a pxr-mediated negative feedback loop attenuates the expression of cyp3a in response to the pxr agonist pregnenalone-16α-carbonitrilepxr-mediated负面反馈循环变弱的表达cyp3a pxr受体激动剂pregnenalone-16α-carbonitrile作为回应.pdfVIP

A PXR-Mediated Negative Feedback Loop Attenuates the Expression of CYP3A in Response to the PXR Agonist Pregnenalone-16a-Carbonitrile 1 1 1 2 1 Ian Bailey , G. Gordon Gibson , Kathryn Plant , Mark Graham , Nick Plant * 1 Faculty of Health and Medical Sciences, Centre for Toxicology, University of Surrey, Surrey, United Kingdom, 2 Safety Assessment, AstraZeneca RD Charnwood, Leicester, United Kingdom 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-16a-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 respon