Single cell RNA sequencing of mouse male and female liver cells with and without acetaminophen-induced injury
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE206782 | GEO | 2023/12/01
REPOSITORIES: GEO
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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.
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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
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and identified by:
BIOMD0000000624.
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To the extent possible under law, all copyright and related or
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2024-09-02 | BIOMD0000000624 | BioModels
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.
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