Organic Anion‐Transporting Polypeptides at the Blood–Brain and Blood–Cerebrospinal Fluid Barriers

doi:10.1016/S0070-2153(07)80004-4

Current Topics in Developmental Biology

Volume 80, 2007, Pages 135-170

https://doi.org/10.1016/S0070-2153(07)80004-4 Get rights and content

Organic anion‐transporting polypeptides (Oatps) are solute carrier family members that exhibit marked evolutionary conservation. Mammalian Oatps exhibit wide tissue expression with an emphasis on expression in barrier cells. In the brain, Oatps are expressed in the blood–brain barrier endothelial cells and blood–cerebrospinal fluid barrier epithelial cells. This expression profile serves to illustrate a central role for Oatps in transporting endo‐ and xenobiotics across brain barrier cells. This chapter will detail the expression patterns and substrate specificities of Oatps expressed in the brain, and will place special emphases on the role of Oatps in prostaglandin synthesis and in the transport of conjugated endobiotics.

Introduction

The contents of the central nervous system (CNS) must be exquisitely regulated in order to maintain proper functioning of this critical system. The brain has a high metabolic demand, and thus requires constant influx of oxygen and nutrients as well as efflux of waste products (Takano et al., 2006). Tight regulation of this homeostasis is accomplished, in part, by the blood–brain barrier (BBB) and blood–cerebrospinal fluid barrier (BCSFB). Transport across these barriers is often a required operation during waste efflux (e.g., glucuronides), nutrient delivery (e.g., glucose), drug delivery (e.g., phenytoin), and hormonal and other biological signaling [e.g., via thyroxine and prostaglandins (PGs)] in the brain (Adachi 2003, Borst 2006, Potschka 2001, Sugiyama 2003). This chapter will discuss the role of an important group of transporters at the BBB and BCSFB barrier: the superfamily of organic anion‐transporting polypeptides (humans: OATPS; rodents and other animals: Oatps). Special focus will be directed at the role OATPs/Oatps play in PG and metabolite transport at the BBB and BCSFB.

Section snippets

BBB Structure and Function

The BBB exists as a selectively permeable barrier composed of a vast network of microvascular endothelium (Hawkins and Davis, 2005) (Fig. 1). Brain endothelia are distinguished from peripheral endothelia by minimal pinosytosis, a lack of fenestrations, and the presence of tight junctions (Fenstermacher 1988, Kniesel 2000, Sedlakova 1999). Although cerebral microvasculatrue endothelia support the features of the BBB, astrocyte foot processes, pericytes, and neurons all surround individual

BCSFB Structure and Function

The choroid plexuses are leaf‐like organs found in the median wall of each lateral ventricle, as well as the roof of the third and fourth ventricles of the brain (Kusuhara 2004, Strazielle 2000). Epithelial cells of these highly vascularized organs form the BCSFB (Strazielle and Preston, 2003). These cells are polarized, consisting of apical or brush border membranes [cerebrospinal fluid (CSF) facing] and basolateral membranes (blood facing) (Fig. 2). Invaginations within the choroid plexus

The OATP/Oatp Superfamily

OATPs/Oatps are involved in both influx and efflux across CNS and other cell barriers. OATPS/Oatps form a diverse and growing superfamily of solute carriers expressed throughout the body (Hagenbuch and Meier, 2003a). These transporters, with 11–12 membrane‐spanning domains, mediate transmembrane transport of various amphipathic organic anions including steroid conjugates, thyroid hormones, prostanoids, bile salts, oligopeptides, drugs, toxins, and other xenobiotics (Hagenbuch 2004, Mikkaichi

Molecular Architecture of the Oatp Superfamily

Although no high‐resolution structure is available for any member of the Oatp superfamily, significant structural inferences have been made from sequence analysis and homology modeling. One common feature of the Oatps is the presence of 12 putative transmembrane‐spanning α‐helices. It should be noted that this is not an empirically determined topology and predictions using the human OATP1C1 sequence and several predictive algorithms yield between 10 and 12 transmembrane spans. Figure 4 shows

Oatp Substrate Structural Features

Clearly the disposition of small molecules in the brain is dependent on the specificity of the membrane transporters that transport them. The pathway in the transporter that the small molecules (substrates) must traverse necessarily contains a molecular surface complimentary to the substrate surface. This means that in three‐dimensional space, the transporter should contain a counter charge for electrostatic interactions, a hydrogen bond donor or acceptor to compliment an acceptor or donor,

OATP/Oatp Expression and Action at the BBB and BCSFB

Currently, there are over 30 mammalian members of the OATP/Oatp superfamily (Hagenbuch and Meier, 2003a). Of these, only a handful are expressed at the BBB and BCSFB. So far, Oatp1a2, Oatp1a4, Oatp1a5, Oatp1c1, and possibly Oatp1a1 have been identified at protein level at both the BBB and/or BCSFB (Kusuhara and Sugiyama, 2005). In addition, previous indirect evidence, in the form of inhibition studies and mRNA expression, suggested a localization of the PG transporter Oatp2a1 at the BBB (

Oatp1a1

Oatp1a1 mediates the uptake of a wide range of bile salts (e.g., cholate), organic anions (e.g., monoglucuronosyl bilirubin), organic cations (e.g., rocuronium), and drugs (e.g., enalapril) (Hagenbuch and Meier, 2004). Oatp1a1 was the first identified Oatp and was initially cloned from rat liver and translates into a protein with 670 amino acids (Jacquemin et al., 1994). Northern blot analysis reveals mRNA expression in liver, kidney, brain lung, skeletal muscle, and proximal colon (Jacquemin

PG Metabolism and Oatps

Cytokine signaling induces cyclooxygenase (COX) to produce PGs in barrier cells. The COX‐1 isotype is responsible for baseline levels of PG, whereas COX‐2 isotype induces increased PG levels in response to cytokine induction (e.g., inflammatory signaling). Both BBB endothelia and choroid plexus epithelia express COX‐2 and synthesize PGs in response to inflammatory stimuli (Lacroix 1998, Mark 2001).

