Dual role of orphan nuclear receptor pregnane X receptor in bilirubin detoxification in mice.
The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are implicated in xenobiotic and endobiotic detoxification, including the clearance of toxic bilirubin. Previous studies have suggested both overlapping and preferential regulation of target genes by these receptors, but the mechanism of cross-talk remains elusive. Here we reveal a dual role of PXR in bilirubin detoxification in that both the loss and activation of PXR led to protection from hyperbilirubinemia induced by bilirubin infusion or hemolysis. The increased bilirubin clearance in PXR-null mice was associated with selective upregulation of detoxifying enzymes and transporters, and the pattern of regulation is remarkably similar to that of transgenic mice expressing the activated CAR. Interestingly, the increased bilirubin clearance and associated gene regulation were absent in the CAR-null or double-knockout mice. In cell cultures, ligand-free PXR specifically suppressed the ability of CAR to induce the multidrug resistance associated protein 2 (MRP2), a bilirubin-detoxifying transporter. This suppression was, at least in part, the result of the disruption of ligand-independent recruitment of coactivator by CAR. In conclusion, PXR plays both positive and negative roles in regulating bilirubin homeostasis, and this provides a novel mechanism that may govern receptor cross-talk and the hierarchy of xenobiotic and endobiotic regulation. PXR is a potential therapeutic target for clinical treatment of jaundice. (HEPATOLOGY 2005;41:497-505.).
Saini
Simrat P S
SP
Center for Pharmacogenetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Mu
Ying
Y
Gong
Haibiao
H
Toma
David
D
Uppal
Hirdesh
H
Ren
Songrong
S
Li
Song
S
Poloyac
Samuel M
SM
Xie
Wen
W
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001663:Bilirubin / Q000378:metabolism*; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011987:Receptors, Steroid / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D001663:Bilirubin