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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Wagner, M; Halilbasic, E; Marschall, HU; Zollner, G; Fickert, P; Langner, C; Zatloukal, K; Denk, H; Trauner, M.
CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice.
Hepatology. 2005; 42(2):420-430
Doi: 10.1002/hep.20784
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- Führende Autor*innen der Med Uni Graz
- Trauner Michael
- Wagner Martin
- Co-Autor*innen der Med Uni Graz
- Denk Helmut
- Fickert Peter
- Halilbasic Emina
- Langner Cord
- Zatloukal Kurt
- Zollner Gernot
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- Abstract:
- Induction of hepatic phase I/II detoxification enzymes and alternative excretory pumps may limit hepatocellular accumulation of toxic biliary compounds in cholestasis. Because the nuclear xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate involved enzymes and transporters, we aimed to induce adaptive alternative pathways with different CAR and PXR agonists in vivo. Mice were treated with the CAR agonists phenobarbital and 1,4-bis-[2-(3,5-dichlorpyridyloxy)]benzene, as well as the PXR agonists atorvastatin and pregnenolone-16alpha-carbonitrile. Hepatic bile acid and bilirubin-metabolizing/detoxifying enzymes (Cyp2b10, Cyp3a11, Ugt1a1, Sult2a1), their regulatory nuclear receptors (CAR, PXR, farnesoid X receptor), and bile acid/organic anion and lipid transporters (Ntcp, Oatp1,2,4, Bsep, Mrp2-4, Mdr2, Abcg5/8, Asbt) in the liver and kidney were analyzed via reverse-transcriptase polymerase chain reaction and Western blotting. Potential functional relevance was tested in common bile duct ligation (CBDL). CAR agonists induced Mrp2-4 and Oatp2; PXR agonists induced only Mrp3 and Oatp2. Both PXR and CAR agonists profoundly stimulated bile acid-hydroxylating/detoxifying enzymes Cyp3a11 and Cyp2b10. In addition, CAR agonists upregulated bile acid-sulfating Sult2a1 and bilirubin-glucuronidating Ugt1a1. 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. Atorvastatin significantly increased Oatp2, Mdr2, and Asbt, while other transporters and enzymes were moderately affected. In conclusion, administration of specific CAR or PXR ligands results in coordinated stimulation of major hepatic bile acid/bilirubin metabolizing and detoxifying enzymes and hepatic key alternative efflux systems, effects that are predicted to counteract cholestasis.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Bile Acids and Salts - metabolism
- Bilirubin - metabolism
- Biological Transport -
- Cholestasis - drug therapy
- Cholesterol - metabolism
- Inactivation, Metabolic -
- Liver - drug effects Liver - metabolism
- Mice -
- Phospholipids - metabolism
- RNA, Messenger - analysis
- Receptors, Cytoplasmic and Nuclear - agonists Receptors, Cytoplasmic and Nuclear - genetics Receptors, Cytoplasmic and Nuclear - physiology
- Receptors, Steroid - agonists Receptors, Steroid - genetics Receptors, Steroid - physiology
- Transcription Factors - agonists Transcription Factors - genetics Transcription Factors - physiology