Expression dynamics of pregnane X receptor-controlled genes in 3D primary human hepatocyte spheroids View Full Text


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Article Info

DATE

2021-10-23

AUTHORS

Tomas Smutny, Veronika Bernhauerova, Lucie Smutna, Jurjen Duintjer Tebbens, Petr Pavek

ABSTRACT

The pregnane X receptor (PXR) is a ligand-activated nuclear receptor controlling hepatocyte expression of numerous genes. Although expression changes in xenobiotic-metabolizing, lipogenic, gluconeogenic and bile acid synthetic genes have been described after PXR activation, the temporal dynamics of their expression is largely unknown. Recently, 3D spheroids of primary human hepatocytes (PHHs) have been characterized as the most phenotypically relevant hepatocyte model. We used 3D PHHs to assess time-dependent expression profiles of 12 prototypic PXR-controlled genes in the time course of 168 h of rifampicin treatment (1 or 10 µM). We observed a similar bell-shaped time-induction pattern for xenobiotic-handling genes (CYP3A4, CYP2C9, CYP2B6, and MDR1). However, we observed either biphasic profiles for genes involved in endogenous metabolism (FASN, GLUT2, G6PC, PCK1, and CYP7A1), a decrease for SHP or oscillation for PDK4 and PXR. The rifampicin concentration determined the expression profiles for some genes. Moreover, we calculated half-lives of CYP3A4 and CYP2C9 mRNA under induced or basal conditions and we used a mathematical model to describe PXR-mediated regulation of CYP3A4 expression employing 3D PHHs. The study shows the importance of long-term time-expression profiling of PXR target genes in phenotypically stable 3D PHHs and provides insight into PXR function in liver beyond our knowledge from conventional 2D in vitro models. More... »

PAGES

195-210

References to SciGraph publications

  • 2018-09-24. Human hepatic 3D spheroids as a model for steatosis and insulin resistance in SCIENTIFIC REPORTS
  • 2020-11-09. Transcriptional and post-transcriptional regulation of the pregnane X receptor: a rationale for interindividual variability in drug metabolism in ARCHIVES OF TOXICOLOGY
  • 2016-05-04. Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease in SCIENTIFIC REPORTS
  • 2010-02-12. Development of a Quantitative Model of Pregnane X Receptor (PXR) Mediated Xenobiotic Metabolizing Enzyme Induction in BULLETIN OF MATHEMATICAL BIOLOGY
  • 2017-09-29. SPA70 is a potent antagonist of human pregnane X receptor in NATURE COMMUNICATIONS
  • 2012-05-30. Best Practice in the Use of Physiologically Based Pharmacokinetic Modeling and Simulation to Address Clinical Pharmacology Regulatory Questions in CLINICAL PHARMACOLOGY & THERAPEUTICS
  • 2013-03-05. Pregnane X Receptor Agonists Impair Postprandial Glucose Tolerance in CLINICAL PHARMACOLOGY & THERAPEUTICS
  • 2019-03-20. On parameter estimation in an in vitro compartmental model for drug-induced enzyme production in pharmacotherapy in APPLICATIONS OF MATHEMATICS
  • 2013-08-23. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME in ARCHIVES OF TOXICOLOGY
  • 2012-01-19. Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins in CELL BIOLOGY AND TOXICOLOGY
  • 1978-04. Clinical Pharmacokinetics of Rifampicin in CLINICAL PHARMACOKINETICS
  • 2013-04-30. Optimization of stress response through the nuclear receptor-mediated cortisol signalling network in NATURE COMMUNICATIONS
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    URI

    http://scigraph.springernature.com/pub.10.1007/s00204-021-03177-y

    DOI

    http://dx.doi.org/10.1007/s00204-021-03177-y

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1142121036

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/34689256


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