AIM: To investigate the effect of resveratrol on biliary secretion of cholephilic compounds in healthy and bile duct-obstructed rats. METHODS: Resveratrol (RSV) or saline were administered to rats by daily oral gavage for 28 d after sham operation or reversible bile duct obstruction (BDO). Bile was collected 24 h after the last gavage during an intravenous bolus dose of the Mdr1/Mrp2 substrate azithromycin. Bile acids, glutathione and azithromycin were measured in bile to quantify their level of biliary secretion. Liver expression of enzymes and transporters relevant for bile production and biliary secretion of major bile constituents and drugs were analyzed at the mRNA and protein levels using qRT-PCR and Western blot analysis, respectively. The TR-FRET PXR Competitive Binding Assay kit was used to determine the agonism of RSV at the pregnane X receptor. RESULTS: RSV increased bile flow in sham-operated rats due to increased biliary secretion of bile acids (BA) and glutathione. This effect was accompanied by the induction of the hepatic rate-limiting transporters for bile acids and glutathione, Bsep and Mrp2, respectively. RSV also induced Cyp7a1, an enzyme that is crucial for bile acid synthesis; Mrp4, a transporter important for BA secretion from hepatocytes to blood; and Mdr1, the major apical transporter for xenobiotics. The findings were supported by increased biliary secretion of azithromycin. The TR-FRET PXR competitive binding assay confirmed RSV as a weak agonist of the human nuclear receptor PXR, which is a transcriptional regulator of Mdr1/Mrp2. RSV demonstrated significant hepatoprotective properties against BDO-induced cirrhosis. RSV also reduced bile flow in BDO rats without any corresponding change in the levels of the transporters and enzymes involved in RSV-mediated hepatoprotection. CONCLUSION: Resveratrol administration for 28 d has a distinct effect on bile flow and biliary secretion of cholephilic compounds in healthy and bile duct-obstructed rats.

• Keywords
• Azithromycin, Bile acids, Bile production, Pregnane X receptor, Resveratrol,
• MeSH
• ATP-Binding Cassette Transporters metabolism   MeSH
• Anti-Inflammatory Agents, Non-Steroidal pharmacology   therapeutic use   MeSH
• Antioxidants pharmacology   therapeutic use   MeSH
• Administration, Oral MeSH
• Azithromycin pharmacokinetics   MeSH
• Cholestasis drug therapy   etiology   physiopathology   MeSH
• Glutathione metabolism   MeSH
• Hepatocytes drug effects   metabolism   MeSH
• Liver drug effects   metabolism   physiopathology   MeSH
• Rats MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Rats, Wistar MeSH
• Pregnane X Receptor MeSH
• Resveratrol MeSH
• Receptors, Steroid agonists   MeSH
• Stilbenes pharmacology   therapeutic use   MeSH
• Bile Acids and Salts chemistry   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ATP-Binding Cassette Transporters MeSH
• Anti-Inflammatory Agents, Non-Steroidal MeSH
• Antioxidants MeSH
• Azithromycin MeSH
• Glutathione MeSH
• Pregnane X Receptor MeSH
• Resveratrol MeSH
• Receptors, Steroid MeSH
• Stilbenes MeSH
• Bile Acids and Salts MeSH