title: Pregnane X receptor regulates drug metabolism and transport in the vasculature and protects from oxidative stress.
abstract: OBJECTIVE
  Circulating endogenous, dietary, and foreign chemicals can contribute to vascular dysfunction. The mechanism by which the vasculature protects itself from these chemicals is unknown. This study investigates whether the pregnane X receptor (PXR), the major transcriptional regulator of hepatic drug metabolism and transport that responds to such xenobiotics, mediates vascular protection by co-ordinating a defence gene programme in the vasculature.
  
  
  RESULTS
  PXR was detected in primary human and rat aortic endothelial and smooth muscle cells (SMC) and blood vessels including the human and rat aorta. Metabolic PXR target genes cytochrome P450 3A, 2B, 2C, and glutathione S-transferase mRNA and activity were induced by PXR ligands in rodent and human vascular cells and absent in the aortas from PXR-null mice stimulated in vivo or in rat aortic SMC expressing dominant-negative PXR. Activation of aortic PXR by classical agonists had several protective effects: increased xenobiotic metabolism demonstrated by bioactivation of the pro-drug clopidogrel, which reduced adenosine diphosphate-induced platelet aggregation; increased expression of multidrug resistance protein 1, mediating chemical efflux from the vasculature; and protection from reactive oxygen species-mediated cell death.
  
  
  CONCLUSIONS
  PXR co-ordinately up-regulates drug metabolism, transport, and antioxidant genes to protect the vasculature from endogenous and exogenous insults, thus representing a novel gatekeeper for vascular defence.
authors.affiliation: Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. k.swales@surrey.ac.uk
authors.forename: Karen E
authors.initials: KE
authors.lastname: Swales
authors.forename: Rick
authors.initials: R
authors.lastname: Moore
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Truss
authors.forename: Arthur
authors.initials: A
authors.lastname: Tucker
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
authors.forename: Masahiko
authors.initials: M
authors.lastname: Negishi
authors.forename: David
authors.initials: D
authors.lastname: Bishop-Bailey
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology; D001692:Biological Transport / Q000502:physiology; D002478:Cells, Cultured; D000077144:Clopidogrel; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D000077297:Pregnane X Receptor; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D011987:Receptors, Steroid / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000077297:Pregnane X Receptor; D017382:Reactive Oxygen Species; D011987:Receptors, Steroid; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D000077144:Clopidogrel; D005982:Glutathione Transferase; D013988:Ticlopidine