Cytoprotective properties of rifampicin are related to the regulation of detoxification system and bile acid transporter expression during hepatocellular injury induced by hydrophobic bile acids

• Published in: Journal of hepato-biliary-pancreatic sciences 2011-09, Vol.18 (5), p.740-750
• Main Authors: González, Raúl, Cruz, Adolfo, Ferrín, Gustavo, López-Cillero, Pedro, Briceño, Javier, Gómez, Miguel A., Rufián, Sebastián, Padillo, Javier, De la Mata, Manuel, Marin, Jose J. G., Muntané, Jordi
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Acids; Animals; Apoptosis; Bile; Bile Acids and Salts - metabolism; Carrier Proteins - biosynthesis; Carrier Proteins - drug effects; Carrier Proteins - genetics; Cells, Cultured; Chemical and Drug Induced Liver Injury - drug therapy; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; cholestasis; Cholestasis - drug therapy; Cholestasis - genetics; Cholestasis - metabolism; Cholesterol; cytochrome P450; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Female; Gastroenterology; Gene Expression Regulation; glucuronosyltransferase; Glycochenodeoxycholic Acid - toxicity; Hepatectomy; hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Hepatology; Humans; Male; Medicine; Medicine & Public Health; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - drug effects; Membrane Glycoproteins - genetics; Middle Aged; nuclear receptor; Original Article; Polymerase Chain Reaction; Rats; Rats, Wistar; Rifampin - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Surgical Oncology
• ISSN: 1868-6974; 1868-6982
• DOI: 10.1007/s00534-011-0396-3

Background/Purpose Rifampicin has been used for the treatment of patients with jaundice and pruritus. This study evaluated the effect of rifampicin on the expression of different detoxification systems and bile acid transporters during in-vivo and in-vitro experimental models of cholestasis. Methods Rifampicin was administered to glycochenodeoxycholic acid (GCDCA)-treated human hepatocytes and bile duct-obstructed rats. Different parameters related to cell death, and the expression of phase I and II drug metabolizing enzymes (DME) and bile acid transporters were determined. Results The induction of hepatocellular injury induced by cholestasis was associated with a reduction in cytochrome P4503A4 (CYP3A4), CYP7A1, and UDP-glucuronosyltransferase 2B4 (UGT2B4) expression, as well as an increase in import (Na + -taurocholate co-transporting polypeptide, NTCP) system expression. The beneficial properties of rifampicin were associated with an increase in DME and export bile acid systems (multidrug resistance-associated protein 4, MRP4, and bile acid export pump to bile duct, BSEP) expression, as well as a reduction in NTCP expression. Conclusions The beneficial effect of rifampicin in cholestasis is associated with an increase in DME expression involved in toxic, bile acid and cholesterol metabolism, as well as a reduction in the bile acid importing system in hepatocytes.