A PXR-mediated negative feedback loop attenuates the expression of CYP3A in response to the PXR agonist Pregnenalone-16α-Carbonitrile

Bailey, I., Gibson, G.G., Plant, K., Graham, M. and Plant, N. 2011. A PXR-mediated negative feedback loop attenuates the expression of CYP3A in response to the PXR agonist Pregnenalone-16α-Carbonitrile. PLoS ONE. 6 (2), p. e16703.

TitleA PXR-mediated negative feedback loop attenuates the expression of CYP3A in response to the PXR agonist Pregnenalone-16α-Carbonitrile
AuthorsBailey, I., Gibson, G.G., Plant, K., Graham, M. and Plant, N.
Abstract

The nuclear receptor superfamily of ligand-activated transcription factors plays a central role in the regulation of cellular responses to chemical challenge. Nuclear receptors are activated by a wide range of both endogenous and exogenous chemicals, and their target genes include those involved in the metabolism and transport of the activating chemical. Such target gene activation, thus, acts to remove the stimulating xenobiotic or to maintain homeostatic levels of endogenous chemicals. Given the dual nature of this system it is important to understand how these two roles are balanced, such that xenobiotics are efficiently removed while not impacting negatively on homeostasis of endogenous chemicals. Using DNA microarray technology we have examined the transcriptome response of primary rat hepatocytes to two nuclear receptor ligands: Pregnenalone-16α-carbonitrile (PCN), a xenobiotic PXR agonist, and lithocholic acid, an endogenous mixed PXR/VDR/FXR agonist. We demonstrate that despite differences in the profile of activated nuclear receptors, transcriptome responses for these two ligands are broadly similar at lower concentrations, indicating a conserved general response. However, as concentrations of stimulating ligand rises, the transcriptome responses diverge, reflecting a need for specific responses to the two stimulating chemicals. Finally, we demonstrate a novel feed-back loop for PXR, whereby ligand-activation of PXR suppresses transcription of the PXR gene, acting to attenuate PXR protein expression levels at higher ligand concentrations. Through in silico simulation we demonstrate that this feed-back loop is an important factor to prevent hyperexpression of PXR target genes such as CYP3A and confirm these findings in vitro. This novel insight into the regulation of the PXR-mediated regulatory signal networks provides a potential mechanistic rationale for the robustness in steroid homeostasis within the cell.

JournalPLoS ONE
Journal citation6 (2), p. e16703
ISSN1932-6203
Year2011
PublisherPublic Library of Science
Digital Object Identifier (DOI)doi:10.1371/journal.pone.0016703
Publication dates
Published2011

Related outputs

Curriculum and beyond: Mathematics support for first year life science students
Bailey, I., Ferrier, C. and Smith, C.L. 2015. Curriculum and beyond: Mathematics support for first year life science students. CETL-MSOR Conference 2015. University of Greenwich 08 Sep 2015 The Sigma Network.

The Robustness of Pathway Analysis in Identifying Potential Drug Targets in Non-Small Cell Lung Carcinoma
Dalby, A.R. and Bailey, I. 2014. The Robustness of Pathway Analysis in Identifying Potential Drug Targets in Non-Small Cell Lung Carcinoma. Microarrays. 3 (4), pp. 212-225.

Differential suppression of tumor-specific CD8+ T cells by regulatory T cells
James, E., Yeh, A., King, C., Korangy, F., Bailey, I., Boulanger, D.S., Van den Eynde, B.J., Murray, N. and Elliott, T.J. 2010. Differential suppression of tumor-specific CD8+ T cells by regulatory T cells. Journal of Immunology. 185 (9), pp. 5048-5055.

Permalink - https://westminsterresearch.westminster.ac.uk/item/8zx03/a-pxr-mediated-negative-feedback-loop-attenuates-the-expression-of-cyp3a-in-response-to-the-pxr-agonist-pregnenalone-16-carbonitrile


Share this
Tweet
Email