary cause of acute liver toxicity in Europe/USA. Therefore, the FDA reconsiders recommendations concerning safe acetaminophen dosage/use. Current tests for liver toxicity are no ideal predictive markers for liver injury. Here, ‘omics techniques (global analysis of metabolomic/gene expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low dose, we evaluated effects of (sub-)therapeutic acetaminophen doses on metabolite formation/global gene-expression changes (including, for the first time, miRNA) in blood/urine samples from healthy human volunteers. Three dose rounds with 6 individuals were performed with 0.5, 2 or 4 g APAP. In the 0.5 and 2 g dose-rounds T0(control) T1, T7 and T25 samples were collected in the 4g round only T0(control) and T25 samples are available.
2011-07-07 | E-GEOD-30418 | biostudies-arrayexpress
Project description:Preclinical biomarkers useful for identification of idiosyncratic drugs have not been identified. It is hypothesized that patterns of transcript expression for the hepatotoxicants, including classical and idiosyncratic hepatotoxicants, are similar and the patterns differ from those of non-hepatotoxicants. This experiment is part of the biomarkers study, and focus on two clasical hepatotoxicants: Acetaminophen and Carbon tetrachloride. We have employed whole genome microarray expression profiling to identify liver gene expression changes induced by hepatotoxicants. For the same animal, urinary microRNA profiling were analyzed. APAP and CCl4 both significantly increased the urinary levels of 44 and 28 miRNAs, respectively. In addition, 10 of the increased miRNAs were in common between APAP and CCl4. Computational analysis was used to predict target genes of the 10 shared hepatotoxicant-induced miRNAs. From the same animals, liver gene expression profiling was performed using whole genome microarrays. Eight putative target genes were found to be significantly altered in the liver of APAP and CCl4 treated animals. Acetaminophen induced liver gene expression changes in rats (Six to seven week-old male Sprague-Dawley rats, provided by the US Food and Drug Administration National Center for Toxicological Research (NCTR) breeding colonies, were used for the study.) were measured at 6 hours, 24 hours, 3 days and 7 days after exposure to doses of 0, 100 and 1250 mg/kg. Carbon tetrachloride induced liver gene expression changes in rats were measured at 6 hours, 24 hours and 3 days after exposure to doses of 0, 50 and 2000 mg/kg. Each group has at least 4 animals, total of 96 samples.
2012-03-15 | E-GEOD-32891 | biostudies-arrayexpress
Project description:Acetaminophen (N-acetyl-p-aminophenol; APAP) is a mild analgesic and antipyretic used commonly worldwide. Although APAP is considered a safe and effective over-the-counter medication, it is also the leading cause of drug-induced acute liver failure. Its hepatotoxicity has been linked to the covalent binding of its reactive metabolite, N-acetyl p-benzoquinone imine (NAPQI), to proteins. The aim of this in vivo study was to identify APAP-protein targets in both rat and mouse liver, and to compare the results from both species, using bottom-up proteomics and targeted multiple reaction monitoring (MRM) experiments. Livers from rats and mice, treated with APAP, were homogenized and digested by trypsin. Digests were then fractionated by mixed-mode solid-phase extraction prior to liquid chromatography-tandem mass spectrometry (LC-MS/MS) using scheduled multiple reaction monitoring (MRM) acquisition. The targeted assays were optimized based on high-resolution MS/MS data from information-dependent acquisition (IDA) using control liver homogenates treated with a custom alkylating reagent forming a positional isomer of the APAP modification on all cysteine residues, in order to build an in-house modified peptide database for targeted analysis. A list of putative in vivo targets of APAP were screened from previous in vitro studies, data-dependent high-resolution MS/MS analyses of liver digests, as well as selected proteins from the target protein database (TPDB), an online resource which references previous reports of proteins found to be modified by acetaminophen. Multiple protein targets of APAP in each species were found, while confirming modification sites.
2022-02-17 | PXD027674 | Pride