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Research ArticleArticle

Constitutive Androstane Receptor-Mediated Changes in Bile Acid Composition Contributes to Hepatoprotection from Lithocholic Acid-Induced Liver Injury in Mice

Lisa D. Beilke, Lauren M. Aleksunes, Ricky D. Holland, David G. Besselsen, Rick D. Beger, Curtis D. Klaassen and Nathan J. Cherrington
Drug Metabolism and Disposition May 2009, 37 (5) 1035-1045; DOI: https://doi.org/10.1124/dmd.108.023317
Lisa D. Beilke
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Lauren M. Aleksunes
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Ricky D. Holland
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David G. Besselsen
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Rick D. Beger
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Curtis D. Klaassen
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Nathan J. Cherrington
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Abstract

Pharmacological activation of the constitutive androstane receptor (CAR) protects the liver during cholestasis. The current study evaluates how activation of CAR influences genes involved in bile acid biosynthesis as a mechanism of hepatoprotection during bile acid-induced liver injury. CAR activators phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or corn oil (CO) were administered to C57BL/6 wild-type (WT) and CAR knockout (CAR-null) mice before and during induction of intrahepatic cholestasis using the secondary bile acid, lithocholic acid (LCA). In LCA-treated WT and all the CAR-null groups (excluding controls), histology revealed severe multifocal necrosis. This pathology was absent in WT mice pretreated with PB and TCPOBOP, indicating CAR-dependent hepatoprotection. Decreases in total hepatic bile acids and hepatic monohydroxy, dihydroxy, and trihydroxy bile acids in PB- and TCPOBOP-pretreated WT mice correlated with hepatoprotection. In comparison, concentrations of monohydroxylated and dihydroxylated bile acids were increased in all the treated CAR-null mice compared with CO controls. Along with several other enzymes (Cyp7b1, Cyp27a1, Cyp39a1), Cyp8b1 expression was increased in hepatoprotected mice, which could be suggestive of a shift in the bile acid biosynthesis pathway toward the formation of less toxic bile acids. In CAR-null mice, these changes in gene expression were not different among treatment groups. These results suggest CAR mediates a shift in bile acid biosynthesis toward the formation of less toxic bile acids, as well as a decrease in hepatic bile acid concentrations. We propose that these combined CAR-mediated effects may contribute to the hepatoprotection observed during LCA-induced liver injury.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK068039]; and the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES011646].

  • Parts of this work were previously presented at the following meeting: Beilke L, Holland R, Besselsen D, Beger R, and Cherrington N (2007) Induction of drug-metabolizing genes during lithocholic acid-induced intrahepatic cholestasis alters individual bile acid concentrations. Mountain West Regional Chapter of the Society of Toxicology Annual Meeting; 2007 Sept 6–7; Breckenridge, CO. Society of Toxicology, Reston, VA.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.023317.

  • ABBREVIATIONS: CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; LCA, lithocholic acid; TCA, taurocholic acid; FXR, farnesoid X receptor; P450, cytochrome P450; CAR, constitutive androstane receptor; PB, phenobarbital; TCPOBOP, 1,4-bis[2,5-dichloropyridyloxy)]benzene; WT, wild-type; CAR-null, CAR knockout; CO, corn oil; HPLC, high-performance liquid chromatography; ESI, electrospray ionization; BAT, bile acid-CoA amino acid N-acyltransferase; bDNA, branched DNA.

  • ↵ Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

    • Received July 11, 2008.
    • Accepted January 30, 2009.
  • U.S. Government work not protected by U.S. copyright.
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Drug Metabolism and Disposition: 37 (5)
Drug Metabolism and Disposition
Vol. 37, Issue 5
1 May 2009
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Research ArticleArticle

Constitutive Androstane Receptor-Mediated Changes in Bile Acid Composition Contributes to Hepatoprotection from Lithocholic Acid-Induced Liver Injury in Mice

Lisa D. Beilke, Lauren M. Aleksunes, Ricky D. Holland, David G. Besselsen, Rick D. Beger, Curtis D. Klaassen and Nathan J. Cherrington
Drug Metabolism and Disposition May 1, 2009, 37 (5) 1035-1045; DOI: https://doi.org/10.1124/dmd.108.023317

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Research ArticleArticle

Constitutive Androstane Receptor-Mediated Changes in Bile Acid Composition Contributes to Hepatoprotection from Lithocholic Acid-Induced Liver Injury in Mice

Lisa D. Beilke, Lauren M. Aleksunes, Ricky D. Holland, David G. Besselsen, Rick D. Beger, Curtis D. Klaassen and Nathan J. Cherrington
Drug Metabolism and Disposition May 1, 2009, 37 (5) 1035-1045; DOI: https://doi.org/10.1124/dmd.108.023317
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