Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA176462 | ENA |
REPOSITORIES: ENA
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Project description:This is the model of atorvastatin metabolism in hepaitc cells described in the article:
A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes
Joachim Bucher , Stephan Riedmaier , Anke Schnabel , Katrin Marcus , Gabriele Vacun , Thomas S Weiss , Wolfgang E Thasler , Andreas K Nussler , Ulrich M Zanger and Matthias Reuss. BMC Systems Biology 2011, 5:66. DOI:10.1186/1752-0509-5-66
Abstract:
Background:
The individual character of pharmacokinetics is of great importance in the risk assessment of new drug leads in pharmacological research. Amongst others, it is severely influenced by the properties and inter-individual variability of the enzymes and transporters of the drug detoxification system of the liver. Predicting individual drug biotransformation capacity requires quantitative and detailed models.
Results:
In this contribution we present the de novo deterministic modeling of atorvastatin biotransformation based on comprehensive published knowledge on involved metabolic and transport pathways as well as physicochemical properties. The model was evaluated in primary human hepatocytes and parameter identifiability analysis was performed under multiple experimental constraints. Dynamic simulations of atorvastatin biotransformation considering the inter-individual variability of the two major involved enzymes CYP3A4 and UGT1A3 based on quantitative protein expression data in a large human liver bank (n=150) highlighted the variability in the individual biotransformation profiles and therefore also points to the individuality of pharmacokinetics.
Conclusions:
A dynamic model for the biotransformation of atorvastatin has been developed using quantitative metabolite measurements in primary human hepatocytes. The model comprises kinetics for transport processes and metabolic enzymes as well as population liver expression data allowing us to assess the impact of inter-individual variability of concentrations of key proteins. Application of computational tools for parameter sensitivity analysis enabled us to considerably improve the validity of the model and to create a consistent framework for precise computer-aided simulations in toxicology.
The model is parameterized for patient 1 and reproduces the time courses in figure 2 of the article.
2011-05-11 | BIOMD0000000328 | BioModels
Project description:Comparison of gene expression profiles induced by the mycotoxin, aflatoxin B1 (AFB1), in primary human hepatocytes and HepaRG cells. Initial mechanisms involved in the complex multistep process leading to malignant transformation by chemicals remain largely unknown. We have analysed changes in gene expression profiles in primary human hepatocytes and differentiated human hepatoma HepaRG cells after a 24 h treatment with 0.05 or 0.25µM aflatoxin B1 (AFB1), a potent genotoxic hepatocarcinogen.
2010-12-07 | GSE25844 | GEO
Project description:Comparison of gene expression profiles induced by the mycotoxin, aflatoxin B1 (AFB1), in primary human hepatocytes and HepaRG cells. Initial mechanisms involved in the complex multistep process leading to malignant transformation by chemicals remain largely unknown. We have analysed changes in gene expression profiles in primary human hepatocytes and differentiated human hepatoma HepaRG cells after a 24 h treatment with 0.05 or 0.25µM aflatoxin B1 (AFB1), a potent genotoxic hepatocarcinogen. Three independent biological replicates of HepaRG cell cultures and two pools of three primary human hepatocyte cultures each, were investigated. Cells were treated with 0.05 or 0.25µM AFB1 for 24 h.
2010-12-07 | E-GEOD-25844 | biostudies-arrayexpress
Project description:Basal transcriptomic profiling of primary human hepatocytes and HepaRG cells We have analysed basal gene expression profiles in 6 primary human hepatocytes (2 technical replicates) and in 2 HepaRG cell passages (3 batches, 4 technical replicates)
2015-10-01 | GSE41289 | GEO
Project description:The aim of this experiment is to determine the similarities and differences between gene expression profiles in HepaRG cells versus primary human hepatocytes, human liver, and the commonly used HepG2 cell. We compared the gene expression profiles from replicate triplicate biological samples of human liver, primary human hepatocytes, HepG2 cells, and HepaRG at differing levels of maturity (differentiated and undifferentiated).
2009-12-28 | E-GEOD-18269 | biostudies-arrayexpress
Project description:Primary human hepatocytes, the gold standard for in vitro studies of liver-related functions, suffer from uncertain availability and high variability in cell activity. Over years, a number of alternative hepatic cell lines have lost major liver-like functions, but not HepaRG cells. Therefore, their increasing use worldwide today arouses the need for establishing a reference functional status of differentiated HepaRG cells known as HPR116, which originate from the initial cell bank. Deep proteome and secretome analyses enabled us to show that they nicely express, at levels generally close to those in primary hepatocytes, master regulators of the hepatic phenotype, structural elements that ensure liver-like polarisation and factors supporting their transdifferentiation properties. Their highly differentiated status, mitochondrial functionality, hepatokine secretion ability and response to insulin was verified. Overall, the HepaRG cell system appears as robust surrogate cell system to primary hepatocytes, versatile enough to study not only xenobiotic detoxification but also the control of hepatic energy metabolism, secretory function and disease-related signalling pathways.
2019-02-27 | PXD010304 | Pride
Project description:The aim of this experiment is to determine the similarities and differences between gene expression profiles in HepaRG cells versus primary human hepatocytes, human liver, and the commonly used HepG2 cell.
2009-12-29 | GSE18269 | GEO
Project description:Proteomic changes associated with the individual and combined exposures of deoxynivalenol (DON) and zearalenone (ZEA) were investigated in human hepatocytes (HepaRG cell line) after 24 hour expousre and at low cytotoxicity levels using liquid chromatography coupled to tandem mass spectrometry.
2017-12-13 | PXD006267 | Pride
Project description:Proteomic changes associated with the individual and combined exposures of deoxynivalenol (DON) and zearalenone (ZEA) were investigated in human hepatocytes (HepaRG cell line) after only 1h exposure and at low cytotoxicity levels using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS)
2017-12-13 | PXD005840 | Pride