Organic Anion Transporting Polypeptides (OATPs): Regulation of Expression and Function

Abstract

Eleven members of the human organic anion transporter (OATP) family (grouped into six families) facilitate the Na(+)- independent transmembrane transport of various endo- and xenobiotics (bile acids, bilirubin, steroid hormone conjugates, thyroid hormones, prostaglandins, clinically used drugs, and toxins). OATPs are 12-transmembrane glycoproteins (643-722 amino acids) and contain many conserved structural features, for example, eleven cysteines in the large extracellular loop 5. They are important for proper transport, for which translocation of substrates through a central, positively-charged pore in a rocker-switch-type mechanism has been proposed. Although OATPs are expressed in various cells and tissues, some members show a more restricted pattern (well-studied OATP1B1/OATP1B3 in liver, OATP4C1 in kidney, and OATP6A1 in testis). In cancer, the distribution pattern is no longer maintained, and OATPs, like OATP1B3, become upregulated in malignant tissues (colon, breast, prostate). Studies in cell lines and animal models further revealed that the expression of OATPs is regulated in a cell- and tissue-specific way by cytokines and activation of nuclear receptors (LXR, FXR, PXR, CAR, HNF4). Also epigenetic mechanisms and postranslational modifications influence their expression and function. Therefore, changes in the expression of OATPs under pathological conditions will influence transport processes causing an altered accumulation of OATP substrates in cells of excretory organs (intestine, liver, kidney) and on various blood/organ barriers (such as brain, testis, placenta). For drugs, this may result in increased toxicity and adverse drug reactions. Therefore, it is important to improve the knowledge on the regulation and function of individual OATPs, and to apply it for therapeutic considerations.

Novel Mechanism of Impaired Function of Organic Anion-Transporting Polypeptide 1B3 in Human Hepatocytes: Post-Translational Regulation of OATP1B3 by Protein Kinase C Activation

“…Activity of membrane transport proteins often is affected by the amount of transport protein localized to the plasma membrane (Köck et al, 2010;Zhou et al, 2011) and post-translational modifications of the transport proteins, which in many cases involves protein phosphorylation (Svoboda et al, 2011). To determine the mechanism(s) involved in rapid downregulation of OATP1B3-mediated transport upon PKC activation, surface levels and phosphorylation status of OATP1B3 were compared between vehicle control-and PMA-treated SCH.…”

Alcohol Cirrhosis Alters Nuclear Receptor and Drug Transporter Expression in Human Liver

“…The identification of single nucleotide polymorphisms in the SLCO1B1 gene and resulting SLCO1B1 polymorphisms results in altered disposition of statins (Generaux et al, 2011). Human SLCO mRNA expression is regulated through transcription factor-mediated pathways, such as liver-X-receptor, farnesoid-X-receptor (FXR), constitutive androstane receptor (CAR), and pregnane-X-receptor (PXR) (Svoboda et al, 2011).…”

Transcriptional and post-transcriptional regulation of Sprouty1, a receptor tyrosine kinase inhibitor in prostate cancer

“…38 It appears that both EGR and GATA transcriptions are upregulated in PCa even though Spry1 expression is downregulated in a significant number of PCa samples. Indeed, several TFs with potential binding sites in the proximal regions of Spry1 promoter act as transcriptional activator [26][27][28] in PCa. Thus, additional studies are needed in order to clarify the Transcriptional and post-transcriptional regulation of Sprouty1 M Darimipourain et al role of these TFs in Spry1 regulation in PCa.…”