Speaker
Description
The pregnane X receptor (PXR) is a ligand-activated transcription factor that is highly concentrated in the liver. It is considered a crucial sensor in the xenobiotic response. PXR regulates the transcription of genes involved in drug metabolism, including cytochrome P450 (CYP) enzymes such as CYP3A4, CYP2C9, and CYP2B6. For example, CYP3A4 metabolizes approximately half of all clinically used drugs. Recently, three-dimensional (3D) primary human hepatocyte (PHH) spheroids have emerged as an in vitro model that resembles in vivo hepatocytes in terms of phenotype and function. This model can be used to study the long-term regulation of drug-handling genes by PXR \cite{smutny2022expression}. We proposed a mathematical model that describes PXR activation and the expression dynamics of select PXR-regulated target genes \cite{lochman2024quantifying}. We calibrated this model using long-term target gene messenger RNA (mRNA) expression data from a state-of-the-art in vitro system of 3D PHH spheroids. We examined the impact of two PXR activators — a model PXR ligand (rifampicin) and its primary metabolite (25-desacetyl rifampicin) — on CYP mRNA expression \cite{kahiya2026insilico}. Finally, we discuss the experimental validation of the theoretical results.
Bibliography
@article{smutny2022expression,
title={{Expression dynamics of pregnane X receptor-controlled genes in 3D primary human hepatocyte spheroids}},
author={Smutny, Tomas and Bernhauerova, Veronika and Smutna, Lucie and Duintjer Tebbens, Jurjen and Pavek, Petr},
journal={Archives of Toxicology},
volume={96},
pages={195--210},
year={2022},
publisher={Springer},
doi={https://doi.org/10.1007/s00204-021-03177-y}
}
@article{lochman2024quantifying,
title={{Quantifying expression and metabolic activity of genes regulated by pregnane X receptor in primary human hepatocyte spheroids}},
author={Lochman, Luk{\'a}{\v{s}} and Kahiya, Ellen Tanaka and Saade, Bechara and Smutn{\'y}, Tom{\'a}{\v{s}} and Tebbens, Jurjen Duintjer and P{\'a}vek, Petr and Bernhauerov{\'a}, Veronika},
journal={PLOS Computational Biology},
volume={21},
number={4},
pages={e1012886},
year={2025},
publisher={Public Library of Science San Francisco, CA USA},
doi={https://doi.org/10.1371/journal.pcbi.1012886}
}
@article{kahiya2026insilico,
title={{In silico comparison of rifampicin and 25-desacetyl rifampicin-induced PXR-mediated CYP450 transcriptional response in 3D primary human hepatocytes}},
author={Kahiya, Ellen Tanaka and Smutn{\'y}, Tom{\'a}{\v{s}} and Smutn\'a, Lucie and Duintjer Tebbens, Jurjen and P{\'a}vek, Petr and Bernhauerov{\'a}, Veronika},
journal={Bulletin of Mathematical Biology (accepted)},
volume={},
number={},
pages={},
year={2026},
publisher={}
}
