University of Surrey

Test tubes in the lab Research in the ATI Dance Research

The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes.

Howe, K, Sanat, F, Thumser, AE, Coleman, T and Plant, N (2011) The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes. Xenobiotica, 41 (7). 519 - 529. ISSN 0049-8254

[img]
Preview
PDF
Howe et al_COMPLETE MANUSCRIPT.pdf - Accepted Version
Available under License : See the attached licence file.

Download (9Mb)
[img] Plain Text (licence)
licence.txt

Download (1516b)

Abstract

1. The therapeutic class of HMG-CoA reductase inhibitors, the statins, are central agents in the treatment of hypercholesterolemia, and the associated conditions of cardiovascular disease, obesity and metabolic syndrome. Whereas statin-therapy is generally considered safe a number of known adverse effects do occur, most commonly treatment associated-muscular pain. 2. In vitro evidence also supports the potential for drug-drug interactions involving this class of agents, and to examine this a ligand-binding assay was used to determine the ability of six clinically used statins for their ability to directly activate the nuclear receptors PXR, FXR and CAR, demonstrating a relative activation of PXR>FXR>CAR. 3. Using reporter gene constructs, we demonstrate this order of activation is mirrored at the transcriptional activation level, with PXR-mediated gene activation being preeminent. Finally, we describe a novel regulatory loop, whereby activation of FXR by statins increases PXR reporter gene expression, potentially enhancing PXRmediated responses. 4. Delineating the molecular interactions of statins with nuclear receptors is an important step in understanding the full biological consequences of statin exposure. This demonstration of their ability to directly activate nuclear receptors, leading to nuclear receptor cross-talk, has important potential implications for their use within a polypharmacy paradigm.

Item Type: Article
Divisions: Faculty of Health and Medical Sciences > Biochemistry and Physiology
Depositing User: Symplectic Elements
Date Deposited: 23 Sep 2011 12:06
Last Modified: 23 Sep 2013 18:45
URI: http://epubs.surrey.ac.uk/id/eprint/7258

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year


Information about this web site

© The University of Surrey, Guildford, Surrey, GU2 7XH, United Kingdom.
+44 (0)1483 300800