Gastroenterology

Gastroenterology

Volume 129, Issue 2, August 2005, Pages 476-485
Gastroenterology

Clinical—liver, pancreas, and biliary tract
Complementary Stimulation of Hepatobiliary Transport and Detoxification Systems by Rifampicin and Ursodeoxycholic Acid in Humans

https://doi.org/10.1053/j.gastro.2005.05.009Get rights and content

Background & Aims: 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. Methods: 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 (4β-hydroxy cholesterol, 4β-OH-C) and bile acid synthesis (7α-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. Results: 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. Conclusions: 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.

Section snippets

Patients

Otherwise healthy patients scheduled for laparascopic cholestectomy for symptomatic gallstone disease were invited to participate in a clinical study of the metabolic and molecular effects of UDCA and RIFA. This approach was taken because such a detailed analysis of liver, bile, serum, and urine is not feasible in patients not scheduled for a surgical abdominal procedure. Potential candidates completed a clinical research file consisting of a detailed questionnaire about the patient’s history

Patients’ Demographics, Routine Biochemistry and Type of Gallstones

The patients randomized to control, RIFA, or UDCA groups did not differ significantly in mean age (range, 29–77 years of age) or body mass index (range, 24.4–35.9 kg/m2). Females outnumbered males (in line with the target population in cholestatic liver diseases such as PBC), and there were more women in the UDCA group (n = 9) than in the RIFA (n = 6) or control (n = 7) groups (Table 1). All patients had cholesterol gallstones.

No adverse effects from study medications were reported. Serum

Discussion

The present study was performed to define the molecular mechanisms of action of 2 drugs—RIFA5, 7, 8 and UDCA (recently reviewed by Paumgartner and Beuers1)—that were shown to improve serum liver biochemistry and symptoms in patients with cholestatic liver diseases such as primary biliary cirrhosis (PBC). We found that RIFA and UDCA both enhance expression of distinct but complementary sets of bile acid/bilirubin metabolizing/detoxifying enzymes and their corresponding hepatobiliary ABC

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    Supported by grants from Karolinska Institutet, Ruth och Richard Julins Fond, and the Swedish Medical Association (to H.U.M.) and by grant 10266 from the Austrian National Bank and P15502 from the Austrian Science Foundation (to M.T.).

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