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
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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].
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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.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.023317.
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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.
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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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