Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Rämistrasse 100, CH-8091 Zürich, Switzerland.
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Rämistrasse 100, CH-8091 Zürich, Switzerland.
Pharmacol Res. 2020 Apr;154:104234. doi: 10.1016/j.phrs.2019.04.018. Epub 2019 Apr 17.
The liver is the primary organ for the metabolic degradation of xenobiotics. Transmembrane transport proteins from the ABC and the SLC families mediate the uptake of endogenous compounds and xenobiotics into the hepatocyte as well as their elimination from the cells. Multiple processes are involved. The uptake of xenobiotics in hepatocytes is mediated by organic anion transporting polypeptides (OATPs) and by organic anion and cation transporters (OATs and OCTs). The elimination of drugs and metabolites from the liver cell back to the bloodstream is accomplished mainly by multidrug resistance-associated protein 3 (MRP3) and MRP4, while the elimination towards the biliary canaliculi is mediated by several different transporters (MRP2, BCRP, MDR1 and MATE1). Since bile acids and their salts are toxic detergents for hepatocytes, they have to be eliminated efficiently. This task is accomplished by the bile salt export pump BSEP. Two further transporters, MDR3 and ATP8B1 are involved in the proper constitution of bile. All these transporters can be influenced, mainly inhibited by a number of drugs, but also by metabolites from endogenous compounds such as estrogens. Additionally, rare monogenetic diseases exist which can be explained by absence of function or dysfunction of specific hepatic transporters, such as progressive familial intrahepatic cholestasis type 2 by genetic modifications in BSEP that lead to a loss of transporter function. Functional impairment of other transporters by genetics or by drugs also leads to liver injury, a potentially life-threatening disease that is still not fully understood. Hence, the interplay between drugs and hepatic transporters is multiple, and the knowledge of this interplay helps in understanding the etiology and molecular mechanisms behind some forms of (drug-induced) liver injury.
肝脏是代谢降解外来化合物的主要器官。ABC 和 SLC 家族的跨膜转运蛋白介导内源性化合物和外来化合物进入肝细胞以及从细胞中排出。涉及多个过程。肝细胞中外来化合物的摄取由有机阴离子转运多肽 (OATPs) 和有机阴离子和阳离子转运体 (OATs 和 OCTs) 介导。药物和代谢物从肝细胞返回到血液中的消除主要由多药耐药相关蛋白 3 (MRP3) 和 MRP4 完成，而向胆小管的消除则由几种不同的转运体 (MRP2、BCRP、MDR1 和 MATE1) 介导。由于胆汁酸及其盐是对肝细胞有毒的清洁剂，因此必须有效地将其排出。这项任务由胆汁盐输出泵 BSEP 完成。另外两种转运体 MDR3 和 ATP8B1 参与胆汁的正确构成。所有这些转运体都可以被许多药物主要抑制，也可以被内源性化合物如雌激素的代谢物抑制。此外，还存在一些罕见的单基因疾病，这些疾病可以通过特定肝脏转运体的功能缺失或功能障碍来解释，例如 BSEP 中的遗传修饰导致转运体功能丧失引起的进行性家族性肝内胆汁淤积症 2 型。遗传或药物引起的其他转运体的功能障碍也会导致肝损伤，这是一种潜在的危及生命的疾病，目前尚未完全了解。因此，药物和肝脏转运体之间的相互作用是多方面的，对这种相互作用的了解有助于理解某些形式的（药物引起的）肝损伤的病因和分子机制。
