Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Marschall, HU; Wagner, M; Zollner, G; Fickert, P; Diczfalusy, U; Gumhold, J; Silbert, D; Fuchsbichler, A; Benthin, L; Grundström, R; Gustafsson, U; Sahlin, S; Einarsson, C; Trauner, M.
Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans.
Gastroenterology. 2005; 129(2):476-485
Doi: 10.1016/j.gastro.2005.05.009
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- Co-Autor*innen der Med Uni Graz
- Fickert Peter
- Silbert-Wagner Dagmar
- Sommer Judith
- Trauner Michael
- Wagner Martin
- Zollner Gernot
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- Abstract:
- Rifampicin (RIFA) and ursodeoxycholic acid (UDCA) improve symptoms and biochemical markers of liver injury in cholestatic liver diseases by largely unknown mechanisms. We aimed to study the molecular mechanisms of action of these drugs in humans. Thirty otherwise healthy gallstone patients scheduled for cholestectomy were randomized to RIFA (600 mg/day for 1 week) or UDCA (1 g/day for 3 weeks) or no medication before surgery. Routine biochemistry, lipids, and surrogate markers for P450 activity (4beta-hydroxy cholesterol, 4beta-OH-C) and bile acid synthesis (7alpha-hydroxy-4-cholesten-3-one, C-4) were measured in serum. Bile acids were analyzed in serum, urine, and bile. A wedge liver biopsy specimen was taken to study expression of hepatobiliary ABC transporters as well as detoxification enzymes and regulatory transcription factors. RIFA enhanced bile acid detoxification as well as bilirubin conjugation and excretion as reflected by enhanced expression of CYP3A4, UGT1A1, and MRP2. These molecular effects were paralleled by decreased bilirubin and deoxycholic acid concentrations in serum and decreased lithocholic and deoxycholic acid concentrations in bile. UDCA on the other hand stimulated the expression of BSEP, MDR3, and MRP4. UDCA became the predominant bile acid after UDCA treatment and lowered the biliary cholesterol saturation index. RIFA enhances bile acid detoxification as well as bilirubin conjugation and export systems, whereas UDCA stimulates the expression of transporters for canalicular and basolateral bile acid export as well as the canalicular phospholipid flippase. These independent but complementary effects may justify a combination of both agents for the treatment of cholestatic liver diseases.
- Find related publications in this database (using NLM MeSH Indexing)
- Biological Transport - drug effects Biological Transport - physiology
- Cholelithiasis - diagnosis Cholelithiasis - surgery
- Cholestasis, Intrahepatic - diagnosis Cholestasis, Intrahepatic - surgery
- Dose-Response Relationship, Drug -
- Drug Administration Schedule -
- Elective Surgical Procedures -
- Female -
- Follow-Up Studies -
- Humans -
- Inactivation, Metabolic -
- Liver Circulation - drug effects
- Male -
- Middle Aged -
- Preoperative Care - methods
- Reference Values -
- Rifampin - pharmacokinetics Rifampin - therapeutic use
- Risk Assessment -
- Severity of Illness Index -
- Treatment Outcome -
- Ursodeoxycholic Acid - pharmacokinetics Ursodeoxycholic Acid - therapeutic use