CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice.
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.
Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine, Medical University Graz, Auenbruggerplatz 15, A-8036 Graz, Austria.
Martin
M
Wagner
Emina
E
Halilbasic
Hanns-Ulrich
HU
Marschall
Gernot
G
Zollner
Peter
P
Fickert
Cord
C
Langner
Kurt
K
Zatloukal
Helmut
H
Denk
Michael
M
Trauner
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001663:Bilirubin / Q000378:metabolism*; D001692:Biological Transport; D002779:Cholestasis / Q000188:drug therapy*; D002784:Cholesterol / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010743:Phospholipids / Q000378:metabolism; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D011987:Receptors, Steroid / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000502:physiology
D001647:Bile Acids and Salts; D000090702:Constitutive Androstane Receptor; D010743:Phospholipids; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D002784:Cholesterol; D001663:Bilirubin