Hepatic drug transporters and nuclear receptors: regulation by therapeutic agents.
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 Class II NRs, 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.
Mottino
Aldo-D
AD
Instituto de Fisiologia Experimental, Universidad Nacional de Rosario, Suipacha 570-Rosario, Argentina. amottino@unr.edu.ar
Catania
Viviana-A
VA
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects* / Q000378:metabolism; D000082:Acetaminophen / Q000494:pharmacology / Q000627:therapeutic use; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008107:Liver Diseases / Q000188:drug therapy*; D000089762:Multidrug Resistance-Associated Protein 2; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism; D013256:Steroids / Q000494:pharmacology / Q000627:therapeutic use
C000715087:ABCC2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D005938:Glucocorticoids; D000089762:Multidrug Resistance-Associated Protein 2; D018160:Receptors, Cytoplasmic and Nuclear; D013256:Steroids; D000082:Acetaminophen