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The canalicular membrane represents the excretory pole of hepatocytes.Bile is an important route of elimination of potentially toxic endo-and xenobiotics(including drugs and toxins),mediated by the major canalicular transporters:multidrug resistance protein 1(MDR1, ABCB1),also known as P-glycoprotein,multidrug resistance-associated protein 2(MRP2,ABCC2),and the breast cancer resistance protein(BCRP,ABCG2).Their activities depend on regulation of expression and proper localization at the canalicular membrane,as regulated by transcriptional and post-transcriptional events,respectively.At transcriptional level,specific nuclear receptors(NR)s modulated by ligands,co-activators and co-repressors,mediate the physiological requirements of these transporters.This complex system is also responsible for alterations occurring in specific liver pathologies.We briefly describe the major ClassⅡNRs, pregnane X receptor(PXR)and constitutive androstane receptor(CAR),and their role in regulating expression of multidrug resistance proteins.Several therapeutic agents regulate the expression of relevant drug transporters through activation/inactivation of these NRs.We provide some representative examples of the action of therapeutic agents modulating liver drug transporters, which in addition,involve CAR or PXR as mediators.
The canalicular membrane represents the excretory pole of hepatocytes. Important is an important route of elimination of potentially toxic endo-and xenobiotics (including drugs and toxins), mediated by the major canalicular transporters: multidrug resistance protein 1 (MDR1, ABCB1), also known as P-glycoprotein, multidrug resistance-associated protein 2 (MRP2, ABCC2), and the breast cancer resistance protein (BCRP, ABCG2). Their activities depend on regulation of expression and proper localization at the canalicular membrane, as regulated by transcriptional and post -Transcriptional events, respectively. At transcriptional level, specific nuclear receptors (NR) s modulated by ligands, co-activators and co-repressors, mediate the physiological requirements of these transporters. This complex system is also responsible for alterations occurring in specific liver pathologies .We describe describe the major Class IINRs, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), and their role in regulating expre ssion of multidrug resistance proteins. Subject therapeutic agents regulate the expression of relevant drug transporters through activation / inactivation of these NRs.We provide some representative examples of the action of therapeutic agents modulating liver drug transporters, which in addition, involve CAR or PXR as mediators .