COX‐2 is localized on the luminal side of the ER membrane (Fig. 5). Crystallographic studies of

Oatp‐Mediated Transport of Conjugated Endobiotics

One of the primary roles of the BBB and BCSFB is to form a biochemical barrier functioning to protect the brain through detoxification enzymes expressed in brain barrier cells. Endogenous chemicals and environmental toxins added selective pressure on the living systems to evolve oxidative and conjugative metabolic pathways with transporting capabilities to neutralize compounds. Thus, Oatps and the Mrps/MRPs work collectively with metabolic enzymes to protect the organism from harmful compounds

Oxidative Metabolism

Cytochrome P450s (CYPs) are members of a superfamily of membrane bound heme‐containing monooxygenases found in the ER of the liver and other extrahepatic tissues including the brain (Hedlund et al., 2001). CYPs are integral membrane proteins imbedded in the ER membrane. The electron components and active site of CYPs are located on the cytoplasmic side of the ER, and a hydrophobic region is responsible for targeting, insertion, and retention in the ER membrane (Neve and Ingelman‐Sundberg, 2000

Summary

The OATP/Oatp superfamily of solute carriers plays a pivotal role in the disposition and flux of multiple endo‐ and xenobiotics in the CNS. Polarized expression of multiple OATPs/Oatps at the BBB and BCSFB contributes to the net directional movement of these compounds. The exact stoichiometric contributions, structural determinants, and developmental expression patterns of individual OATPs/Oatps are currently undetermined. However, the potential for strong physiologic impacts in the CNS

Acknowledgments

This work was supported, in part, by grants from NIH R01 DK054060 and the University of Minnesota Graduate School (GWA), NIH T32HL07741 (TPR), Research Corporation CC6681 (JNR), and a Melendy Summer Research Scholarship (DRS). Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7 were created using ScienceSlides 2006 software from Visiscience. The authors would like to thank Amber Seys and Anna Malin for their contributions toward the data gathered in Table I.

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¹: These authors contributed equally to this work.

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Organic Anion‐Transporting Polypeptides at the Blood–Brain and Blood–Cerebrospinal Fluid Barriers

Introduction

Section snippets

BBB Structure and Function

BCSFB Structure and Function

The OATP/Oatp Superfamily

Molecular Architecture of the Oatp Superfamily

Oatp Substrate Structural Features

OATP/Oatp Expression and Action at the BBB and BCSFB

Oatp1a1

PG Metabolism and Oatps

Oatp‐Mediated Transport of Conjugated Endobiotics

Oxidative Metabolism

Summary

Acknowledgments

J. Biol. Chem.

Science

Front. Neuroendocrinol.

Biochem. Pharmacol.

J. Neurol. Sci.

Cancer Lett.

Neurosci. Lett.

Front. Neuroendocrinol.

Neurosci. Lett.

Toxicol. Appl. Pharmacol.

Exp. Eye Res.

Pharmacol. Biochem. Behav.

Biochim. Biophys. Acta

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Arch. Biochem. Biophys.

Gastroenterology

J. Biol. Chem.

Adv. Drug Deliv. Rev.

NeuroRx

J. Biol. Chem.

J. Biol. Chem.

Drug Metab. Pharmacokinet.

Curr. Opin. Cell Biol.

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Recent Prog. Horm. Res.

Arch. Gerontol. Geriatr.

J. Biol. Chem.

Gastroenterology

J. Mol. Biol.

Prostaglandins Other Lipid Mediat.

Brain Res.

Adv. Drug Deliv. Rev.

J. Biol. Chem.

Molecular characterization of human and rat organic anion transporter OATP‐D

Am. J. Physiol. Renal Physiol.

Control of thyroid hormone action in the developing rat brain

Thyroid

The choroid plexus epithelium is the site of the organic anion transport protein in the brain

Proc. Natl. Acad. Sci. USA

Blood‐brain barrier is involved in the efflux transport of a neuroactive steroid, dehydroepiandrosterone sulfate, via organic anion transporting polypeptide 2

J. Neurochem.

Interaction of methotrexate with organic‐anion transporting polypeptide 1A2 and its genetic variants

J. Pharmacol. Exp. Ther.

Immunologic distribution of an organic anion transport protein in rat liver and kidney

Am. J. Physiol.

ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood‐tumor barrier

Cancer Res.

Differential expression of the insulin‐like growth factor II and transthyretin genes in the developing rat choroid plexus

J. Neuropathol. Exp. Neurol.

Comparative pharmacophore modeling of organic anion transporting polypeptides: A meta‐analysis of rat Oatp1a1 and human OATP1B1

J. Pharmacol. Exp. Ther.

Transport of bile acids, sulfated steroids, estradiol 17‐beta‐D‐glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11)

Mol. Pharmacol.

Tissue distribution and ontogeny of mouse organic anion transporting polypeptides (Oatps)

Drug Metab. Dispos.

Steroidogenic enzyme P450c17 is expressed in the embryonic central nervous system

Endocrinology

Dehydroepiandrosterone: A potential signalling molecule for neocortical organization during development

Proc. Natl. Acad. Sci. USA

Upregulation of the low density lipoprotein receptor at the blood‐brain barrier: Intercommunications between brain capillary endothelial cells and astrocytes

J. Cell Biol.

Receptor‐mediated transcytosis of transferrin through blood‐brain barrier endothelial cells

Am. J. Physiol.

ProbCons: Probabilistic consistency‐based multiple sequence alignment

Genome Res.