Low dose human APAP exposure
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: marlon jetten
PROVIDER: E-GEOD-30418 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
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.
2011-07-07 | GSE30418 | GEO
Project description:Reddyhoff2015 - Acetaminophen metabolism and toxicity
This model examines acetaminophen metabolism and related hepatotoxicity. Multiple pathways associated with APAP metabolism has been included in the model. Using numerical, sensitivity and timescale analysis, key parameters involved in the toxicity has been identified. The model analysis highlights a critical acetaminophen dose in terms of the model parameters.
This model is described in the article:
Timescale analysis of a mathematical model of acetaminophen metabolism and toxicity.
Reddyhoff D, Ward J, Williams D, Regan S, Webb S
J Theor Biol. 2015 Dec 7;386:132-46.
Abstract:
Acetaminophen is a widespread and commonly used painkiller all over the world. However, it can cause liver damage when taken in large doses or at repeated chronic doses. Current models of acetaminophen metabolism are complex, and limited to numerical investigation though provide results that represent clinical investigation well. We derive a mathematical model based on mass action laws aimed at capturing the main dynamics of acetaminophen metabolism, in particular the contrast between normal and overdose cases, whilst remaining simple enough for detailed mathematical analysis that can identify key parameters and quantify their role in liver toxicity. We use singular perturbation analysis to separate the different timescales describing the sequence of events in acetaminophen metabolism, systematically identifying which parameters dominate during each of the successive stages. Using this approach we determined, in terms of the model parameters, the critical dose between safe and overdose cases, timescales for exhaustion and regeneration of important cofactors for acetaminophen metabolism and total toxin accumulation as a fraction of initial dose.
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2024-09-02 | BIOMD0000000609 | BioModels
Project description:Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing and 12 genes were detected with expression profiles significantly altered within 24hrs. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration.
2016-02-16 | GSE70786 | GEO
Project description:Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing and 12 genes were detected with expression profiles significantly altered within 24hrs. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration.
2016-02-16 | GSE70784 | GEO
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:Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing and 12 genes were detected with expression profiles significantly altered within 24hrs. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration. Overdosed patients admitted to the emergency room. Five male and female individuals from 19 - 59 years old were admitted to the emergency room following an overdose on acetaminophen. The patients presented 12hrs to 4 days after ingestion. ALT and AST elevated peaking beyond 400 U/I and 120 U/I. Blood was collected 2 or 5 days following ingestion.
2016-02-16 | E-GEOD-70786 | biostudies-arrayexpress
Project description:Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21+ hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available singlenuclei RNAseq data, we identified a subpopulation of p21+ hepatocytes enriched in a unique secretome of factors, such as Cxcl14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21+ hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, Cxcl14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or Cxcl14 with a neutralizing antibody. We found that targeting Cxcl14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting the senescent hepatocyte had no effect. This data supports that the sustained induction of p21 in hepatocytes with persistent Cxcl14 secretion are critical mechanistic events leading to ALF in mice and human patients.
2024-04-15 | GSE255777 | GEO
Project description:Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing and 12 genes were detected with expression profiles significantly altered within 24hrs. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration. Randomized, single-blind, placebo-controlled, clinical study. Healthy male and female individuals from 18 â 58 years old weighing 55 kg to 85 kg volunteered as subjects in the study. Subjects were enrolled for 14 days each and were acclimated for 3 days on a controlled, standardized whole-food diet in order to assure a uniform nutritional intake. Starting on day 0 and until day 7 relative to the start of dosing, each subject received daily repeat dosing every 6 hrs (i.e. 4x daily) of either 1g of acetaminophen or placebo pills orally. Blood was collected at 8 a.m. on each day of the clinical study for alanine aminotransferase (ALT) measurement and complete blood counts (CBC).
2016-02-16 | E-GEOD-70784 | biostudies-arrayexpress
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: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