Marschall Hanns-Ulrich, Wagner Martin, Zollner Gernot, Fickert Peter, Diczfalusy Ulf, Gumhold Judith, Silbert Dagmar, Fuchsbichler Andrea, Benthin Lisbet, Grundström Rosita, Gustafsson Ulf, Sahlin Staffan, Einarsson Curt, Trauner Michael
Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Gastroenterology. 2005 Aug;129(2):476-85. doi: 10.1016/j.gastro.2005.05.009.
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.
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.
利福平（RIFA）和熊去氧胆酸（UDCA）可改善胆汁淤积性肝病患者的症状及肝损伤生化指标，但其作用机制尚不清楚。我们旨在研究这些药物在人体中的分子作用机制。
30例计划行胆囊切除术的健康胆结石患者被随机分为三组，分别在术前接受RIFA（600mg/天，共1周）、UDCA（1g/天，共3周）治疗或不接受任何药物治疗。检测血清中的常规生化指标、血脂以及P450活性（4β-羟基胆固醇，4β-OH-C）和胆汁酸合成（7α-羟基-4-胆甾烯-3-酮，C-4）的替代标志物。分析血清、尿液和胆汁中的胆汁酸。采集楔形肝活检标本，研究肝胆ABC转运蛋白、解毒酶及调节转录因子的表达。
RIFA可增强胆汁酸解毒以及胆红素结合与排泄，表现为CYP3A4、UGT1A1和MRP2的表达增加。这些分子效应伴随着血清中胆红素和脱氧胆酸浓度降低以及胆汁中石胆酸和脱氧胆酸浓度降低。另一方面，UDCA可刺激BSEP、MDR3和MRP4的表达。UDCA治疗后成为主要的胆汁酸，并降低了胆汁胆固醇饱和指数。
RIFA增强胆汁酸解毒以及胆红素结合和输出系统，而UDCA刺激胆小管和基底外侧胆汁酸输出转运蛋白以及胆小管磷脂翻转酶的表达。这些独立但互补的作用可能支持联合使用这两种药物治疗胆汁淤积性肝病。
