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

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.

Constituents of Passiflora incarnata, but Not of Valeriana officinalis, Interact with the Organic Anion Transporting Polypeptides (OATP)2B1 and OATP1A2

Herbal medication used in the treatment of sleep disorders and anxiety often contain extracts of Valeriana officinalis or Passiflora incarnata. Valerenic acid in V. officinalis and apigenin, orientin, and vitexin in P. incarnata are thought to contribute to their therapeutic effect. It was the aim of this study to test whether these constituents of herbal extracts are interacting with the uptake of estrone 3-sulfate, pregnenolone sulfate, and dehydroepiandrosterone sulfate mediated by the uptake transporters organic anion transporting polypeptide 2B1 (OATP2B1) or organic anion transporting polypeptide 1A2 (OATP1A2). Madin-Darby canine kidney cells overexpressing OATP2B1 or OATP1A2 were used to determine the influence of the constituents on the cellular accumulation of the sulfated steroids. Subsequently, competitive counterflow experiments were applied to test whether identified inhibitors are also substrates of the transporters. Valerenic acid only interacted with OATP2B1, whereas apigenin, orientin, and vitexin interacted with OATP2B1 and OATP1A2. Competitive counterflow revealed that orientin is a substrate of both transporters, while apigenin was transported by OATP1A2 and vitexin by OATP2B1. In a next step, commercially available P. incarnata preparations were assessed for their influence on the transporters, revealing inhibition of transporter-mediated estrone 3-sulfate uptake. HPLC-UV-MS analysis confirmed the presence of orientin and vitexin in these preparations, thereby suggesting that these constituents are involved in the interaction. Our data indicate that constituents of P. incarnata may alter the function of OATP2B1 and OATP1A2, which could affect the uptake of other compounds relying on uptake mediated by the transporters.

Organic anion-transporting polypeptides are involved in the elimination of insecticides from the red flour beetle, Tribolium castaneum

Organic anion-transporting polypeptides (OATPs) are integral membrane transporters that mediate cellular uptake of a broad range of substrates in humans. The functions of OATPs in insects are less well investigated and only poorly understood. A large number of compounds potentially toxic to insects are organic anions that include secondary plant and insecticide-derived metabolites. Some insect OATP genes are expressed in metabolic, neuroprotective and excreting tissues, and they are co-expressed together with genes known to be involved in detoxification and excretion. Therefore, a role in the elimination of insecticides has been proposed for OATPs, but experimental proof was pending. The aim of this study was to identify OATPs that affect tolerance to insecticides in the red flour beetle, Tribolium castaneum, a genomic model species and stored product pest. We determined expression profiles of TcOATP genes in different tissues and developmental stages and analyzed RNAi phenotypes. We found that some TcOATP genes had particularly high transcript levels in relevant tissues and that knockdown of TcOATP4-C1 led to sever developmental defects during larval–pupal molt. Then, we exposed the larvae to different chemically unrelated insecticides and analyzed transcript levels and mortalities. Some genes were specifically upregulated in response to insecticide treatment, and mortalities observed after administering certain insecticides were significantly increased when specific TcOATPs were silenced. By applying systemic RNAi in T. castaneum, we provide first evidence that OATPs are involved in the elimination of insecticides and hence may contribute to insecticide resistance, which becomes an increasingly serious problem in agriculture and forestry. Graphic abstract