Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Halilbasic, E.
Molecular Regulation of Hepatobiliary ABC Transporters by Ligand-activated Nuclear Receptors PXR and CAR
[ Dissertation ] Medical University of Graz; 2005. pp.
- Autor*innen der Med Uni Graz:
- Halilbasic Emina
- Betreuer*innen:
- Fickert Peter
- Trauner Michael
- Wagner Martin
- Altmetrics:
- Abstract:
- Background and Aims: Hepatocellular accumulation of toxic biliary compounds causes liver injury in cholestatic conditions and may be counteracted by induction of hepatic phase I/II detoxification enzymes and alternative excretory pumps. Since the nuclear xenobiotic receptors constitutive androstane receptor (CAR) and pregnane xenobiotic receptor (PXR) regulate the enzymes and transporters involved in bile formation and detoxification, we aimed to induce adaptive alternative transport and metabolic pathways, which may ameliorate cholestasis, with different CAR and PXR agonists in vivo. Methods: Mice were treated with the CAR agonists Phenobarbital (PB) and 1,4-bis [2-(3,5-dichlorpyridyloxy)]benzene (TCPOBOP), as well as the PXR agonists atorvastatin and pregnenolone-16alfa-carbonitrile (PCN). The coordinated effects on the expression of hepatic bile acid and bilirubin metabolizing/detoxifying enzymes (Cyp2b10, Cyp3a11, Ugt1a1, Sult2a1)), their regulatory nuclear receptors, (CAR, PXR, farnesoid X receptor (FXR)) and bile acid/organic anion and lipid transporters (Ntcp, Oatp1, Oatp2, Oatp4, Bsep, Mrp2, Mrp3, Mrp4, Mdr2, Abcg5, Abcg8, Asbt9 in liver and kidney were analyzed by RT-PCR and Western blotting. Potential functional relevance of this treatment was tested in common bile duct ligation (CBDL), representing an animal model of cholestasis. Results: CAR agonists induced mrp2-4 and Oatp2, PXR agonists only Mrp3. Both PXR and CAR agonists profoundly stimulated bile acid hydroxylating/detoxifiyning enzymes Cyp3a11 and Cyp2b10. In addition, CAR agonists upregulated bile acid sulfating enzyme Sult2a1 and bilirubin glucuronidating Ugt1a1. TCPOBOP significantly increased Oatp2 and Mdr2, while other transporters and metabolizing enzymes were only moderately affected. These changes were accompanied by reduced serum levels of bilirubin and bile acids in healthy and CBDL mice and by increased levels of polyhydroxylated bile acids in serum and urine of cholestatic mice. In conclusion, administration of CAR and PXR ligands results in a coordinated stimulation of the expression of major hepatic bile acid/bilirubin metabolizing and detoxifying enzmes (Cyp3a11, Cyp2b10, Sult2a1, Ugt1a1) and key alternative efflux systems (mrp3, Mrp4, Oatp29 in liver, effects which would be predicted to counteract cholestatic liver injury.