Trauner Michael, Fickert Peter, Halilbasic Emina, Moustafa Tarek
Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Wien Med Wochenschr. 2008;158(19-20):542-8. doi: 10.1007/s10354-008-0592-1.
Alterations in bile secretion at the hepatocellular and cholangiocellular levels may cause cholestasis. Formation of 'toxic bile' may be the consequence of abnormal bile composition and can result in hepatocellular and/or bile duct injury. The canalicular phospholipid flippase (Mdr2/MDR3) normally mediates biliary excretion of phospholipids, which normally form mixed micelles with bile acids and cholesterol to protect the bile duct epithelium from the detergent properties of bile acids. Mdr2 knockout mice are not capable of excreting phospholipids into bile and spontaneously develop bile duct injury with macroscopic and microscopic features closely resembling human sclerosing cholangitis. MDR3 mutations have been linked to a broad spectrum of hepatobiliary disorders in humans ranging from progressive familial intrahepatic cholestasis in neonates to intrahepatic cholestasis of pregnancy, drug-induced cholestasis, intrahepatic cholelithiasis, sclerosing cholangitis and biliary cirrhosis in adults. Other examples for bile injury due to the formation of toxic bile include the cholangiopathy seen in cystic fibrosis, after lithocholate feeding (in mice) and vanishing bile duct syndromes induced by drugs and xenobiotics. Therapeutic strategies for cholangiopathies may target bile composition/toxicity and the affected bile duct epithelium itself, and ideally should also have anti-cholestatic, anti-fibrotic and anti-neoplastic properties. Ursodeoxycholic acid (UDCA) shows some of these properties, but is of limited efficacy in the treatment of human cholangiopathies. By contrast to UDCA, its side chain-shortened homologue norUDCA undergoes cholehepatic shunting leading to a bicarbonate-rich hypercholeresis. Moreover, norUDCA has anti-inflammatory, anti-fibrotic and anti-proliferative effects, and stimulates bile acid detoxification. Upcoming clinical trials will have to demonstrate whether norUDCA or other side chain-modified bile acids are also clinically effective in humans. Finally, drugs for the treatment of cholangiopathies may target bile toxicity via nuclear receptors (FXR, PPARalpha) regulating biliary phospholipid and bile acid excretion.
肝细胞和胆管细胞水平上胆汁分泌的改变可能导致胆汁淤积。“毒性胆汁”的形成可能是胆汁成分异常的结果，并可导致肝细胞和/或胆管损伤。胆小管磷脂翻转酶（Mdr2/MDR3）通常介导磷脂的胆汁排泄，磷脂通常与胆汁酸和胆固醇形成混合微团，以保护胆管上皮免受胆汁酸的去污剂特性影响。Mdr2基因敲除小鼠无法将磷脂排泄到胆汁中，并自发发展出胆管损伤，其宏观和微观特征与人类硬化性胆管炎极为相似。MDR3突变与人类广泛的肝胆疾病有关，从新生儿进行性家族性肝内胆汁淤积到妊娠肝内胆汁淤积、药物性胆汁淤积、肝内胆石症、硬化性胆管炎和成人胆汁性肝硬化。由于形成毒性胆汁导致胆汁损伤的其他例子包括囊性纤维化中出现的胆管病、（小鼠）喂食石胆酸盐后以及药物和异生素诱导的胆管消失综合征。胆管病的治疗策略可能针对胆汁成分/毒性以及受影响的胆管上皮本身，理想情况下还应具有抗胆汁淤积、抗纤维化和抗肿瘤特性。熊去氧胆酸（UDCA）具有其中一些特性，但在治疗人类胆管病方面疗效有限。与UDCA相比，其侧链缩短的同系物去氧熊去氧胆酸（norUDCA）进行胆肝分流，导致富含碳酸氢盐的胆汁分泌增多。此外，norUDCA具有抗炎、抗纤维化和抗增殖作用，并刺激胆汁酸解毒。即将进行的临床试验将必须证明norUDCA或其他侧链修饰的胆汁酸在人类中是否也具有临床疗效。最后，用于治疗胆管病的药物可能通过调节胆汁磷脂和胆汁酸排泄的核受体（FXR、PPARα）来靶向胆汁毒性。
