Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.
European Reference Network on Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany.
Int J Mol Sci. 2023 Mar 18;24(6):5823. doi: 10.3390/ijms24065823.
Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver's metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (); 2. the multidrug resistance protein-2 (MRP2, ) regulating the bile salts' independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, ) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, ). Two of the most known proteins involved in bile acids' (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs' secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs.
特发性药物性肝损伤（iDILI）是一个实际存在的健康挑战，占 50 岁以上成年人肝炎病例的 40%以上，占急性肝衰竭病例的 50%以上。此外，大约 30%的 iDILI 为胆汁淤积性（药物性胆汁淤积（DIC））。肝脏对亲脂性药物的代谢和清除依赖于其排入胆汁。因此，许多药物通过与肝转运蛋白相互作用而引起胆汁淤积。主要的胆小管流出转运蛋白包括：1. 胆汁盐输出泵（BSEP）蛋白（）；2. 多药耐药蛋白-2（MRP2，）通过排出谷胱甘肽调节胆汁盐的独立流动；3. 多药耐药蛋白-1（MDR1，）转运有机阳离子；4. 多药耐药蛋白-3（MDR3，）。两种最著名的与胆汁酸（BAs）代谢和转运有关的蛋白是 BSEP 和 MDR3。药物对 BSEP 的抑制导致 BAs 分泌减少和在肝细胞内滞留，导致胆汁淤积，而基因的突变使胆管上皮细胞暴露于 BAs 的有害去污剂作用下，从而增加 DIC 的易感性。本文综述了 DIC 的主要分子途径、与其他家族性肝内胆汁淤积临床形式的联系，以及主要的胆汁淤积诱导药物。
