Expression and Function of Organic Anion Transporting Polypeptides in the Human Brain: Physiological and Pharmacological Implications

Abstract

The central nervous system (CNS) is an important pharmacological target, but it is very effectively protected by the blood–brain barrier (BBB), thereby impairing the efficacy of many potential active compounds as they are unable to cross this barrier. Among others, membranous efflux transporters like P-Glycoprotein are involved in the integrity of this barrier. In addition to these, however, uptake transporters have also been found to selectively uptake certain compounds into the CNS. These transporters are localized in the BBB as well as in neurons or in the choroid plexus. Among them, from a pharmacological point of view, representatives of the organic anion transporting polypeptides (OATPs) are of particular interest, as they mediate the cellular entry of a variety of different pharmaceutical compounds. Thus, OATPs in the BBB potentially offer the possibility of CNS targeting approaches. For these purposes, a profound understanding of the expression and localization of these transporters is crucial. This review therefore summarizes the current state of knowledge of the expression and localization of OATPs in the CNS, gives an overview of their possible physiological role, and outlines their possible pharmacological relevance using selected examples.

Transporter Regulation in Critical Protective Barriers: Focus on Brain and Placenta

“…For other transporters mentioned above, there is not only inconsistency in the proteomic data sets, but there is also the need to clarify their subcellular localization, in order to specify the direction of their contribution to the transcellular transport at the BBB. This applies for both OATP1A2 and OATP2B1 [ 15 ] that have been readily detected in the human brain by mass spectrometry [ 16 , 17 ] and immunohistochemistry [ 16 , 18 ], suggesting, at least for OATP1A2, some expression in glial cells. Similar findings are reported for human MRP4 [ 19 ], with rodent data supporting its apical localization in endothelial cells [ 20 , 21 ].…”

Increased/Targeted Brain (Pro)Drug Delivery via Utilization of Solute Carriers (SLCs)

“…In addition, OATP4A1, OATP5A1, and OATP6A1 have been proposed to be expressed in the brain; however, these transporters are more or less orphans, i.e., whose functions are less well understood and, thus, these latter ones are not discussed in this review. More specifically, OATP1A2 and OATP2B1 are expressed at the BBB (luminal side), OATP1A2, OATP3A1 are neuronal transporters, OATP1C1 is an astrocytic transporter, and OATP2A1 is evenly distributed among neurons, astrocytes, and neurons (Figure 1f; Table 5) [5,[196][197][198][199][200]. Curiously, OATP3A1 has two splice variants (OATP3A1_v1 and OATP3A1_v2) that are expressed in the brain in a dissimilar manner in neurons and choroid plexus.…”

Transport Mechanisms at the Blood–Brain Barrier and in Cellular Compartments of the Neurovascular Unit: Focus on CNS Delivery of Small Molecule Drugs

“…Indeed, enhanced OATP/Oatp-mediated transport is reflected by an increase in the uptake transfer constant (K in ) and, simultaneously, a small but statistically significant augmentation of the efflux rate coefficient (k out ) [ 35 , 70 , 71 ]. Additionally, it is important to consider that OATP2B1 has been detected at the BBB [ 79 , 80 , 81 ] and could potentially contribute to CNS drug permeation. While OATP2B1 localization in cerebral microvasculature has not been confirmed, it is likely that this transporter is expressed at the abluminal membrane and contributes to the movement of solutes out of the endothelial cell and into the brain parenchyma [ 81 ].…”

“…Additionally, it is important to consider that OATP2B1 has been detected at the BBB [ 79 , 80 , 81 ] and could potentially contribute to CNS drug permeation. While OATP2B1 localization in cerebral microvasculature has not been confirmed, it is likely that this transporter is expressed at the abluminal membrane and contributes to the movement of solutes out of the endothelial cell and into the brain parenchyma [ 81 ]. Relevant Oatp transport substrates that exert pharmacological/physiological effects in the brain include statins (i.e., atorvastatin, pravastatin, and rosuvastatin), prostaglandin E 2 , dehydroepiandrosterone sulfate (DHEAS), and estradiol-17β-glucuronide [ 17 , 25 , 82 , 83 ].…”