Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited
Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited
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DOI：
10.1053/jhep.2002.36088
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发表时间：
2002-09-01
期刊：
影响因子：
13.5
通讯作者：
Beuers, U
中科院分区：
文献类型：
--
作者：
Paumgartner, G;Beuers, U
熊去氧胆酸(UCDA)越来越多地用于治疗胆汁淤积性肝病。实验证据表明：(1)通过调节混合磷脂胶束的组成，降低胆汁中胆汁酸的细胞毒性，可能通过降低胆汁中疏水性胆汁酸的浓度，从而保护胆管细胞免受疏水性胆汁酸的细胞毒性作用；(2)刺激肝胆分泌，可能是通过钙离子和蛋白激酶C-a依赖的机制和/或激活p38(MAPK)和细胞外信号调节激酶(ERK)，导致转运体分子(如胆盐输出泵(BSEP)和共轭输出泵(MRP2))插入肝细胞的小管膜，并可能激活插入的载体；(3)保护肝细胞免受胆汁酸诱导的细胞凋亡，包括抑制线粒体膜通透性转变(MMPT)，并可能刺激生存途径。在原发性胆汁性肝硬变中，UDCA(13-15 mg/kg/d)可改善血清肝脏化学指标，可延缓疾病进展为严重纤维化或肝硬变，并可延长无移植生存。在原发性硬化性胆管炎中，UDCA(13-20 mg/kg/d)可改善血清肝脏化学指标和替代预后指标，但对疾病进展的影响有待进一步评估。UDCA在妊娠期肝内胆汁淤积症、囊性纤维化肝病、进行性家族性肝内胆汁淤积症和慢性移植物抗宿主病中也有抗胆汁淤积作用的报道。未来的努力将集中在定义UDCA的其他临床用途，优化给药方案，以及在分子水平上进一步阐明UDCA的作用机制。
Ursodeoxycholic acid (UCDA) is increasingly used for the treatment of cholestatic liver diseases. Experimental evidence suggests three major mechanisms of action: (1) protection of cholangiocytes against cytotoxicity of hydrophobic bile acids, resulting from modulation of the composition of mixed phospholipid-rich micelles, reduction of bile acid cytotoxicity of bile and, possibly, decrease of the concentration of hydrophobic bile acids in the cholangiocytes; (2) stimulation of hepatobiliary secretion, putatively via Ca2+- and protein kinase C-a-dependent mechanisms and/or activation of p38(MAPK) and extracellular signal-regulated kinases (Erk) resulting in insertion of transporter molecules (e.g., bile salt export pump, BSEP, and conjugate export pump, MRP2) into the canalicular membrane of the hepatocyte and, possibly, activation of inserted carriers; (3) protection of hepatocytes against bile acid-induced apoptosis, involving inhibition of mitochondrial membrane permeability transition (MMPT), and possibly, stimulation of a survival pathway. In primary biliary cirrhosis, UDCA (13-15 mg/kg/d) improves serum liver chemistries, may delay disease progression to severe fibrosis or cirrhosis, and may prolong transplant-free survival. In primary sclerosing cholangitis, UDCA (13-20 mg/kg/d) improves serum liver chemistries and surrogate markers of prognosis, but effects on disease progression must be further evaluated. Anticholestatic effects of UDCA have also been reported in intrahepatic cholestasis of pregnancy, liver disease of cystic fibrosis, progressive familial intrahepatic cholestasis, and chronic graft-versus-host disease. Future efforts will focus on definition of additional clinical uses of UDCA, on optimized dosage regimens, as well as on further elucidation of mechanisms of action of UDCA at the molecular level.