Hepatic OATP1B transporters and nuclear receptors PXR and CAR: interplay, regulation of drug disposition genes, and single nucleotide polymorphisms.
Drug uptake transporters are now increasingly recognized as clinically relevant determinants of variable drug responsiveness and unexpected drug-drug interactions. Emerging evidence strongly suggests members of the organic anion transporting polypeptide (OATP) family appear to be particularly important to the disposition of many drugs in clinical use today. Specifically, the liver-enriched OATP1B subfamily members OATP1B1 and OATP1B3 exhibit broad substrate specificity and the ability to transport drugs which are ligands for xenobiotic sensing nuclear receptors such as the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Accordingly, OATP1B transporters may indirectly regulate expression of drug metabolism genes via modulation of the intracellular concentration of PXR and CAR ligands. Moreover, a number of functionally important single nucleotide polymorphisms (SNPs) in OATP1B transporters have been described. In this review, a brief summary of known SNPs in PXR and CAR will be followed by an in-depth outline of OATP1B1 and OATP1B3 transporters particularly in relation to the known SNPs in these OATPs and the interplay between OATP1B transporters with PXR and CAR, both in vitro and in vivo.
Meyer zu Schwabedissen
Henriette E
HE
Department of Pharmacology, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany.
Kim
Richard B
RB
D000818:Animals; D000090702:Constitutive Androstane Receptor; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000077297:Pregnane X Receptor; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000090702:Constitutive Androstane Receptor; D027361:Organic Anion Transporters; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid