Cited by 355Drug Transport and Resistance MechanismsPharmacogenetics and Drug MetabolismDrug-Induced Hepatotoxicity and Protection

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

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Wagner, Martin, Halilbasic, Emina, Marschall, Hanns‐Ulrich, Zollner, Gernot, Fickert, Peter, Langner, Cord, Zatloukal, Kurt, Denk, Helmut +1 more·2005·Hepatology

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 pol…

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Crossref · 10.1002/hep.20784

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Authors
Wagner, M., Halilbasic, E., Marschall, H., Zollner, G., Fickert, P., Langner, C., Zatloukal, K., Denk, H., & Trauner, M.
Affiliations
  • Medical University of Graz (AT)
  • Karolinska University Hospital (SE)
Corresponding author
Trauner, Michael
Venue
Hepatology
Published
2005-08
Volume
42
Issue
2
Pages
420-430
ISSN
0270-9139 (ISSN-L)
OpenAlex
W2044732314
Cited by
355
References
48
Citations by year
2026: 15 · 2025: 14 · 2024: 13 · 2023: 12 · 2022: 18 · 2021: 14 · 2020: 11 · 2019: 12 · 2018: 18 · 2017: 16 · 2016: 16 · 2015: 10 · 2014: 7 · 2013: 12 · 2012: 23
FWCI
12.28
Type
journal article
Language
en
Open access
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
constitutive androstane receptor, pregnane X receptor, PXR agonists, bile acid detoxification, cholestasis, common bile duct ligation, bile acid transporters, MRP2, OATP2, MDR2, ASBT, CYP3A11, Cyp2b10, UGT1A1, SULT2A1, farnesoid X receptor, phenobarbital, atorvastatin, pregnenolone-16α-carbonitrile
MeSH terms
Pregnane X Receptor, Constitutive Androstane Receptor, Animals, Bile Acids and Salts, Bilirubin, Biological Transport, Cholestasis, Cholesterol, Liver, Inactivation, Metabolic, Phospholipids, Receptors, Steroid, RNA, Messenger, Transcription Factors, Receptors, Cytoplasmic and Nuclear, Mice

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