CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice†

• DOI: 10.1002/hep.20784
• Publication Date: 2005-06-28T19:46:29Z
• Authors: Martin Wagner; Emina Halilbasic; Hanns‐Ulrich Mars...; Gernot Zollner; Peter Fickert; Cord Langner; Kurt Zatloukal; Helmut Denk; Michael Trauner
• Keywords: Detoxification; Pregnane X receptor

Induction of hepatic phase I/II detoxification enzymes and alternative excretory pumps may limit hepatocellular accumulation toxic biliary compounds in cholestasis. Because the nuclear xenobiotic receptors constitutive androstane receptor (CAR) pregnane X (PXR) regulate involved transporters, we aimed to induce adaptive pathways with different CAR PXR agonists vivo. Mice were treated phenobarbital 1,4-bis-[2-(3,5-dichlorpyridyloxy)]benzene, as well atorvastatin pregnenolone-16α-carbonitrile. Hepatic bile acid bilirubin-metabolizing/detoxifying (Cyp2b10, Cyp3a11, Ugt1a1, Sult2a1), their regulatory (CAR, PXR, farnesoid receptor), acid/organic anion lipid transporters (Ntcp, Oatp1,2,4, Bsep, Mrp2-4, Mdr2, Abcg5/8, Asbt) liver kidney analyzed via reverse-transcriptase polymerase chain reaction Western blotting. Potential functional relevance was tested common duct ligation (CBDL). induced Mrp2-4 Oatp2; only Mrp3 Oatp2. Both profoundly stimulated acid–hydroxylating/detoxifying Cyp3a11 Cyp2b10. In addition, upregulated acid–sulfating Sult2a1 bilirubin-glucuronidating Ugt1a1. These changes accompanied by reduced serum levels bilirubin acids healthy CBDL mice increased polyhydroxylated urine cholestatic mice. Atorvastatin significantly Oatp2, Asbt, while other moderately affected. conclusion, administration specific or ligands results coordinated stimulation major acid/bilirubin metabolizing detoxifying key efflux systems, effects that are predicted counteract (HEPATOLOGY 2005.)