Title: Constitutive androstane receptor-mediated changes in bile acid composition contributes to hepatoprotection from lithocholic acid-induced liver injury in mice.

Authors: Beilke, Lisa D; Aleksunes, Lauren M; Holland, Ricky D; Besselsen, David G; Beger, Rick D; Klaassen, Curtis D; Cherrington, Nathan J

Published In Drug Metab Dispos, (2009 May)

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.

PubMed ID: 19196849

MeSH Terms: Animals; Bile Acids and Salts/biosynthesis; Bile Acids and Salts/metabolism*; Chemical and Drug Induced Liver Injury/pathology*; Chromatography, High Pressure Liquid; DNA-Binding Proteins/biosynthesis; DNA-Binding Proteins/genetics; DNA/biosynthesis; DNA/genetics; Lithocholic Acid/antagonists & inhibitors*; Lithocholic Acid/toxicity*; Liver/metabolism; Liver/pathology; Male; Mice; Mice, Inbred C57BL; Oligonucleotide Probes; Phenobarbital/pharmacology; Pyridines/pharmacology; RNA/biosynthesis; RNA/genetics; Receptors, Cytoplasmic and Nuclear/biosynthesis; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/metabolism*; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Transcription Factors/biosynthesis; Transcription Factors/genetics; Transcription Factors/metabolism*